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Galvus kol slide deck 2011 pcc approved

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  • Achieving late glycaemic control may generate a bad legacy effectThe lack of effect of intensive therapy on reducing risk of complications in VADT is likely to be due to the long-term consequences of an extended period of poor glycaemic control. The VADT study included patients with poorly controlled T2DM with an inadequate response to maximal dose oral or insulin therapy (mean time since diagnosis = 11.5 years).1 At the time of diagnosis, it is likely that patients had high HbA1c levels and were started in dietary therapy and/or oral hypoglycaemic agents that improved but did not normalise glycaemic control. Over time it is likely that HbA1c levels worsened progressively prior to entering the VADT study. Intensive therapy implemented in the trial resulted in a rapid lowering of plasma glucose levels and subsequent maintenance if HbA1c was close to target. However, this time course is far from ideal and may have generated a bad glycaemic legacy, priming patients for a high risk of complications later in the disease, even if they were then under improved glycaemic control.2ReferencesDuckworth W, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009; 360: 129–139.Del Prato S. Megatrials in type 2 diabetes. From excitement to frustration? Diabetologia. 2009; 52: 1219–1226.
  • Lowering A1C < 7% has been shown to reduce microvascular and neuropathic complications and, if implemented soon after the diagnosis , is associated with long-term reduction in macrovascular disease. Therefore, a reasonable A1C goal for many nonpregnant adults is <7%. (B) Because additional analyses from several randomized trials suggest a small but incremental benefit in microvascular outcomes with A1C values closer to normal, more stringent A1C goals for selected patients are recommended, if this can be achieved without significant hypoglycemia or other adverse effects of treatment. Such patients might include those with short duration of diabetes, long life expectancy, and no significant CVD. (B) Conversely, less stringent A1C goals may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions, and those with longstanding diabetes in whom the general goal is difficult to attain. (C)
  • Reference: Executive Summary: Standards of Medical Care in Diabetes—2011Diabetes Care, Vol 34, Suppl 1, Jan 2011
  • Insulin and Glucagon in IGT ( Insulin / Glucagon Ratio) This slide illustrates postprandial glucose and endocrine hormone levels tracked in 16 persons with normal glucose tolerance (circles) and in 15 persons with impaired glucose tolerance (triangles).1Even at 30 minutes after meal ingestion, the impaired glucose tolerance group showed blunted and delayed insulin secretion, an exaggerated late insulin response, and inadequate suppression of glucagon secretion. In addition, hepatic glucose production was suppressed by 28% in the impaired glucose tolerance group compared with 48% among normal controls.These findings suggest that pancreatic β-cells (insulin) and -cells (glucagon) are already malfunctioning during the early stage of prediabetes.Insufficient Insulin and Elevated Glucagon in T2DM ( Insulin / GlucagonRatio) To determine how pancreatic hormone release is altered in type 2 diabetes mellitus (T2DM), Müller and colleagues compared glucose, insulin, and glucagon levels in 14 subjects with normal glucose tolerance (NGT, circles) and 12 patients with T2DM (triangles), before and after a high carbohydrate meal.1In this study, fasting plasma levels of glucose, insulin, and glucagon tended to be higher among patients with T2DM than among subjects with NGT.The normal insulin response to carbohydrate challenge (middle blue graph) was a rapid and steep rise in plasma insulin. Diabetic patients, on the other hand (middle blue graph), had a blunted and delayed response.Plasma glucagon (bottom red graph) fell rapidly after the carbohydrate challenge in nondiabetic subjects. In patients with diabetes, however, glucagon levels were not suppressed and in fact were inappropriately increased, suggesting a functional defect of α-cell glucose sensing.ReferencesMüller WA, et al. Abnormal alpha-cell function in diabetes: response to carbohydrate and protein ingestion. N Engl J Med. 1970; 283: 109–115.Mitrakou A, et al. Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance. N Engl J Med. 1992; 326: 22–29.
  • Insulin and Glucagon in IGT ( Insulin / Glucagon Ratio) This slide illustrates postprandial glucose and endocrine hormone levels tracked in 16 persons with normal glucose tolerance (circles) and in 15 persons with impaired glucose tolerance (triangles).1Even at 30 minutes after meal ingestion, the impaired glucose tolerance group showed blunted and delayed insulin secretion, an exaggerated late insulin response, and inadequate suppression of glucagon secretion. In addition, hepatic glucose production was suppressed by 28% in the impaired glucose tolerance group compared with 48% among normal controls.These findings suggest that pancreatic β-cells (insulin) and -cells (glucagon) are already malfunctioning during the early stage of prediabetes.Insufficient Insulin and Elevated Glucagon in T2DM ( Insulin / GlucagonRatio) To determine how pancreatic hormone release is altered in type 2 diabetes mellitus (T2DM), Müller and colleagues compared glucose, insulin, and glucagon levels in 14 subjects with normal glucose tolerance (NGT, circles) and 12 patients with T2DM (triangles), before and after a high carbohydrate meal.1In this study, fasting plasma levels of glucose, insulin, and glucagon tended to be higher among patients with T2DM than among subjects with NGT.The normal insulin response to carbohydrate challenge (middle blue graph) was a rapid and steep rise in plasma insulin. Diabetic patients, on the other hand (middle blue graph), had a blunted and delayed response.Plasma glucagon (bottom red graph) fell rapidly after the carbohydrate challenge in nondiabetic subjects. In patients with diabetes, however, glucagon levels were not suppressed and in fact were inappropriately increased, suggesting a functional defect of α-cell glucose sensing.ReferencesMüller WA, et al. Abnormal alpha-cell function in diabetes: response to carbohydrate and protein ingestion. N Engl J Med. 1970; 283: 109–115.Mitrakou A, et al. Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance. N Engl J Med. 1992; 326: 22–29.
  • Micro- and macrovascular complications significantly impact the healthcare costs associated with T2DMacrovascular complications have a more substantial effect on the average cost per patient than microvascular complications Date from the Cost of Diabetes in Europe –Type II (CODE-2) study’ provides the first coordinated attempt to assess the total costs of managing people with Type II (non-insulin-dependent) diabetes mellitus in Europe. In total, 72% of patients in the CODE-2 study had at least one complication, with 19% having microvascular only, 10% having macrovascular onlyand 24% of the total having both microvascular and macrovascular complications. The data confirmed that complication have a significant impact on cost as depicted on the chartThe presence of micro vascular complication led to a 70% increase in cost compared to patient with no complications Cost for patient with macro vascular complication were twice as high as patient with no complications Macrovascular complications (e.g. myocardial infarction, angina, heart failure, stroke, transient ischaemic attack) Microvascular complications (e.g. foot ulcer, microalbuminuria, retinopathy, nephropathy)Reference:CODE-2 Study. Williams R et al.Diabetologia 2002; 45: S13-S17
  • 55-65% of expenditures are due to hospitalizations as a result of diabetes related complications Antidiabetic drugs constitute a small percentage (7%) of the total cost per patient; OADs contribute minimally (13%) to the total pill burden for most diabetes patientsThis study ‘The Cost of Diabetes in Europe – Type II study’ was the first coordinated attempt to measuretotal healthcare costs of Type II (non-insulin dependent) diabetes mellitus in Europe. The studyevaluated more than 7000 patients with Type II diabetes in eight countries – Belgium, France, Germany, Italy,the Netherlands, Spain, Sweden and the United Kingdom.The total direct medical costs of Type II diabetes in the eight European countries was estimated atEUR 29 billion a year (1999 values). The estimated average yearly cost per patient was EUR 2834 a year.Of these costs, hospitalizations accounted for the greatest proportion (55%, range 30–65%). Sources: Source: Jonsson B et al.Diabetologia 2002; 45: S5-S12.
  • As show in the chart The economic burden of type 2 diabetes continues to rise in both developed countries but also emerging marketsWith the exception of the US, most key markets spend similar amounts per patient on diabetes careDiabetes imposes a large economic burden on the individual, national healthcare system and economy. Healthcare expenditures on diabetes are expected to account for 11.6% of the total healthcare expenditure in the world in 2010. About 80% of the countries covered in the IDF report are predicted to spend between 5% and 13% of their total healthcare dollars on diabetesThe United States of America, is projected to spend USD198 billion or 52.7% of global expenditure in 2010, while India, the country with the largest population of people living with diabetes, is expected to spend an estimated USD2.8 billion, or less than 1% of the global total. An estimated average of USD7,383 per person with diabetes is expected to be spent on diabetes-related care in the USA but less than USD10 per person will be spent in Burundi, Côte d’Ivoire and Myanmar in 2010.Reference: IDF Diabetes Atlas 2009 www.eatlas.idf.orghttp://www.diabetesatlas.org/sites/default/files/Economic%20impact%20of%20Diabetes_101123.pdf
  • The HTA group in the UK conducted systematic review and economic evaluation of newer agents for blood glucose control in type 2 Diabetes. Based on the the UKPDS Outcomes Model A model that aims to estimate the first occurrence of a number of diabetes complications they concluded that Vildagliptin is a cost-effective alternative vs Pioglitazone.It’s worth mentioning that the UKPDS Outcomes does not take into account the risk of fracture so the results likely underestimate the value of Vildagliptin. References:Waugh N et al. Newer agents for blood glucose control in type 2 diabetes: systematic review and economic evaluation. Health Technol Assess. 2010 Jul;14(36):1-248.
  • Sulphonylureas work in glucose-independent manner increasing risk of hypoglycemiaSulphonylureas bind to the sulphonlyurea receptors on the surface of the pancreatic β cell which results in closure of the potassium channel and inhibition of efflux of potassium ions in the β cell. This results in depolarization of β cell membrane and opening of voltage-dependent calcium channel ultimately resulting in the exocytosis of insulin from the vesicles. This increases the risk of hypoglycemia1In order to avoid hypoglycemia, patients may indulge in defensive eating which results in weight gain2 ReferencesCheng AY et al. Oral antihyperglycemic therapy for type 2 diabetes mellitus. CMAJ. 2005;172:213-226Levy et al. Utility values for symptomatic non-severe hypoglycaemia elicited from persons with and without diabetes in Canada and the United Kingdom. Health and Quality of Life Outcomes 2008, 6:73
  • Vildagliptin vs glimepiride as add on to metformin: Hypoglycemic events at 2 yearsAfter 2 year treatment, incidence of hypoglycemia was less in vilda 50mg+met than in Glim+met combination1The number of hypoglycemic events were 14 fold higher in Glim+met than in vilda+met combination1The number grade 2 and suspected grade 2 events reported was 14 fold higher in Glim+met than vilda+met combination1 Thirteen patients in Glim+met group discontinued due to hypoglycemia while none discontinued in the Vilda+met group1 References 1. Matthews et al. Vildagliptin add-on to metformin produces similar efficacy and reduced hypoglycaemic risk compared with glimepiride, with no weight gain: results from a 2-year study. Diabetes, Obesity and Metabolism. 2010; 12: 780–789.
  • This chart shows the results from the mixed-treatment comparison meta-analysis Focus was to understand the optimal second-line drug when metformin monotherapyA literature search via MEDLINE (beginning in January 1950) and Cochrane CENTRAL through January 2010 and a manual search of references for additional relevant studies.STUDY SELECTION: Randomized controlled trials (RCTs) with at least 3 months' duration, evaluating noninsulin antidiabetic drugs added to metformin in patients experiencing an inadequate response to maximized and stable (> or = 4 weeks at > or = 1500 mg or maximally tolerated dose) metformin therapy.DATA EXTRACTION: Inclusion/exclusion criteria; duration of patient follow-up; drug, dose, and schedule used; use of concurrent lifestyle modification; and baseline characteristics (age, sex, anthropometrics, glycated hemoglobin A(1c) [HbA(1c)], duration of DM, and metformin dose). End points collected included mean change in HbA(1c), proportion of patients achieving HbA(1c) goal of less than 7%, change in weight, and incidence of hypoglycemia. Mixed-treatment comparison meta-analysis was used to calculate the weighted mean difference for changes from baseline in HbA(1c) and body weight and relative risk (RR) of HbA(1c) goal attainment and hypoglycemia, with associated 95% credible intervals.DATA SYNTHESIS: Overall, 27 RCTs (n = 11 198) were included. Mean (range) trial duration was 32 (12-52) weeks. The different classes of drugs were associated with similar HbA(1c) reductions (range, 0.64%-0.97%) compared with placebo. Although use of thiazolidinediones, sulfonylureas, and glinides were associated with weight gain (range, 1.77-2.08 kg), glucagon-like peptide-1 analogs, alpha-glucosidase inhibitors, and dipeptidyl peptidase-4 inhibitors were associated with weight loss or no weight change. Sulfonylureas and glinides were associated with higher rates of hypoglycemia than with placebo (RR range, 4.57-7.50).The squares represent the pooled effect size for each class of oral antidiabetic drug. Error bars represent 95% credible intervals (CrIs). The number of trials included in each mixed-treatmentcomparison analysis is as follows: 15 trials, AGI=alpha-glucosidase inhibitor; DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; SU=sulfonylurea; TZD=thiazolidinedionesReference_Effect of Noninsulin Antidiabetic Drugs Added to Metformin Therapy on Glycemic Control, Weight Gain, and Hypoglycemia in Type 2 DiabetesOlivia J. Phung; Jennifer M. Scholle; MehakTalwar; Coleman, CI. JAMA. 2010;303(14):1410-1418
  • TZDs increase conversion from preadipocytes into adipocytes in fat tissue as well as in the bone marrow, consequently decreasing other pathways leading to osteoblasts, erythrocytes or lymphocytesAdipocytes and bone cells (both osteoclasts and osteoblasts) have common origin in bone marrow: totipotent stem cell 1 Use of TZDs (PPAR gamma agonists) activates preadipocyte differentiation into adipocyte therefore favoring fat deposition Consequently this shifts the balance of bone marrow cell differentiation into fat instead of bone-forming osteoblasts Importantly, differentiation into erythrocytes and T or B lymphocytes, from hematopoetic stem cell, may also be lower in the face of increased adipocyte formation - this concept is similar to the hypothesis of “anemia of immobility” where physical immobility is linked to increased adipocyte generation at the expense of red blood cells2ReferencesRosen et al. Mechanisms of Disease: is osteoporosis the obesity of bone? Nat ClinPractRheumatol. 2006; 2:35-43 2. Payne et al. Anemia of immobility: Caused by adipocyte accumulation in bone marrow. Medical Hypothesis. 2007; 69:778-786
  • This chart shows the results from the mixed-treatment comparison meta-analysis Focus was to understand the optimal second-line drug when metformin monotherapyA literature search via MEDLINE (beginning in January 1950) and Cochrane CENTRAL through January 2010 and a manual search of references for additional relevant studies.STUDY SELECTION: Randomized controlled trials (RCTs) with at least 3 months' duration, evaluating noninsulin antidiabetic drugs added to metformin in patients experiencing an inadequate response to maximized and stable (> or = 4 weeks at > or = 1500 mg or maximally tolerated dose) metformin therapy.DATA EXTRACTION: Inclusion/exclusion criteria; duration of patient follow-up; drug, dose, and schedule used; use of concurrent lifestyle modification; and baseline characteristics (age, sex, anthropometrics, glycated hemoglobin A(1c) [HbA(1c)], duration of DM, and metformin dose). End points collected included mean change in HbA(1c), proportion of patients achieving HbA(1c) goal of less than 7%, change in weight, and incidence of hypoglycemia. Mixed-treatment comparison meta-analysis was used to calculate the weighted mean difference for changes from baseline in HbA(1c) and body weight and relative risk (RR) of HbA(1c) goal attainment and hypoglycemia, with associated 95% credible intervals.DATA SYNTHESIS: Overall, 27 RCTs (n = 11 198) were included. Mean (range) trial duration was 32 (12-52) weeks. The different classes of drugs were associated with similar HbA(1c) reductions (range, 0.64%-0.97%) compared with placebo. Although use of thiazolidinediones, sulfonylureas, and glinides were associated with weight gain (range, 1.77-2.08 kg), glucagon-like peptide-1 analogs, alpha-glucosidase inhibitors, and dipeptidyl peptidase-4 inhibitors were associated with weight loss or no weight change. Sulfonylureas and glinides were associated with higher rates of hypoglycemia than with placebo (RR range, 4.57-7.50).The squares represent the pooled effect size for each class of oral antidiabetic drug. Error bars represent 95% credible intervals (CrIs). The number of trials included in each mixed-treatmentcomparison analysis is as follows: 15 trials, AGI=alpha-glucosidase inhibitor; DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; SU=sulfonylurea; TZD=thiazolidinedionesReference_Effect of Noninsulin Antidiabetic Drugs Added to Metformin Therapy on Glycemic Control, Weight Gain, and Hypoglycemia in Type 2 DiabetesOlivia J. Phung; Jennifer M. Scholle; MehakTalwar; Coleman, CI. JAMA. 2010;303(14):1410-1418
  • This chart shows the Kaplan Meier curves with the relationship between TZD use and time to first fracture among women (A) and men (B) with type 2 DM.HR denotes the unadjusted hazard ratio. Thiazolidinedione (TZD) use has been associated with an increased risk of fracturesThis study was conducted as a retrospective cohort study in a large health system in southeastMichigan.Conclusions: TZD use was associated with an increased risk for fractures in women,particularly at agesabove 65 yr. Clinicians should be aware of this association when considering TZD therapy so as toappropriately manage and counsel their patients.References Aubert RE, Herrera V, Chen W, Haffner SM, Pendergrass M. Rosiglitazone and pioglitazone increase fracture risk in women and men with type 2 diabetes. Diabetes Obes Metab. 2010;12(8):716-7212. Thiazolidinediones and Fractures in Men and Women Colin R. Dormuth, ScD; Greg Carney, BSc; Bruce Carleton, BPharm, PharmD; Ken Bassett, MD, PhD; James M. Wright, MD, PhD Arch Intern Med. 2009;169(15):1395-1402.
  • In this study they aimed to determine systematically the risk of fractures associated with thiazolidinedione therapyThe concluded that the risk of fractures among women with type 2 diabetes,without a significant increase in risk of fractures amongmen with type 2 diabetes.Results: analyzed data from 10 randomized controlledtrials involving 13 715 participants and from 2 observational studies involving 31 679 participants. Rosiglitazone and pioglitazonewere associated with a significantly increased risk of fractures overall in the 10 randomized controlled trials (OR 1.45, 95% confidence interval [CI] 1.18–1.79;p < 0.001). Five randomized controlled trials showed a significantly increased risk of fractures among women (OR 2.23, 95% CI 1.65–3.01; p < 0.001) but not among men (OR1.00, 95% CI 0.73–1.39; p = 0.98). The 2 observational studies demonstrated an increased risk of fractures associated withrosiglitazone and pioglitazone. Bonemineral densityin women exposed to thiazolidinediones was significantly reduced at the lumbar spine (weighted mean difference –1.11%, 95% CI –2.08% to –0.14%; p = 0.02) and hip(weighted mean difference –1.24%, 95%CI –2.34% to –0.67%; p < 0.001) in 2 randomized controlled trials.References:Loke YK, Singh S. Furberg C. Long-term use of thiazolidinediones and fractures in type 2diabetes: a meta-analysis CMAJ Jan 6 2009 180 (1)
  • The Tables shows th estimated costs for each fracture type using a common methodology. UK data has been used wherever possible, however where this did not exist, or was inapplicable, data from Sweden was used as a proxy. Where both UK and Swedish data were available it was seen that in comparison costs are greater in the UK and thus our values are likely to be conservative. The average lengths of stay per fracture and cost per bed-day have been used to calculate the inpatient costs incurred by those admitted to hospital. Ratios of inpatient to out-patient costs from Sweden have been used to estimate the cost of out-patient care, which was also assumed equal to the costs incurred by patients with a clinical fracture where hospitalisation was not required. Whilst fractures at the hip, pelvis and other femoral sites incur the largest costs, it is seen that the costs of fractures at the tibia, fibula, spine, proximal humerus and humerus shaft are far from insignificant and should be included in all health-economic analyses of osteoporosis interventions.References:Stevenson M, Davis S, Kanis J. The hospitalisation costs and out-patient costs of fragility fractures. Women's Health Med 2006;3:149–151.
  • Mechanisms by which hypoglycemia may affect cardiovascular events. Hypoglycemicevents may trigger inflammation by inducing the release of C-reactive protein (CRP), IL-6, andvascular endothelial growth factor (VEGF). Hypoglycemia also induces increased platelet andneutrophil activation. The sympathoadrenal response during hypoglycemia increases adrenalinesecretion and may induce arrhythmias and increase cardiac workload. Underlying endothelialdysfunction leading to decreased vasodilation may also contribute to cardiovascular risk.Desouza CV et al. Hypoglycemia, Diabetes, and Cardiovascular Events. Diabetes Care 2010; 33: 1389-1394.
  • Hypoglycemia consequences- A study in France reported that 10,800 out of 40,000 events of severe hypoglycemia led to hospitalization. The average length of stay in hospital was 6.6 days, at a cost of FF14,000 (at 1992 prices). The total cost of hypoglycemia in patients with Type 2 diabetes in Sweden was estimated to be approximately €4,250,000 (€14.1 per patient with Type 2 diabetes). Moderate hypoglycemia contributed the largest proportion of these costs4-The occurrence of or fear of hypoglycaemia is a major impediment to achieving optimal glycaemic control and thus reducing the risk of serious vascular complications associated with hyperglycaemia. Implementing intensive therapy (or even more conventional therapy) without due attention to minimisinghypoglycaemia may partially counteract any improvements in CV outcomes5- The weight gain may be related in part to an increase in “defensive eating” to prevent a decline from normoglycemia to hypoglycemia6 Severe hypoglycaemia can be associated with serious morbidity, including seizures, unconsciousness (which may be particularly debilitating in the elderly due to falls and fractures) and coma and can provoke major vascular events and occasionally death5 Crashes were significantly more frequent in people with a history of severe hypoglycemia (defined as loss of consciousness) during the previous 2 years than in those without severe events (20 vs. 15%, p=0.01)3 Patients with at least 1 episode of hypoglycemia had an increased risk of dementia compared with those with no episodes. Patients with 2 or more episodes appeared to be at somewhat greater risk with an HR of 2.15 (95% CI, 1.64-2.81), as did patients with 3 or more episodes (HR, 2.60; 95% CI 1.78-3.79)1- Hypoglycemia may cause serious morbidity, provoking major vascular events such as stroke, myocardial infarction, acute cardiac failure, and ventricular arrhythmias.The morbidity associated with hypoglycemia, such as impaired consciousness and convulsions, can be particularly debilitating in the elderly, who are at increased risk of injury and bone fractures2References 1. Whitmer RA et al. Hypoglycemic Episodes and Risk of Dementia in Older Patients With Type 2 Diabetes Mellitus. JAMA. 2009; 301:1565-15722. Zammitt NN et al Diabetes Care 2005, 28:2948-29613. Canadian Diabetes Association’s Clinical Practice Guidelines for Diabetes and Private and Commercial Driving. Canadian Journal Of Diabetes. 2003;27(2):128-140. 4. Jönsson L et al. Cost of Hypoglycemia in Patients with Type 2 Diabetes in Sweden. Value In Health. 2006; 9: 193-1985. Barnett AH, Avoiding hypoglycaemia while achieving good glycaemic control in type 2 diabetes through optimal use of oral agent therapy. CMRO. 2010; 26:1333-1342.6. Foley J & Jordan J. Weight neutrality with the DPP-4 inhibitor, vildagliptin: Mechanistic basis and clinical Experience. Vascular Health Risk Management. 2010;6:541-548.
  • Incretin hormones are the body’s natural way to maintain glycemic controlBioactive GLP-1(7-36) amide and GIP (1-42) are released from the small intestine after meal ingestion and enhance glucose stimulated insulin secretion (incretin action). DPP-4 rapidly converts GLP-1 and GIP to their inactive metabolites GLP-1 (9-36) and GIP (3-42) in vivo. -Inhibition of DPP-4 activity prevents GLP-1 and GIP degradation, thereby enhancing incretin action.- Both GLP1 and GIP promote insulin biosynthesis, insulin secretion, and islet β cell survival. GLP1 exerts additional actions important for regulation of glucose homeostasis, including inhibition of glucagon secretion and gastric emptying, and induction of satiety. GIP, but not GLP1, directly engages receptors on adipocytes coupled to energy storage. In contrast, CCK and gastrin do not seem to acutely regulate levels of plasma glucose but might be important for stimulating the formation of new β cells by stimulating islet neogenesis.ReferencesL Baggio and DJ Drucker. Biology of Incretins: GLP-1 and GIP.Gastroenterology . 2007;132:2131-2157DJ Drucker. The role of gut hormones in glucose homeostasis.The J Clin Invest. 2007;117:24-32
  • Sitagliptin 100 mg qd added to insulin (~50 U/day) & many patients on maximum tolerated metformin At week 24, the addition of sitagliptin to ongoing stable dose insulin therapy (±metformin) significantly (p < 0.001) reduced HbA1c by 0.6% from a baseline of 8.7% compared with no change from a baseline of 8.6% in the placebo group1- When added to ongoing insulin therapy, the incidence of symptomatic hypoglycaemia was significantly (p = 0.003) increased in patients treated with sitagliptin [% (n/N) 16% (50/322)] compared with those treated with placebo [8%(25/319)]1References 1.Vilsbøll T, et al. Efficacy and safety of sitagliptin when added to insulin therapy in patients with type 2 diabetes. Diabetes Obes Metab. 2010;12:167–177
  • Vildagliptin Monotherapy: Reductions in HbA1c over 24 WeeksThis 24-week, double-blind, randomized, placebo-controlled, parallel-group study was conducted to assess the efficacy and tolerability of vildagliptin at three different dose regimens to determine: 1) whether vildagliptin exhibits dose-related efficacy; and 2) whether twice-daily dosing is necessary to obtain maximum efficacy. Drug-naïve patients (n=354) with type 2 diabetes mellitus (HbA1c 7.5–10.0%) were randomized to receive one of three vildagliptin doses (50 mg once daily, 50 mg twice daily, or 100 mg once daily) or placebo. Mean baseline HbA1c was ~8.4%. At end point, the between-treatment differences (vildagliptin − placebo) in HbA1c were −0.5, −0.7, and −0.9% for vildagliptin 50 mg once daily, 50 mg twice daily, and 100 mg once daily, respectively. Overall, the percentage of patients who achieved the target level of HbA1c <7% was significantly greater in the vildagliptin 50 mg once-daily (25%), vildagliptin 50 mg twice-daily (30%), and vildagliptin 100 mg once-daily (39%) groups compared with the placebo group (14%; P ≤0.01).Effective FPG ReductionBaseline fasting plasma glucose (FPG) levels averaged 10.7, 10.4, 10.9, and 10.0 mmol/L in patients randomized to placebo, vildagliptin 50 mg once daily, 50 mg twice daily, and 100 mg once daily, respectively. Both the 50 mg twice-daily and 100 mg once-daily dosing regimens for vildagliptin significantly decreased mean FPG versus placebo (P=0.001). The study demonstrated that vildagliptin 50 mg once daily, 50 mg twice daily, and 100 mg once daily provided effective reduction of FPG.Pi-Sunyer F, et al. Efficacy and tolerability of vildagliptin monotherapy in drug-naïve patients with type 2 diabetes. Diabetes Res Clin Pract. 2007; 76: 132–138.
  • Vildagliptin has a good safety profile and a better GI tolerability than metformin in elderly patients: AEs with incidence ≥3% in any group- The proportion of patients experiencing one or more GI Aes in patients receiving metformin 1500 mg daily (24.8%) was ;1.7-fold that in patients receiving vildagliptin 100 mg qd (15.0%, p ¼ 0.028), mainly as a result of a higher reported rate of diarrhoea (3.0 vs. 13.3%)1Reference 1. Schweizer A, et al. Comparison of vildagliptin and metformin monotherapy in elderly patients with type 2 diabetes: a 24-week, double-blind, randomized trial. Diabetes Obes Metab. 2009; 11: 804–812.
  • HbA1c reduction after 12 weeks of treatment was significantly higher in the vildagliptin (HbA1c reduction -0.95%) than in the voglibose (HbA1c -0.38%) arm, p< 0.001.
  • Vildagliptin add on to metformin in Chinese patients : Effects of vildagliptin as add on to metformin in Chinese patients on HbA1c, FPP and PPGHbA1c level decreased rapidly from the start of the treatment until Week 12, and thereafter the efficacy was maintained up to 24 weeks in the vildagliptin groupFPG decreased rapidly during the 24-week treatment period in patients receiving vildagliptin, with the maximum benefit achieved within the first 4 weeks after randomization. The AMΔ from baseline was higher in the vildagliptin 50 mg bid (-0.95 mmol/L) than in the vildagliptin 50 mg qd (-0.84 mmol/L) and placebo (-0.26 mmol/L) groups. The changes in PPG were similar in all groups. After 24 weeks of treatment, the change in 2-h PPG was -2.37±0.39, -2.07±0.42, and -0.84±0.40 mmol/L with vildagliptin 50 mg bid, vildagliptin 50 mg qd, and placebo, respectively. The difference between the treatment groups was significant (p<0.05).ReferenceData on file LAF237A23140
  • Vildagliptin add on to metformin in Chinese patients : Responder rates at endpointThe percentage of patients meeting at least one responder criteria was higher in both the vildagliptin groups compared with the placebo group. The percentage of responders was numerically higher in the vildagliptin 50 mg bid than in the vildagliptin 50 mg qd groupReference Data on file LAF237A23140
  • Vildagliptin provides similar HbA1C reduction than gliclazide but with a better tolerability profile than gliclazide- Grade 1 Hypoglycemic events defined as symptoms suggestive of hypoglycemia, where the patient is able to initiate self-treatment and plasma glucose measurement is < 3.1 mmol/L. Body weight data: p-value were from an ANCOVA model containing terms for treatment, baseline and pooled center.- After 52 weeks of treatment, vildagliptin achieved similar HbA1C reduction compared to gliclazide in patients failing to metformin and having mean baseline HbA1C levels of around 8.5%.Though the number of hypoglycemic events was low in both groups, there were twice as many hypoglycemic events in gliclazide-treated patients, even though gliclazide is regarded as the SU least likely to cause hypoglycemia.- In addition, vildagliptin-treated patients did not gain weight while gliclazide patients gained an average of 1.4kg Reference1. Filozof and Gautier. Diabetes Medicine. 2010; 27: 318-326.
  • Vildagliptin vs. gliclazide as add on to metformin: AEs with incidence in ≥4% in any groupSafetyThe overall incidence of AEs was similar in the vildagliptin group (61.8%) and the gliclazide group (61.3%). The most commonly reported AEs (≥4% in any group). Except for nasopharyngitis, frequency of common AEs (headache, pain in extremity, asthenia, bronchitis, fatigue, tremor and hyperhidrosis) was higher in the gliclazide group compared with the vildagliptin group.Reference 1. Filozof and Gautier. A comparison of efficacy and safety of vildagliptin and gliclazide in combination with metformin in patients with Type 2 diabetes inadequately controlled with metformin alone: a 52-week, randomized studyDiabetes Medicine. 2010;27:318-326
  • Initial Combination of Vildagliptin and Metformin: Effective across the HyperglycemiaSpectrum (Data from Core Study and Open-label Sub-study)This was a 24-week, double-blind, randomized, multicenter, active-controlled study in drug-naïve patients.1Patients received vildagliptinmonotherapy (n=287), metformin monotherapy (n=285), low-dose fixed-combination vildagliptin/metformin (n=277), or high-dose fixed-combination vildagliptin/metformin (n=285).In an open-label sub-study, patients with a high baseline HbA1c received vildagliptin100 mg daily as an add-on to metformin 2000 mg.1Mean baseline HbA1c was ~8.6% overall.In patients receiving high-dose fixed-combination vildagliptin/metformin (50/1000 mg twice daily, n=285) the reduction in HbA1c at 24 weeks was −1.8%.In patients receiving high-dose fixed-combination vildagliptin/metformin (50/1000 mg twice daily) with baseline HbA1c >8% (mean 9.2%, n=201) the reduction in HbA1c at 24 weeks was −2.1%.2In patients receiving high-dose fixed-combination vildagliptin/metformin (50/1000 mg twice daily) with baseline HbA1c >9% (mean 9.9%, n=96) the reduction in HbA1c at 24 weeks was −2.6%.2There was a greater reduction in HbA1c in patients with higher initial HbA1c (>8%) who received high-dose fixed-combination vildagliptin/metformin compared with patients HbA1c 7.5–11% at baseline.ReferenceBosi E, et al. Vildagliptin plus metformin combination therapy provides superior glycaemic control to individual monotherapy in treatment-naïve patients with type 2 diabetes mellitus. Diabetes ObesMetab. 2009; 11: 506–515.Data on file, Novartis Pharmaceuticals, LMF237A2302 and LMF237A2302S1.Bosi 2009 reference has been updated. Data on file reference needed for>8% and >9% subgroups and open-label N value
  • The purpose of this study was to evaluate the efficacy and safety of vildagliptin 50 mg bid as an add-on therapy to SU in Japanese patients in a 12 weeks treatment period. As glimepiride is the most widely used SU in Japan, it was selected in this study and used at 1 to 6 mg daily.Reference:1. Kikuchi M et al. Diab Res ClinPract. 2010; 89:216-223
  • Vildagliptin as add-on to glimepiride in Japanese patients is more efficient than placebo- Adjusted HbA1c reduction after 12 weeks treatment was statistically greater in the vildagliptin + SU group vs SU + placebo group ( -1.0% in vildagliptin + glimepiride and -0.06% in SU + placebo p<0.001) . Reference Kikuchi M et al. Diab Res ClinPract 2010 89:216-223.
  • Responder rates were also higher in the vildagliptin +SU group compared to SU + placebo with 54.9% patients meeting the >= 1% HbA1c reduction at end point vs 5.0% in the SU+ placebo group, p<0.001. Similarly 45% of patients treated with vildagliptin + Glimepiride reached the HbA1c <=6.5% target (the Japanese standard9) compared with 3.0% of patients in the SU + placebo group, p<0.001.
  • Effects of Vildagliptin Treatment on the Sensitivity of the α-cell to GlucoseIn this randomized, double-blind, crossover study assessing the effects of 4 weeks of vildagliptin (100 mg once daily), 30 drug-naïve patients with type 2 diabetes mellitus and mild hyperglycemia (HbA1c <7.5%) were screened for 4 weeks before being randomized to receive either vildagliptin or placebo for 4 weeks.This was followed by a 4-week washout period before patients received the alternate treatment for a further 4 weeks. On Day 28 of each treatment period, overnight-fasted patients received study medication followed by a standardized breakfast meal. Two hours later, a hyperinsulinemic, stepped glucose clamp was performed (45 minutes per step, target glucose levels = 7.5 nM, 5.0 nM and 2.5 nM).During the hyperglycemic and euglycemic steps, glucagon levels were significantly lower with vildagliptin 100 mg once daily than with placebo.During the hypoglycemic steps, glucagon levels increased from a significantly lower baseline to a slightly higher level with vildagliptin compared with placebo.The effect of vildagliptin to decrease glucagon in hyperglycemic states and increase glucagon in hypoglycemic states is consistent with the GLP-1 effect to enhance the glucose sensitivity of the α-cells to glucose.Vildagliptin may reduce the risk of hypoglycemia by this relative enhancement of glucagon secretion at low glucose levels.ReferenceAhrén B, et al. Vildagliptin Enhances Islet Responsiveness to Both Hyper- and Hypoglycemia in Patients with Type 2 Diabetes. JClinEndocrinolMetab. 2009;94(4):1236–1243
  • Vildagliptin increases pancreatic beta cell mass in neonatal ratsHistological and morphometric analysis of pancreatic islets from neonatal rats (n =6/group/timepoint) that were treated once daily with vehicle or vildagliptin (60 mg/kg) for 19 days from day 2 to day 20 and pancreatic tissues were analyzed 24 h after the last dose. All bar graphs at the left panel show quantitation of A. BrdU-positive cells per insulin-positive islet area (1X105μM); B. Apoptag-positive cells per insulin-positive islet area (1X105μM); and C. Beta cell mass (mg). The middle and right panels show photomicrographs of histological representation of A. BrdU-immuno-positive, B. Apoptag-immuno-positive islet cells at day 7 and C. insulin-immuno-positive islet cells at day 21 from vehicle and vildagliptin treated rats. Arrows indicate the positively stained cells. Values are expressed as the mean ± S.E.M., *P<0.05; **P<0.01.These data show that the DPP-4 inhibitor vildagliptin increased pancreatic beta cell mass through enhanced beta cell replication and reduced apoptosis. The increased beta cell mass wassustained for 12 days after vildagliptin washout. This study demonstrates that DPP-4 inhibitors can elicit beneficial effects on beta cell turnover that could help to prevent or retard the progression of type 2 diabetes.Reference Duttaroy A. et al. European Journal of Pharmacology.2011;650: 703–707
  • Vildagliptin does not increase fasting parameters of bone metabolism and calcium homeostasis Additional markers of bone metabolism and calcium homeostasis, such as fasting serum alkaline phosphatase, calcium, and phosphate also remained unaffected following one-year treatment (adjusted between-group LSM±SE difference: +7.1±7.2; p=0.327, +0.00±0.02; p=0.981 and +0.01±0.03; p=0.762, respectively).Reference Diamant M, et al. Poster Presentation 0706-P. Presented at: 70th Scientific Sessions of the American Diabetes Association 2010.
  • Vildagliptinvs Glimepiride: Hypoglycemic Events in Add-on toMetformin Treatment (Interim Analysis)This 1-year interim analysis of a multicenter, randomized, double-blind active-controlled study compared the long-term efficacy and safety of vildagliptin 50 mg twice daily and glimepiride up to 6 mg daily in patients with inadequate glycemic control (HbA1c 6.5–8.5%) while receiving a stable metformin dose (~1.9 g daily).11.7% of patients in the vildagliptin group (n=1389) and 16.2% of patients in the glimepiride group (n=1383) experienced ≥1 hypoglycemic events.There were 39 hypoglycemic events in the vildagliptin group and 554 in the glimepiride group.There were no severe (grade 2 and suspected grade 2) hypoglycemic events in the vildagliptin group and 10 severe hypoglycemic events in the glimepiride group.There were fewer hypoglycemic events in the vildagliptin group over the 52-week period.ReferenceFerrannini E, et al. 52-week efficacy and safety of vildagliptin versus glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy. Diabetes ObesMetab. 2009; 11: 157–166.
  • Vildagliptin vs glimepiride as add on to metformin: Hypoglycemic events at 2 yearsAfter 2 year treatment, incidence of hypoglycemia was less in vilda 50mg+met than in Glim+met combination1The number of hypoglycemic events were 14 fold higher in Glim+met than in vilda+met combination1The number grade 2 and suspected grade 2 events reported was 14 fold higher in Glim+met than vilda+met combination1 Thirteen patients in Glim+met group discontinued due to hypoglycemia while none discontinued in the Vilda+met group1 References 1. Matthews et al. Vildagliptin add-on to metformin produces similar efficacy and reduced hypoglycaemic risk compared with glimepiride, with no weight gain: results from a 2-year study. Diabetes, Obesity and Metabolism. 2010; 12: 780–789.
  • Vildagliptin: No Weight Gain in Interim Analysis at 52 WeeksThis 1-year interim analysis of a multicenter, randomized, double-blind active-controlled study compared the long-term efficacy and safety of vildagliptin 50 mg twice daily and glimepiride up to 6 mg daily in patients with inadequate glycemic control (HbA1c 6.5–8.5%) while receiving a stable metformin dose (~1.9 g daily).1During the study period the weight of patients taking vildagliptin had remained stable, whereas those who had taken glimeripride had experienced an increase in weight.The difference between groups after 52 weeks was 1.8 kg.1After 52 weeks of treatment, there was no weight gain in patients receiving vildagliptin 50 mg twice daily + metformin.ReferenceFerrannini E, et al. 52-week efficacy and safety of vildagliptin versus glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy. Diabetes Obes Metab. 2009; 11: 157–166.Ferrannini 2009 reference has been updated. The data on filereference is needed to support the weight data over time
  • Neutral effect of vildagliptin on body weight while patients in the gliclazide group experience an increase in body weightBodyweight was maintained in the vildagliptin group during the study period (+0.08 kg),whereas a mean increase of 1.36 kg was observed in the gliclazide group (+0.08 vs. +1.36, P < 0.001).ReferenceFilozof et al. A comparison of efficacy and safety of vildagliptin and gliclazide in combination with metformin in patients with Type 2 diabetes inadequately controlled with metformin alone: a 52-week, randomized study. Diabetes Medicine. 2010 ;27: 318-326.
  • age related impairment of hypoglycemia awareness is independent of the counterregualtory hormonal response suggested a diminished capability of perceiving physiological and cognitive alterations due to hypoglycemia
  • Very elderly (≥ 75years) data form pooled analysisNo specific data with a DPP-4 inhibitor are available to date in the elderly patient segment of ≥ 75 years, in line with the general paucity of data in this particular age group. While it is challenging to study this population in a dedicated study, the large clinical database available for vildagliptin has allowed collecting data in a sizeable number of these elderly patients. We report here the experience with vildagliptin in patients with T2DM ≥ 75 years based on a new pooled analysis of Phase II and III clinical trials from randomized, double-blind, controlled, parallel group studies with duration ≥ 24 and with patients ≥ 75years. Only studies with the approved dose of 50 mg bid. It included 7 monotherapy and 3 add-on to metformin studies. In addition safety profile from a pool of 38 Phase II and III studies which include monotherapy and add-on therapy.ReferenceSchweizer A. et al. Clinical experience with vildagliptin in the management of type 2 diabetes in a patient population ≥75 years: A pooled analysis from a database of clinical trials. Diabetes, Obesity and Metabolism. 2011;13: 55–64.
  • Very elderly patients analysis: change in HbA1c and body weight – at 24 weeks treatment, and hypoglycemic events - In the patient group ≥ 75 years, treatment with vildagliptin significantly reduced mean HbA1c by -0.9% from a baseline of 8.3% in the pooled monotherapy efficacy population (p<0.0001) and by -1.1% from a baseline of 8.5% in the pooled add-on therapy to metformin efficacy population (p=0.0004).- Vildagliptin did not induce weight gain in older or younger patients as either monotherapy or add-on therapy to metformin. In the patient group ≥ 75 years, modest mean weight reductions of -0.9 kg from a baseline of 75 kg (p=0.0277) in the pooled monotherapy efficacy population and of -0.2 kg from a baseline of 83 kg (p=0.6381) in the pooled add-to therapy to metformin efficacy population were seen.An analysis of hypoglycemia in the age groups showed that in patients ≥ 75 years, no confirmed-hypoglycemic events were reported with vildagliptin in monotherapy and add-on therapy to metformin, and that most notably no severe episodes were observed.ReferenceSchweizer A. et al. Clinical experience with vildagliptin in the management of type 2 diabetes in a patient population ≥75 years: A pooled analysis from a database of clinical trials. Diabetes, Obesity and Metabolism. 2011;13: 55–64.
  • Transcript

    • 1. Galvus® (vildagliptin) Introduction
    • 2. Disclaimer • This slide deck has been produced for educational purposes for the medical profession. The information is intended as a source of discussion or presentation at scientific meetings only. • Where applicable, figures, images and tables used in this slide deck have been reproduced with permission from the relevant copyright holders. • Before local implementation, you must ensure compliance with all applicable laws and regulations, including local industry codes, as well as local Novartis companies’ policies. • Novartis will only implement programs that are fully consistent with all applicable laws and regulations as well as Novartis companies policies. • Before local implementation, you must ensure compliance with all applicable laws and regulations, including local industry codes, as well as local Novartis companies’ policies.
    • 3. IMPACT slide content
    • 4. 1) The legacy effect: the importance of early control 1.1) How low should we go and when?: The legacy effect
    • 5. Relative risk* Microvascular complications  37% Any diabetes-related endpoint  21% Diabetes-related death  21% All-cause mortality  14% Fatal and non-fatal MI  14% Glycaemic exposure and complications of diabetes: decrease in risk for 1% reduction in HbA1c HbA1c=haemoglobin A1c; MI=myocardial infarction. *P <0.0001. Observational analysis of relationship between glycaemic exposure and complications of diabetes as estimated by decrease in risk per 1% reduction in HbA1c concentration. Stratton IM, et al. BMJ. 2000; 321: 405–412.
    • 6. Incidence of microvascular complications increases with mean HbA1c with no evidence of a threshold HbA1c=haemoglobin A1c. Incidence rates and 95% confidence intervals for myocardial infarction and microvascular complications by category of mean HbA1c concentration, adjusted for age, sex and ethnic group, expressed for white men aged 50–54 years at diagnosis and with mean duration of diabetes of 10 years. Stratton IM. et al. BMJ. 2000; 321: 405–412. 80 60 40 20 0 Adjustedincidence per1000personyears(%) 5 6 7 8 9 10 11 Mean HbA1c (%) Myocardial infarction Microvascular endpoints
    • 7. VADT1 (n=1700) ACCORD2 (n=10250) ADVANCE3 (n=11140) HbA1c – Std vs. Intensive 8.4 vs. 6.9 7.5 vs. 6.5 7.3 vs. 6.5 Primary outcome Non-fatal MI Non-fatal stroke CVD death Hospitalization for CHF Revascularization Non-fatal MI Non-fatal stroke CVD death Non-fatal MI Non-fatal stroke CVD death Hazard Ratio for primary outcome (95% CI) 0.87 (0.730 – 1.04) 0.90 (0.78 – 1.04) 0.94 (0.84 – 1.06) Hazard Ratio for mortality (95% CI) 1.065 (0.801 – 1.416) 1.22 (1.01 – 1.46) 0.93 (0.83 – 1.06) *P=0.04 1W. Duckworth et al presented at EASD Annual Meeting, 2008; 2The ACCORD Study Group NEJM 2008;358:2545; 3The ADVANCE Collaborative Group NEJM 2008,358:2560 * Three studies assessed the association between intensive glycemic control and long-term CV complication
    • 8. Reaching target in late stages of the disease does not reduce vascular complications P=0.14. Primary outcome: first occurrence of a major cardiovascular event (a composite of myocardial infarction, stroke, death from cardiovascular causes, congestive heart failure, surgery for vascular disease, inoperable coronary disease, and amputation for ischaemic gangrene). Duckworth W, et al. N Engl J Med. 2009; 360: 129–139. 1.0 0.8 0.6 0.4 0.2 0.0 0 2 4 6 8 Probabilityofsurvival Years Standard therapy Intensive therapy 892 899 774 770 707 693 No. at risk Intensive Standard 639 637 582 570 510 471 252 240 62 55 0 0 VADT Primary outcome
    • 9. HbA1c=haemoglobin A1c; T2DM=type 2 diabetes mellitus. Adapted from Del Prato S. Diabetologia. 2009; 52: 1219–1226. Achieving late glycaemic control may generate a bad legacy effect increasing risk of complications • Hypothetical representation of the natural history of diabetic patients in the VADT study: initial poor glycaemic control increases risk of complications later in disease course 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Ideal HbA1c Generation of a ‘bad glycaemic legacy’ drives risk of complications HbA1c(%) Time since diagnosis (years) Before entering VADT intensive treatment arm After entering VADT intensive treatment arm
    • 10. Early glucose control not only reduces complications but has a long-term legacy effect Aggregate endpoint 1997 2007 Any diabetes-related endpoint RRR = P = 12% 0.029 9% 0.040 Microvascular disease RRR = P = 25% 0.0099 24% 0.001 MI RRR = P = 16% 0.052 15% 0.014 All-cause mortality RRR = P = 6% 0.44 13% 0.007 After median 8.5 years’ post-trial follow-up MI=myocardial infarction; RRR=relative risk reduction; P=log rank. Diabetes Trials Unit. UKPDS Post Trial Monitoring. UKPDS 80 Slide Set. Available at: http://www.dtu.ox.ac.uk/index.php?maindoc=/ukpds/. Accessed 12 September, 2008; Holman RR, et al. N Engl J Med. 2008; 359: 1577–1589; UKPDS 33. Lancet. 1998; 352: 837–853.
    • 11. Acheiving early glycaemic control may generate a good legacy effect HbA1c=haemoglobin A1c. Diabetes Trials Unit. UKPDS Post Trial Monitoring. UKPDS 80 Slide Set. Available at: http://www.dtu.ox.ac.uk/index.php?maindoc=/ukpds/. Accessed 12 September, 2008; Holman RR, et al. N Engl J Med. 2008; 359: 1577–1589; UKPDS 33. Lancet. 1998; 352: 837–853. MedianHbA1c(%) 0 6 7 8 9 UKPDS 1998 Conventional Metformin Holman et al 2008 Legacy effect 1997 Difference in HbA1c was lost after first year but patients in the initial intensive arm still had lower incidence of any complication: • 24% reduction in microvascular complications • 15% reduction in MI • 13% reduction in all-cause mortality 2007
    • 12. 2011 ADA recommendations  Lowering A1C < 7% has been shown to reduce microvascular and neuropathic complications and, if implemented early, is associated with long-term reduction in macrovascular disease  Analyses from several randomized trials suggest a small but incremental benefit in microvascular outcomes with A1c values closer to normal, more stringent A1c goals for selected patients* are recommended, if this can be achieved without significant hypoglycemia or other adverse effects of treatment  Less stringent A1c goals may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions, and those with longstanding diabetes in whom the general goal is difficult to attain * Such patients might include those with short duration of diabetes, long life expectancy, and no significant CVD Executive summary: Standard of Medical care in diabete 2011. Diabetes Care 2011: 34 (1):S4-S7
    • 13. 2) Islet dysfunction 2.1) Both insulin resistance and islet dysfunction contribute to the onset of type 2 diabetes
    • 14. Roles of insulin and glucagon in normal glucose homeostasis *Insulin and glucagon secretion are also influenced by other nutrients, hormones, and neural input. Adapted from Berne RM, Levy MN, eds. Physiology. St. Louis, Mo: Mosby, Inc; 1998: 822–847. + Glucagon* (plasma concentration) – – Insulin* (plasma concentration) + Glucose (plasma concentration)
    • 15. Pancreatic islet dysfunction leads to hyperglycemia in T2DM ↑ Glucose Fewer -cells -cells Hypertrophy Insufficient Insulin Excessive Glucagon –+ ↓ Glucose Uptake ↑ HGO + HGO=hepatic glucose output. Adapted from Ohneda A, et al. J Clin Endocrinol Metab. 1978; 46: 504–510; Gomis R, et al. Diabetes Res Clin Pract. 1989; 6: 191–198.
    • 16. CI=confidence interval; IGT=impaired glucose tolerance; NGT=normal glucose tolerance; T2DM=type 2 diabetes mellitus. Adapted from Weyer C, et al. J Clin Invest. 1999; 104: 787–794. Inadequate -cell compensation for insulin resistance Insulinsecretion Insulin resistance T2DM IGT NGT Nonprogressors (n=23) Progressors (n=11) NGT NGT NGT 95% CI Resistant Sensitive
    • 17. 250 200 150 100 50 Insulin secretion deteriorates with progressive impairment of glucose tolerance IGT=impaired glucose tolerance; NGT=normal glucose tolerance; T2DM=type 2 diabetes mellitus. Adapted from Stumvoll M, et al. Horm Metab Res. 2000; 32: 230–232. Time (min) Glucose(mg/dL) 500 400 300 200 100 0 Time (min) Insulin(pmol/L) N=58Plasma Glucose Insulin Response NGT IGT T2DM Hyperglycemic Clamp –20 0 20 40 60 80 100 120 140 –20 0 20 40 60 80 100 120 140
    • 18. HOMA=homeostasis model assessment; T2DM=type 2 diabetes mellitus. *Tolbutamide, metformin. Adapted from Levy J, et al. Diabet Med. 1998; 15: 290–296. N=432 2–4 5–7 8–10 Diet only Years in which progression necessitated adding oral hypoglycemic* or insulin β-cell function declines while insulin sensitivity remains stable over course of T2DM—Belfast Diet Study 80 60 40 20 0 0 2 4 6 HOMA%B Years from Diagnosis β-cell Function 80 40 20 0 0 2 4 6HOMA%S Years from Diagnosis Insulin Sensitivity
    • 19. IFG=impaired fasting glucose; IGT=impaired glucose tolerance; NGT=normal glucose tolerance. Adapted from International Diabetes Center. Type 2 Diabetes BASICS. Minneapolis, Minn: International Diabetes Center; 2000. Prediabetes (IFG / IGT) NGT Diabetes Insulin resistance Islet cell functionDiabetes onset Treatment targets: deteriorating islet cell function in the setting of insulin resistance Age,life style, environmental factors
    • 20. 2.2) α-cells sensitivity to glucose is impaired in T2DM, resulting in excessive glucagon secretion, leading to excess glucose production from the liver
    • 21. Roles of insulin and glucagon in normal glucose homeostasis *Insulin and glucagon secretion are also influenced by other nutrients, hormones, and neural input. Adapted from Berne RM, Levy MN, eds. Physiology. St. Louis, Mo: Mosby, Inc; 1998: 822–847. + Glucagon* (plasma concentration) – – Insulin* (plasma concentration) + Glucose (plasma concentration)
    • 22. Pancreatic islet dysfunction leads to hyperglycemia in T2DM ↑ Glucose Fewer -cells -cells Hypertrophy Insufficient Insulin Excessive Glucagon –+ ↓ Glucose Uptake ↑ HGO + HGO=hepatic glucose output. Adapted from Ohneda A, et al. J Clin Endocrinol Metab. 1978; 46: 504–510; Gomis R, et al. Diabetes Res Clin Pract. 1989; 6: 191–198.
    • 23. Glucagon 25 30 35 40 45 pmol/L Time (min) -60 0 60 120 180 240 300 NGT IGT 0 Insulin 200 400 600 pmol/L Glucose Glucose 50 100 150 200 250 mg/dL NGT IGT NGT IGT Elevated glucagon not only in T2DM but in IGT as well ( insulin / glucagon ratio) IGT T2DM CHO=carbohydrate; NGT=normal glucose tolerance; T2DM=type 2 diabetes mellitus. Adapted from Müller WA, et al. N Engl J Med. 1970; 283: 109–115. IGT=impaired glucose tolerance; NGT=normal glucose tolerance. Adapted from Mitrakou A, et al. N Engl J Med. 1992; 326: 22–29. CHO meal 0 NGT T2DM -60 Time (min) 0 60 120 180 240 Glucose100 200 300 400 mg/dL 0 Insulin 50 100 150 μU/mL NGT T2DM Glucagon 75 100 125 150 pg/mL NGT T2DM
    • 24. NGT=normal glucose tolerance; T2DM=type 2 diabetes mellitus. Adapted from Kelley D, et al. Metabolism. 1994; 43: 1549–1557. Suppression of endogenous glucose production is impaired in T2DM Time (min) –30 –15 0 30 60 90 120 150 180 210 240 270 300 Meal 2 6 10 14 18 EndogenousGlucose (µmol/min/kg) NGT (n=12) T2DM (n=18)
    • 25. 2.3) β-cells mass progressively declines, loses sensitivity to glucose leading to insufficient insulin secretion
    • 26. Roles of insulin and glucagon in normal glucose homeostasis *Insulin and glucagon secretion are also influenced by other nutrients, hormones, and neural input. Adapted from Berne RM, Levy MN, eds. Physiology. St. Louis, Mo: Mosby, Inc; 1998: 822–847. + Glucagon* (plasma concentration) – – Insulin* (plasma concentration) + Glucose (plasma concentration)
    • 27. Pancreatic islet dysfunction leads to hyperglycemia in T2DM ↑ Glucose Fewer -cells -cells Hypertrophy Insufficient Insulin Excessive Glucagon –+ ↓ Glucose Uptake ↑ HGO + HGO=hepatic glucose output. Adapted from Ohneda A, et al. J Clin Endocrinol Metab. 1978; 46: 504–510; Gomis R, et al. Diabetes Res Clin Pract. 1989; 6: 191–198.
    • 28. CI=confidence interval; IGT=impaired glucose tolerance; NGT=normal glucose tolerance; T2DM=type 2 diabetes mellitus. Adapted from Weyer C, et al. J Clin Invest. 1999; 104: 787–794. Inadequate -cell compensation for insulin resistance Insulinsecretion Insulin resistance T2DM IGT NGT Nonprogressors (n=23) Progressors (n=11) NGT NGT NGT 95% CI Resistant Sensitive
    • 29. Compensatory increase in β-cell insulin secretion fails during progression of T2DM T2DM=type 2 diabetes mellitus. Protocol: 3H-3-glucose administered for 2 hours in control group (n=72) and 3 hours in diabetic group (n=77). Adapted from DeFronzo RA, et al. Metabolism. 1989; 38: 387–395. FastingPlasmaInsulin(µU/mL) Fasting Plasma Glucose (mg/dL) N=149 0 25 20 15 10 5 0 60 100 140 180 220 260 260
    • 30. β-cell function continues to decline regardless of intervention in T2DM T2DM=type 2 diabetes mellitus. *β-cell function measured by homeostasis model assessment (HOMA). Adapted from UKPDS Group. Diabetes. 1995; 44: 1249–1258. 0 20 40 60 80 100 –5 –4 –3 –2 –1 0 1 2 3 4 5 6 Years since Diagnosis β-cellFunction(%)* Progressive Loss of β-cell Function Occurs prior to Diagnosis Metformin (n=159) Diet (n=110) Sulfonylurea (n=511)
    • 31. Glucagon 25 30 35 40 45 pmol/L Time (min) -60 0 60 120 180 240 300 NGT IGT 0 Insulin 200 400 600 pmol/L Glucose Glucose 50 100 150 200 250 mg/dL NGT IGT NGT IGT Insufficient or impaired insulin not only in T2DM but in IGT as well ( insulin / glucagon ratio) IGT T2DM CHO=carbohydrate; NGT=normal glucose tolerance; T2DM=type 2 diabetes mellitus. Adapted from Müller WA, et al. N Engl J Med. 1970; 283: 109–115. IGT=impaired glucose tolerance; NGT=normal glucose tolerance. Adapted from Mitrakou A, et al. N Engl J Med. 1992; 326: 22–29. CHO meal 0 NGT T2DM -60 Time (min) 0 60 120 180 240 Glucose100 200 300 400 mg/dL 0 Insulin 50 100 150 μU/mL NGT T2DM Glucagon 75 100 125 150 pg/mL NGT T2DM
    • 32. 3) Burden of T2DM 3.1) T2DM causes significant clinical complications and financial burden
    • 33. Type 2 diabetes mellitus is associated with a high and increasing burden  Diabetes is estimated to be responsible for almost 1/10 of deaths in most developing countries among people aged 35–64 years1  The complications of type 2 diabetes include microvascular disease (e.g. diabetic retinopathy, nephropathy) and macrovascular disease (e.g. CHS)  Diabetes accounts for 2–19% of the healthcare budget in countries in Europe2  Type 2 diabetes is associated with a high burden for the patient, patients’ families and carers, and society  Nearly 1/5 hospitalizations were related to Diabetes (US) 3 1. Roglic G et al. Diabetes Care 2005; 28: 2130-5. 2. Federation of European Nurses in Diabetes. Diabetes. The policy puzzle: Is Europe making progress? 2nd edition, 2008. http://www.fend.org.
    • 34. Spending on diabetes is predicted to triple between 2009 and 2034 Huang ES et al. Diabetes Care 2009; 32(12): 2225-9. 68 16545 171 0 50 100 150 200 250 300 350 400 2009 2034 Spendingonpeoplewithdiabetes (US$billion) Non-Medicare population Medicare-eligible population US data 113 336
    • 35. Eyes (retinopathy, glaucoma, cataracts) Brain and Cerebral Circulation (stroke, TIA) Heart and Coronary Circulation (angina, MI, CHF)Kidneys (nephropathy, ESRD) Peripheral Nervous System (peripheral neuropathy) Peripheral Vascular Tree (peripheral vascular disease, gangrene, amputation) Serious long-term complications in T2DM CHF=congestive heart failure; ESRD=end-stage renal disease; MI=myocardial infarction; TIA=transient ischemic attack; T2DM=type 2 diabetes mellitus. Adapted from International Diabetes Federation. Complications. Available at: http://www.eatlas.idf.org/complications. Accessed April 14, 2006.
    • 36. Microvascular and macrovascular complications are the key drivers of the costs associated with type 2 diabetes Source: CODE-2 Study. Williams R et al. Diabetologia 2002; 45: S13-S17. 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 Microvascular & Macrovascular 3.5x Macrovascular 2.0x Microvascular 1.7x No Complications 1.0x Effect of Complications on Average Cost per Patient CostImpactFactor Costs were assessed retrospectively for 6 months Incremental cost due to complications Base cost without complications
    • 37. Breakdown of Pharmacotherapy for Diabetes Patients Breakdown of Direct Diabetes Costs per Patient Diabetes-related healthcare expenditures Other Cardiovascular and lipid lowering Oral antidiabetic Insulin Gastrointestinal Anti-infectives 26% 42% 13% 11% 6% 2% Source: Jonsson B et al. Diabetologia 2002; 45: S5-S12. 7% 18% Hospitalizations 55% Other medications 21% Ambulatory
    • 38. Economic burden of type 2 diabetes continues to rise in both developed countries and emerging markets • Direct costs for diabetes-related care are projected to reach USD 376 billion globally in 2010 and USD 490 billion by 2030 22 5 28 17 8 JapanChinaGermanyFranceUKUS 198 3'125 115 3'751 4'141 3'574 7'383 JapanChinaGermanyFranceUKUS Estimated 2010 Total Costs for Diabetes (US$ Bn) Estimated 2010 Cost per Patient (US$) Source: IDF Diabetes Atlas 2009 www.eatlas.idf.org
    • 39. Vildagliptin is a cost effective alternative vs. pioglitazone “In summary, the gliptins and the glitazones appear roughly equivalent in glycaemic effect, but the former have an advantage in avoidance of weight gain, which, together with their lower (at present) costs may give them an edge.” Waugh N et al. Health Technol Assess. 2010 Jul;14(36):1-248 No Complications With Complications Vildaglilptin Pioglitazone Net Vildaglilptin Pioglitazone Net UKPDS QALYS 8.561 8.590 -0.029 8,353 8,378 -0.025 8.468 8.479 -0.011 8,262 8,269 -0.007 Direct drug cost (£) 5371 5824 -453 5220 5665 -445 Total cost (£) 15,731 16,180 -449 16,309 16,756 -446 ICER (£) 39,846 66,799
    • 40. 4) Unmet need and limitations of current treatments 4.1) T2DM is a progressive disease and most patients do not achieve HbA1c goals
    • 41. ADOPT study: progression of hyperglycemia in T2DM *Significant difference rosiglitazone vs other treatment groups with Hochberg adjustment. Kahn SE, et al. N Engl J Med. 2006; 355: 2427–2443. Time (Years) 6.0 7.6 8.0 6.8 0 1 2 3 4 5 HbA1c(%) 7.2 0 Rosiglitazone, 0.07 (0.06 to 0.09) Metformin, 0.14 (0.13 to 0.16)* Glyburide, 0.24 (0.23 to 0.26)* 6.4 No. of Patients 4012 3308 2991 2583 2197 822 Treatment difference (95% CI) Rosiglitazone vs metformin, 0.13 (0.22 to 0.05); P=0.002 Rosiglitazone vs glyburide, 0.42 (0.50 to 0.33); P <0.001 Annualized slope (95% CI)
    • 42. Percentages of Adults reaching targets (Data from European countries) Most patients with T2DM do not achieve HbA1c goals A1C <6.5% 7.6% < A1C 6.5<= A1C <=7.6% %patientsreachingtarget Alvarez Guisasola F. et al. Diab Metab Obes. 2008. 10 (suppl 1): 8-15 Real-Life Effectiveness and Care Patterns of Diabetes Management (RECAP-DM) study
    • 43. 4.2) Mechanism of action of different anti-diabetic treatments
    • 44. Pharmacologic targets of current drugs used in the treatment of T2DM -glucosidase inhibitors Delay intestinal carbohydrate absorption Thiazolidinediones Decrease lipolysis in adipose tissue, increase glucose uptake in skeletal muscle and decrease glucose production in liver Sulfonylureas Increase insulin secretion from pancreatic -cells GLP-1 analogs Improve pancreatic islet glucose sensing, slow gastric emptying, improve satiety DDP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus. Adapted from Cheng AY, Fantus IG. CMAJ. 2005; 172: 213–226. Ahrén B, Foley JE. Int J Clin Pract. 2008; 62: 8–14. Glinides Increase insulin secretion from pancreatic -cells DPP-4 inhibitors Prolong GLP-1 action leading to improved pancreatic islet glucose sensing, increase glucose uptake
    • 45. 4.3) Use of SUs is associated with hypoglycemia and weight gain
    • 46. Pancreatic  cell Sulphonylureas do not work in glucose-dependent manner increasing risk of hypoglycemia Adapted from: Cheng AYY, et al CMAJ. 2005; 172: 213–216. * Levy AR et al. Health and Quality of Life Outcomes 2008, 6:73 • Increased secretion of insulin independently of glucose level • Increased risk of hypoglycemia • Chronic effect: weight gain due to defensive eating* SU K+ X Release of insulin Pancreas Insulin
    • 47. Risk of hypoglycemia with different sulfonylureas *<50 mg/dL. Tayek J. Diabetes Obes Metab. 2008; 10: 1128–1130. 0 5 10 15 20 25 30 Gliclazide 0.85 Glipizide 8.70 Glimepiride 0.86 Tolbutamide 3.50 Chlorpropamide 16.00 Glyburide 16.00 Severe hypoglycemia* n/1000 person years = RelativeRisk(%)
    • 48. Short-term consequences: unpleasant symptoms (and potential risky situations) related with the actual episode Long-term consequences: pattern of “fear of hypoglycemia” with negative impact on patients´ HRQOL” Hypoglycemia and QoL: The impact can be substantial for both patients and caregivers HRQoL=health-related quality of life. Levy AR, et al. Health Qual Life Outcomes. 2008, 6: 73. Patients suffering hypoglycemic episodes are more prone to anxiety and panic attacks. In order to avoid hypoglycemic events, some patients alter treatment and others may engage in behaviors like overeating Hypoglycemia facilitates clinical inertia: "the failure to initiate or intensify therapy in a defined time among patients who haven't attained clinical goals and whom intensification is likely to benefit."
    • 49. TZDs4–6 Metformin + TZD5,6,9 Metformin + SU1–3 Meglitinides4,7,8 SUs1–4 Metformin1–3 Weight Change (kg)OAD Agents OAD=oral antidiabetic agent; SU=sulfonylurea; TZD=thiazolidinedione. 1Glucophage [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company, 2004. 2Glucovance [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company, 2004. 3Metaglip [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company, 2002. 4Malone M. Ann Pharmacother. 2005; 39: 2046–2055. 5Actos [package insert]. Indianapolis, Ind: Eli Lilly and Company, 2004. 6Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline, 2005. 7Starlix [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2004. 8Prandin [package insert]. Princeton, NJ: Novo Nordisk, Inc, 2004. 9Avandamet [package insert]. Research Triangle Park, NC: GlaxoSmithKline, 2005. Weight gain is a common side effect of treatments with SU −5 −4 −3 −2 −1 0 1 2 3 4 5 -3.8–0.5 -0.4–1.7 0.9–4.6 0.3–3.0 -0.3–1.9 0.8–2.1
    • 50. 13 0 2 4 6 8 10 12 14 Vildagliptin vs glimepiride as add on to metformin: No severe hypoglycemic events at 2 years Safety population; * any episode requiring the assistance of another party Vilda= vildagliptin; Glim= glimepiride; Met= metformin Matthews DR et al Diab Obes Metab. 2010; 12:780-789 Glim up to 6 mg qd + Met (n=1546) Vilda 50 mg bid + Met (n=1553) Number of hypoglycemic events Number of Severe hypo events* Patients with one or more hypoglycemic events (%) 2.3 18.2 0 4 8 12 16 20 59 838 0 100 200 300 400 500 600 700 800 900 0 15 0 2 4 6 8 10 12 14 16 Incidence(%) Numberofevents Numberofevents This hypoglycemic profile was maintained in patients > 65 years Discontinuation due to hypoglycemia 0 Numberofevents
    • 51. No.ofevents Duration: 104 weeks, add-on to metformin: vildagliptin vs glimepiride Hypoglycaemia 2 1) Per protocol population. 2) Safety population. 3) Intent-to-treat population. a) any episode requiring the assistance of another party *p <0.001. BL=baseline; EP = week 104 endpoint; Met= metformin; hypo = hypoglycemia; HbA1c= glycosylated hemoglobin. Matthews DR et al. Diab Obes Metab 2010; 12: 780–789. Vildagliptin was as effective as glimepiride when added to metformin at 104 weeks with no weight gain and low incidence of hypoglycemia No.ofevents Incidence(%) 18.2 Patients with > 1 hypo (%) Discontinuations due to hyposNumber of severe events aNumber of hypo events 1553 1546N = Glimepiride up to 6 mg qd +met Vildagliptin 50 mg bid + met No.ofevents 59 1553 1546N = 1553 1546N = 1553 1546N = Mean HbA1c 1 Adjusted mean change in HbA1c was comparable between vildagliptin and glimepiride treatment: −0.1% (0.0%) for both Primary objective of non-inferiority was met: 97.5% CI= (-0.00, 0.17); upper limit 0.3% 0 13 0 2 4 6 8 10 12 14 16 0 15 0 2 4 6 8 10 12 14 16 -0.3 -1.5 1.2 -2.0 -1.0 0.0 1.0 2.0Adjustedmeanchange inbodyweight(kg) 1539n = 1520 * Change in body weight 3 Change from BL to EP (BL Mean ~89kg) Between-treatment Difference 51
    • 52. -0.3 -1.5 1.2 -2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0 Change from BL to EP (BL Mean ~ 89 kg) Between-treatment difference Vildagliptin: weight loss vs. glimepiride as add on to metformin at 2 years Intention-to-treat (ITT) population; *P <0.001. BL=baseline; EP=week 104 end point; glim=glimiperide; met=metformin; vilda=vildagliptin. Matthews DR et al Diab Obes Metab. 2010; 12:780-789 AdjustedMeanChangein Bodyweight(kg) 1539 1520N= * Glim up to 6 mg once daily + met Vilda 50 mg twice daily + met
    • 53. Weight gain is a common side effect of diabetes treatments Effect of Noninsulin Antidiabetic Drugs Added to Metformin Therapy on Glycemic Control, Weight Gain, and Hypoglycemia in Type 2 Diabetes Olivia J. Phung; Jennifer M. Scholle; Mehak Talwar; Coleman, CI. JAMA. 2010;303(14):1410-1418 AGIS
    • 54. 4.4) Use of TZDs is associated with weight gain, edema, cardiovascular risk and bone fractures
    • 55. Totipotent Stem cell Hematopoietic Stem cell Osteoblast Mesenchymal stem cell Bone formation Preadipocyte PPARɣ Adipocyte Preosteoblast + Myeloid Precursors Lymphoid Precursors Erythroid lineage Myeloid, Monocyte, Granulocyte lineages T, NK, B cell lineages Preosteoclast Osteoclast TZDs increase conversion from preadipocytes into adipocytes in fat tissue as well as in the bone marrow, consequently decreasing other pathways leading to osteoblasts, erythrocytes or lymphocytes Adapted from Rosen et al. Nat Clin Pract Rheumatol 2006, 2:35-43 and Payne et al Medical Hypothesis 2007, 69:778-786. *PPARγ agonists determine MSC lineage commitment towards adipocytes instead of osteoblasts or erythrocytes TZDs
    • 56. PROactive: incidence of edema, and magnitude of weight gain with pioglitazone 21.6 13.0 0 5 10 15 20 25 3.6 -0.4 -1 0 1 2 3 4 % of Edema without HF Weight Gain (kg) Placebo Pioglitazone <45 mg daily HF=heart failure. Adapted from Dormandy JA, et al. Lancet. 2005; 366: 1279–1289. P <0.0001
    • 57. Weight gain is a common side effect of diabetes treatments Effect of Noninsulin Antidiabetic Drugs Added to Metformin Therapy on Glycemic Control, Weight Gain, and Hypoglycemia in Type 2 Diabetes Olivia J. Phung; Jennifer M. Scholle; Mehak Talwar; Coleman, CI. JAMA. 2010;303(14):1410-1418 AGIS
    • 58. Edema is common with TZDs (pioglitazone) TZDs=thiazolidinediones. 1Actos [prescribing information]. Indianapolis, IN: Eli Lilly and Company, 2004. 4.8 7.2 6.0 15.3 1.2 2.1 2.5 7.0 0 2 4 6 8 10 12 14 16 18 Monotherapy Combination with SU Combination with metformin Combination with insulin ProportionofPatients(%) Pioglitazone1 Placebo or combination
    • 59. Use of TZDs is associated with increased incidence of congestive heart failure NumberofCHFEvents P=0.01 CHF=congestive heart failure; TZDs=thiazolidinediones. Adapted from DREAM Trial Investigators, et al. Lancet. 2006; 368: 1096–1105. HF=heart failure Adapted from Dormandy JA, et al. Lancet. 2005; 366: 1279–1289. P <0.0001 14 2 0 5 10 15 20 11 8 0 5 10 15 Rosiglitazone Placebo PatientswithHF(%) Placebo Pioglitazone ≤45 mg daily DREAM Study PROactive Study
    • 60. Risk of myocardial infarction and death from cardiovascular causes with rosiglitazone CI=confidence interval; CV=cardiovascular. Adapted from Nissen SE, Wolski K. N Engl J Med. 2007; 356: 2457–2471. Myocardial infarction Small trials combined DREAM ADOPT Overall Death from CV causes Small trials combined DREAM ADOPT Overall 2.0 4.01.0 Log Odds Ratio (95% CI) 0.5 1.43 (1.03–1.98) P=0.03 1.45; P=0.15 1.65; P=0.22 1.33; P=0.27 2.40; P=0.02 1.20; P=0.67 0.80; P=0.78 1.64 (0.98–2.74) P=0.06
    • 61. RECORD study results: secondary endpoints – cardiovascular All cause Heart failure* Hazard Ratio (95% CI) 0.86 (0.68, 1.08); P=0.19 0.84 (0.59, 1.18); P=0.32 0.72 (0.49, 1.06); P=0.10 0.93 (0.74, 1.15); P=0.50 2.10 (1.35, 3.27); P=0.001 MI Stroke CV death, MI or stroke *Fatal and non-fatal. CI=confidence interval; CV=cardiovascular; MI=myocardial infarction. Home PD et al. Lancet. 2009; 373: 2125–2135. Rosiglitazone (n=2220) Control (n=2227) 46 64 154 63 2961 165 56 1.14 (0.80, 1.63); P=0.47 Hazard ratio (95% CI) 0.5 1.0 2.0 3.0 4.0 Death CV 136 60 157 71
    • 62. Rosiglitazone: EMA / FDA decision 23rd September 2010 23rd of September 2010: • FDA notified healthcare professionals and patients that it will significantly restrict the use of the diabetes drug Avandia (rosiglitazone) to patients with Type 2 diabetes who cannot control their diabetes on other medications. • These new restrictions are in response to data that suggest an elevated risk of cardiovascular events, such as heart attack and stroke, in patients treated with Avandia • EMA (European Medicines Agency) recommended the suspension of the marketing authorisations for the rosiglitazone-containing anti-diabetes medicines Avandia, Avandamet and Avaglim. • Data from clinical trials, observational studies and meta-analyses of existing studies that have become available over the last three years have suggested a possibly increased risk of ischaemic heart disease associated with the use of rosiglitazone. • GBA has decided to withdraw reimbursment of rosiglitazone* * GBA= Gemeinsame Bundesausschuss (The German Health Care System and the Federal Joint Committee) http://www.g-ba.de/institution/sys/english/
    • 63. ADOPT Study: proportion of female patients with limb fractures was almost twice as high with rosiglitazone compared to metformin-treated patients *P <0.01; **P <0.05 vs rosiglitazone (unadjusted, contingency 2 test). Kahn SE, et al. N Engl J Med. 2006; 355: 2427–2443. 9.3 5.6 3.4 5.1 3.1 1.7 3.5 1.3 1.5 0 2 4 6 8 10 Overall Lower limb Upper limb Patients(%) * * Rosiglitazone (n=1456) Glyburide (n=1441) Metformin (n=1454) * ** **
    • 64. RECORD study results: increased limb fractures in patients with rosiglitazone *P <0.0001 Rosiglitazone vs control Home PD, et al. Lancet. 2009; 373: 2125–2135. Women Men 124 1078 68 1075 47 1078 63 1078 36 1075 16 1075 61 1142 23 1142 50 1152 19 1152 23 1142 11 1152 Rosiglitazone Active control All Distal lower limb Upper limb All Distal lower limb Upper limb Patients(%) n (events) N (patients) Overall incidence of bone fractures higher with rosiglitazone (p<0.0001*)
    • 65. Pioglitazone has a similar risk of fractures as rosiglitazone 77% increased risk of peripheral fracture in women2 Aubert RE, et al. Diabetes Obes Metab. 2010;12(8):716-721 Colin R. Arch Intern Med. 2009;169(15):1395-1402.
    • 66. 1-year number need to harm range from 21 - 55 Loke YK, Singh S. Furberg C. Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis CMAJ Jan 6 2009 180 (1) *mean age 56 years; diabetes diagnosed within 3 years before study; no previous use of oral hypoglycemic agent Number needed to harm via excess fractures with TZDs ranges from 21 to 55 Population Baseline risk of fractures per 1000 Patent-years Odds ratio of fracture (95% CI) from meta- analysis 1-year number needed to harm* (95% CI) Excess fractures with TZD use per 100 patient-years (95% CI) Women in the metformin arm of the ADOPT study:* 15.4 2.23 (1.65-3.01) 55 (34-103) 18 (10-29) Elderly postmenopausal women in Women’s Health Initiative Observational Study; mean age 65 years 28.6 2.23 (1.65-3.01) 31 (19-57) 32 (18-53) Older cohort of women with diabetes not using insulin; mean age 72 years 43.5 2.23 (1.65-3.01) 21 (14-39) 48 (26-71) Note: ADOPT- A Diabetes Outcome and Progression Trial. * Number of patients with type 2 diabetes who must be treated with a thiazolidinedione, rather than another intervetnion, for 1 additional patient to have a fracture.
    • 67. In patients failing on metformin vildagliptin is the only DPP-4 inhibitor showing similar efficacy to pioglitazone at 1 year without weight gain HbA1c=hemoglobin A1c, NI=non-inferiority, * P<0.001 pio vs BL Intention-to-treat population. Vildagliptin (n=295); pioglitazone (n=281). Bolli G, et al. Diabetes Obes Metab. 2009; 11: 589–595. Vildagliptin 50 mg bid + metformin Pioglitazone 30 mg od + metformin 24-week analysis Vilda NI established −4 0 4 12 16 24 32 40 52 Time (Weeks) 7.0 7.5 8.0 8.5 9.0 MeanHbA1c(%) Duration: 52 weeks add-on to metformin: vildagliptin vs pioglitazone n=277n=293 UnadjustedMean ChangeinBodyWeight(kg) * Change in Body Weight (Mean BL Body Weight ~91 kg) *P <0.001 change from baseline Change in HbA1c
    • 68. 0.3 0.1 1.9 2.6 0.0 0.5 1.0 1.5 2.0 2.5 3.0 All Patients Mean BL ~91.8 kg n = Pioglitazone added greater body weight burden to obese patients (BMI >35 kg/m2) BL=baseline; BMI=body mass index; met=metformin; pio=pioglitazone; vilda=vildagliptin. *P <0.001 vs pioglitazone. Per protocol population. Adjusted mean change derived from analysis of covariance model. Bolli G, et al. Diabetes Obes Metab. 2008; 10: 82–90. AdjustedMeanChangein BodyWeight(kg)toWeek24 BMI >35 kg/m2 Mean BL ~110.4 kg 264 246 7073 Pio 30 mg once daily + met Vilda 50 mg twice daily + met * * Duration: 24 weeks Add-on to met: vilda vs pio
    • 69. Vildagliptin demonstrated to be likely more cost-effective than pioglitazone - even without considering the recent evidence on the increased risk of fractures in men an women Costs QALYs Net benefit ICER Vildagliptin Pioglitazone Diff % Vildagliptin Pioglitazone Diff % £20,222 £20,245 -£23 -0.1% 9.4541 9.4527 0.001 4 0.01 % £50 Vildagliptin dominates QALY: quality adjusted life year; ICER: incremental cost-effectiveness ratio; net benefit: (payer acceptability threshold £20l x ΔQALYs) – Δ costs Pricing assumption: Vildagliptin at £1.20 for 100mg daily Efficacy data based on study LAF237A2354  Long-term HbA1c trend is assumed to be similar to vildagliptin – this is mainly explained by the weight gain beyond the first year of treatment, which is a significant disadvantage of the glitazones  Cost of liver function testing was shown to have little impact on the cost-effectiveness of vildagliptin in the first year of treatment Source: http://www.ispor.org/congresses/Greece1108/Posters2.aspx ESTIMATING THE COST EFFECTIVENESS IN THE UK OF VILDAGLIPTIN COMPARED TO PIOGLITAZONE AS ADD-ON THERAPY TO METFORMIN USING THE SHEFFIELD TYPE 2 DIABETES MODEL Brennan A, Gillett M, Duenas A , University of Sheffield, Sheffield, United Kingdom Vildagliptin vs pioglitazone as add-on to metformin
    • 70. 4.5) Bone fractures cause significant healthcare cost
    • 71. Fractures cause a significant direct economic burden Unit cost of a fragility fracture (Stevenson et al 2006) Fracture site Proportion of fractures hospitalized Length of stay per hospitalization (days) Total cost per fracture Hip 100% 26.0 £10,760 Vertebrae 35% 15.0 £1,706 Proximal humerus 32% 10.6 £1,112 Wrist 25% 5.4 £527 Data for the cost of fracture were taken from a publication by Stevenson et al (2006), which calculates the average unit cost of a fragility fracture in the UK. Unit costs are reported for fractures at the hip, spine, proximal humerus and humeral shaft, and forearm. Stevenson M, Davis S, Kanis J. The hospitalisation costs and out-patient costs of fragility fractures. Women's Health Med 2006;3:149–151.
    • 72. Fractures have significant health related quality of life impact in elderly women Mayo Clin Proc. 2010; 85: 806-13. Epub 2010 Jul 15. Impact of prevalent fractures on quality of life: baseline results from the global longitudinal study of osteoporosis in women. Adachi JD, Adami S, Gehlbach S, Anderson FA Jr, Reductions in health-related quality of life (EQ-5D, for women with previous fractures compared with women without fracture history or medical condition, adjusted for all listed conditions plus age and study site EQ-5D (N=51,165) Reduction 95% CI P value Comparison condition Arthritis (n=22,331) 0.12 0.11-0.12 <0.001 Type 1 diabetes (n=1950) 0.09 0.08-0.09 <0.001 Lung disease (n=8659) 0.06 0.05-0.06 <0.001 Previous fracture location Ankle (n=3123) 0.04 0.03-0.04 <0.001 Wrist (n=4250) 0.01 0.001-0.01 <0.05 a EQ-5D= European Quality of Life 5 Dimensions Index; CI= Confidence Interval; b Reduction in score between comparison groups (eg, with vs without diabetes);
    • 73. 4.6) GLP-1 analogs are associated with gastrointestinal adverse events
    • 74. Gastrointestinal adverse events are common during treatment with exenatide *In three 30-week placebo-controlled trials. Adapted from Byetta [prescribing information]. San Diego, CA: Amylin Pharmaceuticals Inc, 2005. 18% 4% 6% 44% 13% 13% 0 5 10 15 20 25 30 35 40 45 50 Nausea Vomiting Diarrhea ProportionofPatients(%) Placebo (n=483) Exenatide (n=963)
    • 75. bid=twice daily; GLP-1=glucagon-like peptide-1; SU=sulfonylurea. *In three 30-week placebo-controlled trials; exenatide and placebo were administered before the morning and evening meals. Adapted from Byetta [prescribing information]. San Diego, CA: Amylin Pharmaceuticals Inc, 2005. Incidence of hypoglycemia during treatment with exenatide 5.3% 3.3% 12.6% 4.5% 14.4% 19.2% 5.3% 35.7% 27.8% 0 5 10 15 20 25 30 35 40 Combination with metformin Combination with SU Combination with metformin + SU ProportionofPatients(%) Placebo Exenatide 5 mcg bid Exenatide 10 mcg bid
    • 76. 4.7) Hypoglycemia has clinical, social and economic consequences
    • 77. Mechanisms by which hypoglycemia may affect cardiovascular events Desouza CV et al. Hypoglycemia, Diabetes, and Cardiovascular Events. Diabetes Care 2010; 33: 1389-1394. IL6: interleukin 6 CRP: C-reactive protein VEGF: vascular endothelial growth factor
    • 78. Hypoglycemia consequences 1: Whitmer RA et al JAMA 2009, 301:1565-1572 2: Zammitt NN et al Diabetes Care 2005, 28:2948-2961 3 Canadian Diabetes Association’s Clinical Practice Guidelines for Diabetes and Private and Commercial Driving. Canadian Journal Of Diabetes. 2003;27(2):128-140. 4:Jönsson L et al. Cost of Hypoglycemia in Patients with Type 2 Diabetes in Sweden. Value In Health. 2006; 9: 193-198 5: Barnett AH, CMRO 26, 1333-1342, 2010 6. Foley J & Jordan J, Vascular Health Risk Management, 2010 6:541-548 Hypoglycemia CV complications5 Weight gain by defensive eating6 Coma5 Car accident3 Hospitalization costs4 Dizzy turn unconsciousness5 Seizures5 Death2 Increased risk of dementia1
    • 79. *P=0.01; **P=0.02; ***P <0.01. CL=confidence limit; HDL-C=high-density lipoprotein cholesterol. Abraira C. Oral Presentation. Presented at the 68th Scientific Sessions of the American Diabetes Association; 6–10 June 2008, San Francisco, USA. HR (Lower CL, Upper CL) Risk of death Lower Higher Hypoglycemia HbA1c HDL-C Age Prior event 4.042 (1.449, 11.276)* 1.213 (1.038, 1.417)** 0.699 (0.536, 0.910)* 2.090 (1.518, 2.877)*** 3.116 (1.744, 5.567)*** Hypoglycemia was a strong predictor of CV death in VADT study 0 2 4 6 8 10 12 Hazard Ratio
    • 80. Short-term consequences: unpleasant symptoms (and potential risky situations) related with the actual episode Long-term consequences: pattern of “fear of hypoglycemia” with negative impact on patients´ HRQOL” Hypoglycemia and QoL: The impact can be substantial for both patients and caregivers HRQoL=health-related quality of life. Levy AR, et al. Health Qual Life Outcomes. 2008, 6: 73. Patients suffering hypoglycemic episodes are more prone to anxiety and panic attacks. In order to avoid hypoglycemic events, some patients alter treatment and others may engage in behaviors like overeating Hypoglycemia facilitates clinical inertia: "the failure to initiate or intensify therapy in a defined time among patients who haven't attained clinical goals and whom intensification is likely to benefit."
    • 81. Hypoglycemia increases costly hospital admissions UK 2007-08 Admitted Patient Care Mandatory Tariff Cc = comorbidity or complication; HRG = Healthcare resource group HRG Name Healthcare Resource Group Non-elective spell tariff (£) % applied in calculation of reduced short stay emergency tariff Reduced short stay emergency tariff (£) Weighted Average (£) Diabetes with Hypoglycaemic Emergency >69 years or with cc 2,171 20% 434 1,824 Diabetes with Hypoglycaemic Emergency <70 years without cc 776 50% 388 582 Gillette M, Fitzgerald P, Brennan A. Analysis of the economic impact of hypos – comparison of vildagliptin versus sulphonylurea. Modelling phase report. University of Sheffield, School of Health and Related Research. October 2009. (Prepared for Novartis) Costs Of Hypoglycaemia Per NHS Reference Costs UK Payer Perspective
    • 82. 5) Incretin hormones and DPP-4 inhibitors 5.1) Incretins restore the physiological balance between glucagon and insulin in a glucose-dependent manner
    • 83. The incretins Y A E G T F I S D Y S I A M D K I H Q Q DFVN WLLA QKGKKNDW K H N QTI GIP: Glucose-dependent Insulinotropic Peptide H A E G T F T S D V S S Y L E G Q A A K EFIAWLVKGRG GLP-1: Glucagon-like Peptide-1 Amino acids shown in orange are homologous with the structure of glucagon.
    • 84. L-cell (ileum) Proglucagon GLP-1 [7–37] GLP-1 [7–36 NH2] K-cell (jejunum) ProGIP GIP [1–42] GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1. Adapted from Drucker DJ. Diabetes Care. 2003; 26: 2929–2940. GLP-1 and GIP are synthesized and secreted from the gut in response to food Intake
    • 85. Food intake  cells  cells Insulin secretion Insulin biosynthesis cell proliferation cell survival Glucose sensing Glucagon secretion Intestinal secretion of GLP1 (7-36) amide + GIP (1-42) DPP4 Action on  cells and  cells GLP-1 (9-36) amide And GIP (3-42) DPP4 inhibitors Adapted from L Baggio and DJ Drucker Gastroenterology 2007 132:2131-2157 And DJ Drucker The J Clin Invest 2007, 117:24-32 Incretin hormones are the body’s natural way to maintain glycemic control Intestine Pancreas Blood Glucose level 85
    • 86. IV=intravenous. Adapted from Nauck MA, et al. J Clin Endocrinol Metab. 1986; 63: 492–498. Oral Glucose Tolerance Test and Matched IV Infusion PlasmaGlucose(mg/dL) 0 50 100 150 200 –30 0 30 60 90 120 150 180 210 Time (min) PlasmaInsulin(pmol/L) 0 100 200 300 400 –30 0 30 60 90 120 150 180 210 Time (min) Proof of a gastrointestinal ‘incretin effect’: different responses to oral vs i.v. glucose Oral IV 50 g Glucose N=6
    • 87. GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus. *P <0.05. †GLP-1(7–36 amide) infused at 1.2 pmol/kg/min for 240 minutes. Adapted from Nauck MA, et al. Diabetologia. 1993; 36: 741–744. GLP-1 restores insulin and glucagon responses in a glucose-sensitive manner in patients with T2DM 0 50 100 150 200 250 300 * * * * * * * –30 0 30 60 90 120 150 180 210 240 Time (min) GLP-1 infusion Glucose (mg/dL)N=10 0.0 0.5 1.0 1.5 2.0 2.5 3.0 * * * * * * * * –30 0 30 60 90 120 150 180 210 240 Time (min) GLP-1 infusion C-peptide (nmol/L) –30 0 30 60 90 120 150 180 210 240 Time (min) 0 5 10 15 20 25 30 * * * * GLP-1 infusion Glucagon (pmol/L) GLP-1† Placebo
    • 88. 5.2) Oral DPP-4 inhibitors enhance the physiological effects of incretin hormones such as GLP-1 and GIP
    • 89. Inhibition of DPP-4 increases active GLP-1 GLP-1 inactive (>80% of pool) Active GLP-1 Meal DPP-4 Intestinal GLP-1 release GLP-1 t½=1–2 min DPP-4 inhibitor DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1. Adapted from Rothenberg P, et al. Diabetes. 2000; 49 (Suppl 1): A39. Abstract 160-OR. Adapted from Deacon CF, et al. Diabetes. 1995; 44: 1126–1131.
    • 90. Acute effects of vildagliptin on insulin, glucose and glucagon levels in patients with T2DM OGTT 30 min after Single Oral Dose of Vildagliptin (100 mg) OGTT=oral glucose tolerance test. *P <0.01. He YL, et al. J Clin Pharmacol. 2007; 47: 633–641. Vildagliptin 100 mg once daily was used in this study. Galvus (vildagliptin) is approved for 50 mg once or twice daily in combination with metformin or a TZD, and Galvus (vildagliptin) 50 mg once daily in combination with a sulfonylurea. Galvus is NOT approved for 100 mg qd, 7.5 12.5 17.5 22.5 Glucose (mmol/L) 0 60 80 100 120 40 20 Insulin (pmol/L) 60 80 100 120 140 Glucagon (ng/L) −90 −60 −30 0 30 60 90 120 150 180 210 240 270 300 −90 −60 −30 0 30 60 90 120 150 180 210 240 270 300 −90 −60 −30 0 30 60 90 120 150 180 210 240 270 300 Time Vildagliptin 100 mg (n=15) Placebo (n=16) 75 g Glucose Dose
    • 91. Meal * * * * * * * * * * * * Vildagliptin 100 mg (n=16) Placebo (n=16) Acute effects of vildagliptin on GLP-1 levels in patients with T2DM: increased GLP-1 levels that persist beyond the post-meal period GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus. *P <0.05. Balas B, et al. J Clin Endocrinol Metab. 2007; 92: 1249–1255. Vildagliptin 100 mg once daily was used in this study. Galvus (vildagliptin) is approved for 50 mg once or twice daily in combination with metformin or a TZD, and Galvus (vildagliptin) 50 mg once daily in combination with a sulfonylurea. Galvus is NOT approved for 100 mg qd, 0.0 4.0 8.0 12.0 16.0 17:00 20:00 23:00 02:00 05:00 08:00 Time ActiveGLP-1(pmol/L) * 91
    • 92. Effects of vildagliptin and vildagliptin plus metformin on fasting GLP-1 levels 0 2 4 6 8 10 12 14 * IntactGLP-1(pM) Fasting Levels of Intact GLP-1 at Baseline and at 3 Months BL=baseline; GLP-1=glucagon-like peptide-1; met=metformin; PBO=placebo; vilda=vildagliptin. *P <0.05 vildagliptin 3 months vs baseline; **P <0.05 vildagliptin add-on metformin significantly improved at 3 months vs baseline. †Contains patients on vildagliptin alone and those on vildagliptin plus metformin. D’Alessio DA, et al. J Clin Endocrinol Metab. 2009; 94: 81-88. Vilda group† Placebo BL BL3 months 3 months n = 20 20 19 19 IntactGLP-1(pM) ** 0 2 4 6 8 10 12 14 Vilda only Fasting Levels of Intact GLP-1 in Vildagliptin Subgroups at 3 Months Vilda + met 7 13 Vildagliptin: 50 mg bid
    • 93. 5.3) Mode of action evidence supports potential intra-class differentiation of vildagliptin vs. sitagliptin
    • 94. Vildagliptin vs Sitagliptin: what do we know so far? Chemical structures of DPP-4 inhibitors 1Januvia Prescribing Information. http://www.merck.com/product/usa/pi_circulars/j/januvia/januvia_pi.pdf. Accessed January 2010. 2Burkey BF, et al. Poster 0788 presented at EASD 2006. 3Neumiller JJ. J Am Pharm Assoc. 2009; 49: S16–S29. 4Onglyza Prescribing Information. http://packageinserts.bms.com/pi/pi_onglyza.pdf. Accessed January 2010. Ahren B et al, Diab Obes Metab 2011 "Accepted Article"; doi: 10.1111/j.1463-1326.2010.01321.x N N O H3C O N CN NH3 + PhCO2 - Alogliptin3 Non- covalent F F F O N NH2 N N N CF3 Sitagliptin1 Non- covalent Vildagliptin2 HO N H O N NC Covalent (cyanopyrrolidine) Competitive inhibitors Substrates acting as inhibitors Saxagliptin4 N O H H NC HO NH2 Covalent (cyanopyrrolidine)
    • 95. Different binding kinetics within DPP-4 class DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1. Burkey BF, et al. Poster 0788 presented at EASD 2006; Deacon CF, Holst JJ. Adv Ther. 2009; 26: 488–499; Miller SA, St Onge EL. Ann Pharmacother. 2006; 40: 1336–1343; Neumiller JJ. J Am Pharm Assoc. 2009; 49: S16–S29; Potashman MH & Duggan ME. J Med Chem 2009; 52: 1231-1246. White JR. Clin Diabetes. 2008; 26: 53–57. Inhibitor: DPP-4 complex Inhibitor + DPP-4 K-1 K1 Competitive inhibitor: (sitagliptin, alogliptin) Fast dissociation Substrate acting as inhibitor: (vildagliptin, saxagliptin) DPP-4Substrate-like enzyme blocker + DPP-4 K-1 K1 Substrate-like enzyme blocker: DPP-4 complex K2 Slow (~ 1 h) Inactive substrate-like enzyme blocker + Slow dissociation Natural substrate: (GLP-1) GLP-1 + DPP-4 K-1 K1 GLP-1: DPP-4 complex K2 Fast (~1 sec) DPP-4 Inactive GLP-1 +
    • 96. Comparison of plasma GLP-1 levels following 3 Months’ treatment with vildagliptin or sitagliptin GLP-1=glucagon-like peptide-1. *P <0.05 vs vildagliptin group, Plasma levels during 24-h sampling comprising three standardized meals after 3 months of treatment in type 2 diabetic patients. Marfella R, et al. J Diabetes Complications. 24: 79-83, 2010.. 30 25 20 15 10 5 0 -20 0 15 30 60 90 120 180 240 300 0 15 3060 90 120 180 240 300 0 15 3060 90 120 180 240 300 min Breakfast Lunch Dinner IntactGLP-1(pmol/L) Sitagliptin 100 mg once daily + metformin (N=20) Vildagliptin 50 mg twice daily + metformin (N=18) Retrospective analysis of patients on sitagliptin (N=20) or vildagliptin (N=18)
    • 97. -0.5 -0.7 -0.2 -0.1 -0.8 -0.6 -0.4 -0.2 0.0 Vildagliptin Add-on to Insulin: Significant Reduction in HbA1c and Fewer Hypoglycemic Events >65 Years Mean BL = 8.4%Overall Mean BL = 8.4% ChangeinHbA1c(%) Add-on Treatment to Insulin 140 ** 149 42 41n = * Duration: 24 weeks Add-on to insulin: vilda vs PBO PBO + insulin Vilda 50 mg twice daily + insulin PBO=placebo; vilda=vildagliptin; *P <0.001; **P <0.05 between groups. Fonseca V, et al. Diabetologia. 2007; 50: 1148–1155. No. of Hypoglycemic Events No. of Severe Hypoglycemic Events 0 40 80 120 160 200 0 2 4 6 8 10 No.ofSevereEvents 113 185 0 6 * ** No.ofEvents
    • 98. Vilsbøll T, et al. Diabetes Obes Metab 2010;12:167–177 8.6 8.1 7.8 7.9 8.0 8.1 8.2 8.3 8.4 8.5 8.6 8.7 Placebo Sitagliptin HbA1c(%) 8 16 0 2 4 6 8 10 12 14 16 18 Placebo Sitagliptin Patients(%) HbA1c (%) Symptomatic hypoglycaemia Sitagliptin Placebo * ** 1 severe hypo in placebo 2 severe hypos with Sitagliptin Sitagliptin in add-on to insulin setting Mean insulin dose ~50 U/day 98
    • 99. Meal * * * * * * * * * * * * Vildagliptin 100 mg (n=16) Placebo (n=16) Acute effects of vildagliptin on GLP-1 levels in patients with T2DM: increased GLP-1 levels that persist beyond the post-meal period GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus. *P <0.05. Balas B, et al. J Clin Endocrinol Metab. 2007; 92: 1249–1255. Vildagliptin 100 mg once daily was used in this study. Galvus (vildagliptin) is approved for 50 mg once or twice daily in combination with metformin or a TZD, and Galvus (vildagliptin) 50 mg once daily in combination with a sulfonylurea. Galvus is NOT approved for 100 mg qd, 0.0 4.0 8.0 12.0 16.0 17:00 20:00 23:00 02:00 05:00 08:00 Time ActiveGLP-1(pmol/L) * 99
    • 100. Acute effects of vildagliptin on glucagon levels in patients with T2DM: decreased glucagon levels persist beyond the post-meal period Meal * * ** * * * * *P <0.05 vs placebo. Balas B, et al. J Clin Endocrinol Metab. 2007; 92: 1249–1255. Vildagliptin 100 mg once daily was used in this study. Galvus (vildagliptin) is approved for 50 mg once or twice daily in combination with metformin or a TZD, and Galvus (vildagliptin) 50 mg once daily in combination with a sulfonylurea. Galvus is NOT approved for 100 mg qd, −60 −50 −40 −30 −20 −10 0 10 20 17:00 Time DeltaGlucagon(ng/L) 20:00 23:00 02:00 05:00 08:00 Placebo (n=16) Vildagliptin 100 mg (n=16) * 100
    • 101. Acute effects of vildagliptin on endogenous glucose production (EGP) levels in patients with T2DM: decreased EGP levels persist beyond post-meal period EGP=endogenous glucose production. *P <0.05 vs placebo. Balas B, et al. J Clin Endocrinol Metab. 2007; 92: 1249–1255. Vildagliptin 100 mg once daily was used in this study. Galvus (vildagliptin) is approved for 50 mg once or twice daily in combination with metformin or a TZD, and Galvus (vildagliptin) 50 mg once daily in combination with a sulfonylurea. Galvus is NOT approved for 100 mg qd, 0 −0.3 −0.6 −0.9 −1.2 −1.5 DeltaEGP(mg/kg/min) 17:00 20:00 23:00 02:00 05:00 08:00 Time ********* * * * **************** Placebo (n=16) Vildagliptin 100 mg (n=16) Meal
    • 102. 6) Vildagliptin in monotherapy settings 6.1) Vildagliptin demonstrates favorable efficacy and tolerability profile in monotherapy settings
    • 103. Vildagliptin comprehensive phase III clinical development program Early Type 2 Diabetes Glucose intolerance Advanced Type 2 Diabetes Diabetic Complications in IFG In IGT Efficacy/safety in mono settings vs. PBO (2) Mono vs PBO, Japan Mono long-term safety, Japan H2H vs TZD (rosiglitazone) H2H vs met (2) -General population -Elderly H2H vs SU (glicl.) H2H vs α-GI (acarbose), China H2H vs α-GI (voglibose), Japan Add-on to metformin: vs. PBO - Genaral population - Chinese population vs TZD (pioglitazone) vs SU (glim. or glicl.) - Low BLHbA1c - High BL HbA1c vs up-titration of met Initial combination met Add-on to TZD (p incl Japanio): - PBO controlled - Initial combo Add-on to SU (glim) Add-on to SU (glim), Japan Add-on insulin In mild hyperglycemia Moderate and severe renal impairment (ongoing) CHF (ongoing) Asian studies
    • 104. FPG=fasting plasma glucose; IGT=impaired glucose tolerance; OGTT=oral glucose tolerance test. Rosenstock J, et al. Diabetes Care. 2008; 31: 30–35. Objective: to assess the effects of vildagliptin on prandial glucose control, incretin hormone levels, and islet function Target population: drug-naïve patients with IGT documented by OGTT (FPG <7.0 mmol/L and 2-h glucose >7.8 and <11.1 mmol/L) Study DesignStudy Design n=89: Placebo 12 weeks4 weeks N=179 n=90: Vildagliptin 50 mg once daily IGT patients diagnosed by OGTT Vildagliptin monotherapy in IGT : study design and objective
    • 105. Vildagliptin’s effect on GLP-1 and glucagon is fully evident in IGT population 12.0 8.0 4.0 0.0 GLP-1(pmol/L) –30 0 30 60 90 120 Time (min) Meal Vildagliptin 50 mg once daily (n=89) Placebo (n=89) 9.0 8.0 7.0 6.0 Glucose(mmol/L) –30 0 30 60 90 120 Time (min) Meal 26 22 20 18 Glucagon(pmol/L) –30 0 30 60 90 120 Time (min) 24 Meal Insulin secretion relative to glucose 8.0 6.0 4.0 2.0 0.0 –2.0 –4.0 Vildagliptin 50 mg once daily (n=89) Placebo (n=89) * a b c d Intention-to-treat population. *P=0.002 vs placebo. Rosenstock J, et al. Diabetes Care. 2008: 31: 30–35. ISRAUC0-2h/GlucoseAUC0-2h (pmol/L•min-1•m-2•mM) GLP-1 β-cell Function Glucose Glucagon
    • 106. Objective: to assess the long-term efficacy and safety of vildagliptin in patients with T2DM and mild hyperglycemia during 108 weeks of treatment Target population: drug-naïve patients with T2DM (HbA1c 6.2-7.2%); completed 52-week core; HbA1c <8% at Week 52 core 52 weeks2 weeks N=306* n=156: Vilda 50 mg once daily n=150: Placebo Washout Washout 52 weeks4 weeks 4 weeks n=63: Placebo n=68: Vilda 50 mg once daily Core Extension** *Randomized population; **Extension population. HbA1c=hemoglobin A1c; T2DM=type 2 diabetes mellitus; vilda=vildagliptin. Scherbaum WA, et al. Diabetes Obes Metab. 2008; 10: 1114–1124. Vildagliptin in T2DM patients with mild hyperglycemia: study design and objective
    • 107. 0.1 -0.4 0.5 -0.5 -0.4 -0.3 -0.2 -0.1 0.0 0.1 0.2 0.3 0.4 0.5 0.6 Change from BL to EP (BL Mean ~6.64%) MeanChangeinHbA1c(%) Mean Difference vs Placebo n = 67 63 Placebo Vildagliptin 50 mg once daily * Vildagliptin therapeutic effects are fully manifested in patients with mild hyperglycemia : change from baseline in HbA1c Extension intention-to-treat population. *P <0.001 vs core baseline. BL=core baseline; EP=study end point (Week 108); HbA1c=hemoglobin A1c. Scherbaum WA, et al. Diabetes Obes Metab. 2008; 10: 1114–1124. Duration: 2 years Vildagliptin vs placebo
    • 108. Vildagliptin 50 mg once daily Placebo MeanHbA1c(%) Time (Weeks)Extension intention-to-treat population. HbA1c=hemoglobin A1c. --- = washout period (52-56 weeks, 108-112 weeks); vildagliptin (n=67 at Week 0, 56 at Week 108, 51 at Week 112); placebo (n=63 at Week 0, 47 at Week 108, 44 at Week 112). Scherbaum WA, et al. Diabetes Obes Metab. 2008; 10: 1114–1124. Treatment period Wk 0–52 Treatment period Wk 56–108Washout Washout Vildagliptin efficacy in mild hyperglycemia: mean HbA1c over 112 weeks Duration: 2 years Vildagliptin vs placebo
    • 109. 0.1 -0.3 0.4 -0.6 -0.4 -0.2 0.0 0.2 0.4 0.6 Change from BL to Week 112 (BL Mean ~6.64) Mean Difference vs Placebo MeanChangeinHbA1c(%) 57 50n = Placebo Vildagliptin 50 mg once daily * Vildagliptin efficacy in mild hyperglycemia: maintenance of effects after washout Extension intention-to-treat population. BL=core baseline; HbA1c=hemoglobin A1c. *P <0.001 from core baseline. Scherbaum WA, et al. Diabetes Obes Metab. 2008; 10: 1114–1124. Duration: 2 years Vildagliptin vs placebo
    • 110. Vildagliptin dose-ranging study: study design and objective HbA1c=hemoglobin A1c; T2DM=type 2 diabetes mellitus. Pi-Sunyer FX, et al. Diabetes Res Clin Pract. 2007; 76: 132–138. Drug-naïve 24 weeks2 weeks N=354 n=88: Vildagliptin 50 mg once daily n=83: Vildagliptin 50 mg twice daily n=91: Vildagliptin 100 mg once daily* n=92: Placebo Design: a 24-week, double-blind, randomized, placebo-controlled, parallel-group study Objective: to demonstrate superior HbA1c reduction of vildagliptin versus placebo Target population: drug-naïve patients with T2DM; HbA1c 7.5–10% *100 mg once daily is NOT an approved dose
    • 111. 100 mg once daily is NOT an approved dose Vildagliptin 100 mg once daily (n=89) Vildagliptin 50 mg twice daily (n=79) Vildagliptin 50 mg once daily (n=84) Placebo (n=88) Pi-Sunyer FX, et al. Diabetes Res Clin Pract. 2007; 76: 132–138. Vildagliptin dose-ranging study: efficacy over 24 weeks without weight gain -0.6 -1.3 -1.3-1.6 -1.2 -0.8 -0.4 0.0 0.4 ChangeinFPG(mmol/L) ** Change in FPG from BL vs Placebo Mean BL ~10.5 mmol/L ** HbA1c 7.0 7.4 7.8 8.2 8.6 9.0 -4 -2 0 2 4 6 8 10 12 14 16 18 20 22 24 MeanHbA1c(%) * ** ** HbA1c=hemoglobin A1c. BL=baseline; FPG=fasting plasma glucose. Primary intention-to-treat population. * p=0.01 **p <0.001 vs placebo. Time (Weeks)
    • 112. n=238 n=179: Rosiglitazone 8 mg once dailyDrug-naïve N=697* n=459 n=354: Vildagliptin 50 mg twice daily 80 weeks2 weeks HbA1c=hemoglobin A1c; T2DM=type 2 diabetes mellitus. *Patient number refers to primary intention-to-treat population. Drug-naïve patients: defined as patients who had had no treatment with oral antidiabetic agents for at least 12 weeks prior to study entry (visit 1) and no treatment with oral antidiabetic agents >3 consecutive months at any time in the past. For this study, 8 mg given as a single daily dose was selected because usage data indicate that in clinical practice 80% of patients treated with 8 mg daily take it as a single dose. aRosenstock J, et al. Diabetes Care. 2007; 30: 217–223; bRosenstock J, et al. Diabetes Obes Metab. 2009; 11: 571–578. Objective: to assess the long-term efficacy (HbA1c reduction) and safety of vildagliptin compared with rosiglitazone Target population: drug-naïve patients with T2DM; HbA1c 7.5–11% 24 weeks Vildagliptin vs rosiglitazone: study design and objective Core studya Extension studyb
    • 113. Vildagliptin provides HbA1c reductions that are sustained over two years of treatment *Not non-inferior; **Statistically significant larger increase in body weight from baseline to end point was seen in the rosiglitazone group than in the vildagliptin group; ** P <0.001. aHead-to-head vildagliptin vs rosiglitazone comparison: 80-week extension to 24-week core study; extension intention-to-treat population; bVildagliptin n=354, rosiglitazone n=179; observations censored at rescue med; error bars represent standard error values; cPitting edema, peripheral edema, and other edema. Rosenstock J, et al. Diabetes Obes Metab. 2009; 11: 571–578. Data on file, Novartis Pharmaceuticals. LAF237A2354. Vildagliptin vs rosiglitazone: 104 weeksa (including 80-week extension to the 24-week core study) Not NI* Change in HbA1c Change in Body Weight −4.7kg P<0.001** Rosiglitazone 8 mg qd Vildagliptin 50 mg bid Adjustedmean%change −8 −6 −4 −2 0 2 4 6 8 10 12 14 TG TC LDL-C HDL-C ** **
    • 114. Vildagliptin vs metformin: study design and objective HbA1c=hemoglobin A1c; T2DM=type 2 diabetes mellitus. *Patient number refers to randomized population. aRefers to the extension intention-to-treat population. Drug-naïve patients: defined as patients who had had no treatment with oral antidiabetic agents for at least 12 weeks prior to study entry (visit 1) and no treatment with oral antidiabetic agents >3 consecutive months at any time in the past. Metformin was uptitrated: 1000 mg daily for 1 week; 1500 mg daily for 2 weeks; 2000 mg daily thereafter. †Schweizer A, et al. Diabet Med. 2007; 24: 955–961; ††Göke B, et al. Horm Metab Res. 2008; 40: 892–895. Objective: to demonstrate that HbA1c reduction with vildagliptin is not inferior to metformin Target population: drug-naïve patients with T2DM; HbA1c 7.5–11% Drug-naïve N=780* 52 weeks2 weeks n=254: Metformin 1000 mg n=158a twice daily n=526: Vildagliptin 50 mg n=300a twice daily 52 weeks Core study† Extension study††
    • 115. Vildagliptin vs metformin monotherapy : HbA1c efficacy and tolerability at 2 years 6.5 7.0 7.5 8.5 9.5 −2 0 4 8 24 32 40 52 76 104 9.0 8.0 886412 16 AE=adverse event; HbA1c=hemoglobin A1c *Not non-inferior; **P <0.001 vs metformin (Fisher’s exact test). Göke B, et al. Horm Metab Res. 2008; 40: 892–895. Metformin 1000 mg twice daily Vildagliptin 50 mg twice daily Mean HbA1c (%) 0 10 20 30 40 50 25.0 45.6 Gastrointestinal AE Incidence (%) ** Time (Weeks) Duration: 104 weeks (including 52-week extension to the 52-week core study) Vildagliptin vs metformin Not NI*
    • 116. Study purpose: to demonstrate the efficacy and safety of vildagliptin compared to metformin in elderly treatment-naïve patients with T2DM Target population: Drug-naïve elderly patients (age ≥ 65 years) with T2DM (baseline HbA1c 7-9%) n=166 Met up to 1500 mg daily** N* = 335 n=169 Vilda 100 mg qd 2 weeks 24 weeks *Randomized population (original target before amendment: N = 850) ** Metformin dosing: 2 x 500 mg in the morning and 1 x 500 mg in the evening; titrated over 3 weeks T2DM= Type 2 diabetes mellitus; Met= metformin; Vilda= vildagliptin; HbA1c= glycosylated hemoglobin. Schweizer et al Diabetes, Obesity and Metabolism 2009, 11:804-812. Vildagliptin compared to metformin in elderly treatment-naïve patients: study design and objective
    • 117. Vildagliptin in elderly patients: similar HbA1c reductions compared to metformin 159 Change from BL to EP Mean BL ~ 7.7% 161N= Between-treatment difference -0.64 0.11 -0.75 -1.0 -0.8 -0.6 -0.4 -0.2 0.0 0.2 AdjustedMeanChange inHbA1c(%) Intention-to-treat population. BL=baseline; EP=end point; HbA1c=glycosylated hemoglobin. *95% CI (–0.08, 0.29), P=0.258; pre-specified non-inferiority margin = 0.4% and 0.3%. Schweizer A, et al. Diabetes Obes Metab. 2009; 11: 804–812. Vildagliptin 100 mg once daily Metformin 1500 mg once daily Non-inferior* Vildagliptin 100 mg qd is not approved. 117
    • 118. Vildagliptin has a good safety profile and a better GI tolerability than metformin in elderly patients: AEs with incidence ≥3% in any group AE preferred term, % patients Vilda 100 mg qd N=167 Met 1500 mg/daily N=165 Any preferred term 44.3 50.3 Nasopharyngitis 4.8 5.5 Dizziness 4.2 2.4 Headache 3.6 1.8 Hypertension 3.6 4.2 Abdominal pain 3.0 3.0 Cataract 3.0 0 Constipation 3.0 0.6 Diarrhea 3.0 13.3 Nausea 3.0 5.5 Osteoarthritis 3.0 1.2 Cough 1.2 3.0 Safety population Vilda= vildagliptin; Met= metformin; AE= adverse events A patient with multiple occurrences of an AE under 1 treatment is counted only once in the AE category Data on file, Novartis Pharmaceuticals, LAF237A2398. Schweizer A, et al. Diabetes Obes Metab. 2009; 11: 804–812.
    • 119. Study purpose: To compare efficacy and safety of long-term vildagliptin vs. gliclazide monotherapy in drug naïve patients with T2DM in a two-year randomized, double-blind multicenter study Target population: Drug naïve patients with T2DM (baseline HbA1c = 7.5%-11%) n=546 Gliclazide up to 320 mg daily N* = 1092 n=546 Vildagliptin 50 mg bid 2 weeks 104 weeks *Randomized population T2DM= Type 2 diabetes mellitus; HbA1c= glycosylated hemoglobin. J Foley & S Sreenan, Horm Metabo Res 2009.41:905-909. erratum in Horm Metab Res 2009 41:909 Long term efficacy and safety of vildagliptin vs SU: study design and objective
    • 120. Vildagliptin vs gliclazide in monotherapy setting: less weight gain and less hypoglycemia despite the unmet non inferiority Per protocol population; ANCOVA results for change in HbA1c (%) or in body weight (kg) from baseline to endpoint † The associated 95% CI for the difference in mean change was (-0.06%, 0.33%) thus the study failed to meet the non-inferiority criterion of an upper limit of the CI of 0.3%, Adjusted mean change from BL to EP and between-treatment difference were from an ANCOVA model containing terms for treatment, baseline and pooled centers * p=0.004 between-treatment difference; 95% CI (-1.42,-0.27) Vilda= vildagliptin; Glic= gliclazide; HbA1c= glycosylated hemoglobin; BL= baseline; EP= end point; BL= baseline J Foley & S Sreenan, Horm Metabo Res 2009.41:905-909. erratum in Horm Metab Res 2009 41:909 Glic up to 320 mg daily Vilda 50 mg bid AdjustedMeanChange inHbA1c(%) HbA1c Change(a) from BL to EP † MeanChangeinBody weight(kg) Body weight Change(a) from BL to EP Hypoglycemia(b) %patientswithmild hypoglycemia a: per protocolepopulation; b: safety population 120
    • 121. Vildagliptin vs acarbose in Chinese population: study design and objective * Randomized population. HbA1c=glycosylated hemoglobin; T2DM=type 2 diabetes mellitus Pan C. et al. Diabeteic Medicine. 2008. 25:435-441 Objective: To assess the efficacy and safety of vildagliptin compared with acarbose in patients with T2DM during 24 weeks of treatment Target Population: Drug-naïve T2DM patients; HbA1c 7.5%–11% n=220 Acarbose ≤100 mg tidDrug naïve N=661* n=441 Vildagliptin 50 mg bid 24 weeks2 weeks
    • 122. Vildagliptin is as effective as acarbose but with half the incidence of gastrointestinal side effects Change in HbA1c is expressed for ITT population. Gastrointestinal adverse events reports from the safety population; ***p<0.001 vs acarbose BL=core baseline; CI=confidence interval; EP=study end point; HbA1c=glycosylated hemoglobin NI: Non-inferiority of vildagliptin as compared to acarbose demonstrated; 95% CI (-0.32, -0.10); statistical significance for non-inferiority margin defined by CI upper limit of 0.4%. Pan C. et al. Diabeteic Medicine. 2008. 25:435-441 Change from BL to EP* (BL Mean ~8.6) Vildagliptin 50 mg bid Acarbose ≤100 mg tid MeanChangeinHbA1c(%) 12.3 25.5 0 5 10 15 20 25 30 (%patientsreporting GIadverseevents) Gastrointestinal adverse events n= 440 220n= 441 220 *** NI -1.4 -1.3 -1.5 -1 -0.5 0
    • 123. Vildagliptin monotherapy vs voglibose in Japanese population: study design and objective n=188 Vildagliptin 50 mg BID 12 weeks Objective: To compare the efficacy and tolerability of vildagliptin vs voglibose, an α-glucosidase inhibitor, in a Japanese population with T2DM. Design: Randomized, double-blind, active-controlled, parallel- arm 12 weeks study. N=380 n=192 Voglibose 0.2 mg TID T2DM=type 2 diabetes mellitus. Vildagliptin monotherapy is not approved in EU, please refer to your local label (SmPC). Vildagliptin monotherapy is approved in Japan (Japan label). 2 weeks Drug-naïve Iwamoto Y et al. Diab Obes Metab 2010, 12:700-708.
    • 124. AdjustedMeanChangein HbA1c(%) 188 192n= Vildagliptin monotherapy is superior to voglibose monotherapy in Japanese population Change from BL to Wk 12 Mean BL ~ 7.5 % Voglibose 0.2 mg tid Vildagliptin 50 mg bid •p< 0.001 vs voglibose Iwamoto Y et al. Diab Obes Metab 2010, 12:700-708. At 12 weeks treatment Vildagliptin monotherapy is not approved in EU, please refer to your local label (SmPC). Vildagliptin monotherapy is approved in Japan (Japan label). Target HbA1c ≤6.5% Reduction ≥ 1.0% %patientsreachingtarget n 65 65 71 72 -0.95 * -0.38 -1 -0.8 -0.6 -0.4 -0.2 0
    • 125. % patients Vildagliptin 50 md BID (n=188) Voglibose 0.2 mg TID (n=192) Any AE 61.2 71.4 Serious AE 0.0 2.1 Suspected drug-related AE 25.0 40.6 DC due to AE 2.1 2.1 Hypoglycemia 0.0 0.5 Gastrointestinal AE 18.6** 32.8 Specific AEs occurring in >4% of either group Nasopharyngitis 18.1 16.7 Constipation 6.9 6.8 Flatulence 3.2 12.0 Abdominal distension 2.1 7.3 Diarrhoea 1.6 5.7 ↑ Alanine aminotransferase 1.6 5.7 Better GI tolerability with vildagliptin monotherapy vs voglibose monotherapy in Japanese population **P=0.002 vs voglibose. AE=adverse event; DC=discontinuation. Iwamoto Y et al. Diab Obes Metab 2010, 12:700-708. Vildagliptin monotherapy is not approved in EU, please refer to your local label (SmPC). Vildagliptin monotherapy is approved in Japan (Japan label).
    • 126. 7) Vildagliptin in combination therapy settings 7.1) Vildagliptin on top of metformin demonstrates favorable efficacy and tolerability profile
    • 127. Effects of vildagliptin and vildagliptin plus metformin on fasting GLP-1 levels 0 2 4 6 8 10 12 14 * IntactGLP-1(pM) Fasting Levels of Intact GLP-1 at Baseline and at 3 Months BL=baseline; GLP-1=glucagon-like peptide-1; met=metformin; PBO=placebo; vilda=vildagliptin. *P <0.05 vildagliptin 3 months vs baseline; **P <0.05 vildagliptin add-on metformin significantly improved at 3 months vs baseline. †Contains patients on vildagliptin alone and those on vildagliptin plus metformin. D’Alessio DA, et al. J Clin Endocrinol Metab. 2009; 94: 81-88. Vilda group† Placebo BL BL3 months 3 months n = 20 20 19 19 IntactGLP-1(pM) ** 0 2 4 6 8 10 12 14 Vilda only Fasting Levels of Intact GLP-1 in Vildagliptin Subgroups at 3 Months Vilda + met 7 13 Vildagliptin dosing: 50 mg bid
    • 128. Vildagliptin add-on to metformin: significantly lowers HbA1c over 52 weeks 6.8 7.2 7.6 8.0 8.4 −4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Week Vilda 50 mg daily + met (extension, ITT n=42) PBO + met (extension, ITT n=29) Vilda 50 mg daily + met (core, ITT n=56) PBO + met (core, ITT n=51) HbA1c(%) P <0.0001 P <0.0001  –1.1 ± 0.2% n refers to ITT population. HbA1c=hemoglobin A1c; ITT=intention-to-treat; met=metformin; PBO=placebo; vilda=vildagliptin. Adapted from Ahrén B, et al. Diabetes Care. 2004; 27: 2874–2880. Duration: 52 weeks Vilda add-on to met
    • 129. Vildagliptin add-on to metformin: study design and objective Objective: to demonstrate superior HbA1c reduction with vildagliptin + metformin vs metformin monotherapy Target population: T2DM on maximal dose of metformin; HbA1c 7.5–11% HbA1c=hemoglobin A1c; T2DM=type 2 diabetes mellitus. *Patient number refers to primary intention-to-treat population. Bosi E, et al. Diabetes Care. 2007; 30: 890–895. n=130: Placebo + metformin n=143: Vildagliptin 50 mg twice daily + metformin n=143: Vildagliptin 50 mg once daily + metformin 24 weeks Metformin >1500 mg (monotherapy, stable dose) 4 weeks N=416*
    • 130. Vildagliptin produces clinically meaningful, dose related decreases in A1C and FPG as add-on therapy to metformin. Placebo + metformin (n=130) Vildagliptin 50 mg twice daily + metformin (n=143) Vildagliptin 50 mg once daily + metformin (n=143) FPG=fasting plasma glucose; HbA1c=hemoglobin A1c. *P <0.001; **P=0.003 vs placebo; ***P <0.001 vs placebo. Primary intention-to-treat population. Bosi E, et al. Diabetes Care. 2007; 30: 890–895. 7.2 7.4 7.6 7.8 8.0 8.2 8.4 8.6 −4 0 4 8 12 16 20 24 Time (Weeks) MeanHbA1c(%) −0.7% vs placebo −1.1% vs placebo * * Duration: 24 weeks Vildagliptin add-on to metformin Time (Weeks) MeanFPG(mmol/L) −4 0 4 8 12 16 20 24 8 9 10 11 −0.8 vs placebo −1.7 vs placebo ** *** Duration: 24 weeks Vildagliptin add-on to metformin Add-on Treatment to Metformin (2.1 g Mean Daily) Reduction in HbA1c Reduction in FPG
    • 131. Vildagliptin: enhances β-cell function and improves PPG when metformin alone is not sufficient AUC=area under the curve; ISR=insulin secretion rate; met=metformin; PBO=placebo; PPG=postprandial glucose; vilda=vildagliptin. *P ≤0.001 vs PBO. Bosi E, et al. Diabetes Care. 2007; 30: 890–895. Vilda 50 mg twice daily + met (n=57) β-cell Function Placebo-adjusted values AdjustedMeanChangein ISRAUC/GlucoseAUC * * 5.2 5.7 0.0 2.0 4.0 6.0 8.0 10.0 AdjustedMeanChangein 2-hPPG(mmol/L) * * -1.9 -2.3 -3.0 -2.0 -1.0 0.0 Vilda 50 mg once daily + met (n=53) Duration: 24 weeks Vilda add-on to met 2-h PPG Placebo-adjusted values
    • 132. Vildagliptin: efficacious in elderly and obese patients and those with poorly controlled T2DM BL=baseline; BMI=body mass index; HbA1c=hemoglobin A1c; met=metformin; PBO=placebo; T2DM=type 2 diabetes mellitus; vilda=vildagliptin. Primary intention-to-treat population. Data on file, Novartis Pharmaceuticals, LAF237A2303. >65 years Mean BL ~8.3% BL BMI >30 kg/m2 Mean BL ~8.3% Vilda 50 mg twice daily + met PBO + met ChangefromBLinHbA1c(%) n= 20 22 103 86 29 29 BL HbA1c >9% Duration: 24 weeks Vilda add-on to met Add-on Treatment to Metformin (2.1 g Mean Daily)
    • 133. Primary objective: To compare efficacy and safety of vildagliptin as add-on to metformin Target population: Chinese T2DM patients not controlled (HbA1c 6.4-10.8%) on a stable metformin monotherapy n=144 Placebo + Metformin ‡ N = 438 n= 146 Vildagliptin 50 mg bid + Metformin‡ 2 weeks 24 weeks Metformin n= 148 Vildagliptin 50 mg qd + Metformin‡ ‡ metformin dose >= 1500 mg daily Vildagliptin add on to metformin in Chinese patients : Study design and objective Data on file LAF237A23140
    • 134. Vildagliptin add on to metformin in Chinese patients : significant improvement in HbA1c, FPP and PPG Note: 50 qd data for HbA1c change vs baseline were secondary endpoint Data on file LAF237A23140 Table s 11-4, 11-5, 11.7, 11-8, Figure 11.1 Change in FPG (mmol/L) from baseline to endpoint Change in 2h prandial glucose from baseline to end point Vilda 50 mg qd Vilda 50 mg bid placebo * P<0.001 vs. Placebo ** P=0.001 vs. Placebo *** P<0.05 vs Placebo ** * Adjustedmeanchange *** *** Adjustedchangein2-hrprandial glucose(mmol/L) N=40 N=46 N=44 N=147 N=145 N=144 * ** HbA1c reduction BL 8.768.788.72 BL 13.1313.4912.29
    • 135. Vildagliptin increases number of patients reaching targets in Chinese patients not controlled with metformin Reduction HbA1c <7.0% at end point Reduction HbA1c <= 6.5% at end point *p =0.018 vs placebo; ** p=0.002 vs placebo; *** p=0.222 vs placebo; ****p=0.061 Data on file LAF237A23140, Table 11-6 48.9 26.2 53.7 29.7 34.8 20.1 0 10 20 30 40 50 60 70 vilda 50 qd + met vilda 50 mg bid + met Placebo n / N = 67/147 73 / 145 48/144 38/147 43/145 29/144 ** *** * **** %patientsreachingtarget
    • 136. Preferred term Vilda 50 mg qd* Vilda 50 mg bid Placebo Diarrhea 3.4 4.1 2.1 Papitations 2.7 2.7 1.4 Urinary tract infection 2.7 0.7 0.0 Dizziness 2.7 2.7 2.1 Diabetic nephropathy 2.7 0.7 2.8 Nasopharyngitis 2.0 0.7 2.8 Nausea 1.4 0.7 3.5 Hyperhidrosis 0.7 3.4 2.1 Abdominal disconfort 0.0 0.7 2.8 Vildagliptin add on to metformin in Chinese patients : % patients reporting AEs (≥ 2.5% in any group) Safety population **Vildagliptin 100 mg once daily is not a therapeutic dose according to the Basic Prescribing Information document Data on file LAF237A23140 Table 12-3
    • 137. Vildagliptin vs pioglitazone as add-on to metformin: study design and objective Primary objective: to compare efficacy and safety of vildagliptin 50 mg twice daily vs pioglitazone 30 mg once daily both as add-on to metformin during 52 (with interim analysis at 24 weeks) Target population: patients with T2DM inadequately controlled with metformin monotherapy (baseline HbA1c 7.5–11%) n=281: Pioglitazone 30 mg once daily + metformin N=576* n=295: Vildagliptin 50 mg twice daily + metformin 24 weeks4 weeks 28 weeksInterim analysis Double-blind1 Single-blind2 Metformin ≥1500 mg HbA1c=haemoglobin A1c; T2DM=type 2 diabetes mellitus. 1Bolli G, et al. Diabetes Obes Metab. 2008; 10: 82–90; 2 Bolli G, et al. Diabetes Obes Metab. 2009; 11: 589–595.
    • 138. -1.0 -1.5-1.5 -0.9 -1.8 -1.6 -1.4 -1.2 -1.0 -0.8 -0.6 -0.4 -0.2 0.0 In patients uncontrolled with metformin vildaglipitn achieves similar HbA1c drop compared with pioglitazone Overall Mean BL ~8.4% BL=baseline; HbA1c=hemoglobin A1c; met=metformin; pio=pioglitazone; vilda=vildagliptin. Per protocol population. *Non-inferiority of vildagliptin to pioglitazone established at both 0.4% and 0.3% margins, 95% confidence interval=(-0.05, 0.26). Adjusted mean change derived from analysis of covariance model. Bolli G, et al. Diabetes Obes Metab. 2008; 10: 82–90. AdjustedMean ChangeinHbA1c(%) HbA1c >9% Mean BL ~9.7% n = 264 246 Pio 30 mg once daily + met Vilda 50 mg twice daily + met 63 58 Non-inferior* Duration: 24 weeks Add-on to met: vilda vs pio Add-on Treatment to Metformin (2.0 g Mean Daily)
    • 139. In patients uncontrolled with metformin vildagliptin is the only DPP-4 inhibitor showing similar efficacy to pioglitazone at 1 year without weight gain HbA1c=hemoglobin A1c, NI=non-inferiority, * P<0.001 pio vs BL Intention-to-treat population. Vildagliptin (n=295); pioglitazone (n=281). Bolli G, et al. Diabetes Obes Metab. 2009; 11: 589–595. Vildagliptin 50 mg bid + metformin Pioglitazone 30 mg od + metformin 24-week analysis Vilda NI established −4 0 4 12 16 24 32 40 52 Time (Weeks) 7.0 7.5 8.0 8.5 9.0 MeanHbA1c(%) Duration: 52 weeks add-on to metformin: vildagliptin vs pioglitazone n=277n=293 UnadjustedMean ChangeinBodyWeight(kg) * Change in Body Weight (Mean BL Body Weight ~91 kg) *P <0.001 change from baseline Change in HbA1c 0.2 2.6 0.0 0.5 1.0 1.5 2.0 2.5 3.0
    • 140. Vildagliptin vs. glimepiride as add-on to metformin: study design and objective Study purpose: To demonstrate long-term efficacy and safety of add-on therapy with vildagliptin vs glimepiride in patients with T2DM inadequately controlled with ongoing metformin monotherapy Interim analysis: To demonstrate non-inferiority of vildagliptin vs glimepiride at 1 year Target population: Patients with T2DM inadequately controlled on stable metformin monotherapy (metformin minimum dose 1500 mg/day; baseline HbA1c 6.5–8.5%) n=1393: Glimepiride up to 6 mg once daily + metformin n=1396: Vildagliptin 50 mg twice daily + metformin 4 weeks Metformin HbA1c=haemoglobin A1c; SU=sulfonylurea; T2DM=type 2 diabetes mellitus.* Randomised population. Ferrannini E et al. Diabetes Obes Metab 2009; 11: 157–166. 1-year interim analysis N=2789* 104 weeks
    • 141. In patients uncontrolled with metformin monotherapy vildagliptin is as effective as glimepiride over 1 year with low incidence of hypoglycaemia and no weight gain Glimepiride up to 6 mg once daily + metformin Vildagliptin 50 mg twice daily + metformin Number of hypoglycaemic events Patients with 1 hypos (%) Number of severe hypoglycaemic events c Incidence(%) 1389 1383 1389 1383 1389 1383n = No.ofevents No.ofevents 16.2 1.7 39 554 Duration: 52 weeks, add-on to metformin: vildagliptin vs glimepiride Mean HbA1c reduction a Incidence of hypoglycaemia b BL=baseline; CI=confidence interval NI=non-inferiority; aPer protocol population ; bSafety population. cGrade 2 or suspected grade 2 events. *P <0.001; adjusted mean change from BL to Week 52, between-treatment difference and P value were from an ANCOVA model containing terms for treatment, baseline and pooled centre. Ferrannini E et al. Diab Obes Metab 2009; 11: 157–166. MeanHbA1c(%) 0.0 6.5 6.7 6.9 7.1 7.3 7.5 -8 -4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 NI: 97.5% CI (0.02, 0.16) −0.4% −0.5% Time (weeks) Adjustedmeanchangein bodyweight(kg)fromBL (BL mean ~88.8kg) 1117n = 1071 Change in body weight a
    • 142. No.ofevents Duration: 104 weeks, add-on to metformin: vildagliptin vs glimepiride Hypoglycaemia 2 1) Per protocol population. 2) Safety population. 3) Intent-to-treat population. a) any episode requiring the assistance of another party *p <0.001. BL=baseline; EP = week 104 endpoint; Met= metformin; hypo = hypoglycemia; HbA1c= glycosylated hemoglobin. Matthews DR et al. Diab Obes Metab 2010; 12: 780–789. Vildagliptin was as effective as glimepiride when added to metformin at 104 weeks with no weight gain and low incidence of hypoglycemia No.ofevents Incidence(%) 18.2 Patients with > 1 hypo (%) Discontinuations due to hyposNumber of severe events aNumber of hypo events 1553 1546N = Glimepiride up to 6 mg qd +met Vildagliptin 50 mg bid + met No.ofevents 59 1553 1546N = 1553 1546N = 1553 1546N = Mean HbA1c 1 Adjusted mean change in HbA1c was comparable between vildagliptin and glimepiride treatment: −0.1% (0.0%) for both Primary objective of non-inferiority was met: 97.5% CI= (-0.00, 0.17); upper limit 0.3% 0 13 0 2 4 6 8 10 12 14 16 0 15 0 2 4 6 8 10 12 14 16 -0.3 -1.5 1.2 -2.0 -1.0 0.0 1.0 2.0Adjustedmeanchange inbodyweight(kg) 1539n = 1520 * Change in body weight 3 Change from BL to EP (BL Mean ~89kg) Between-treatment Difference
    • 143. AE preferred term, % patients Vilda 50 mg bid + met n=1553 Glim up to 6 mg + met n=1546 Any AE 83.1 86.4 Nasopharyngitis 14.7 13.6 Headache 9.6 9.2 Back pain 9.4 9.5 Bronchitis 9.1 7.3 Dizziness 8.2 16.0 Arthralgia 7.8 6.3 Influenza 7.6 6.4 Diarrhoea 7.4 7.3 Hypertension 6.7 8.1 Upper respiratory tract infection 6.6 5.2 Vildagliptin vs. glimepiride as add-on to metformin: AEs with incidence 5% in any group AE preferred term, % patients Vilda 50 mg bid + met n=1553 Glim up to 6 mg + met n=1546 Cough 6.2 5.4 Pain in extremity 5.7 6.3 Fatigue 5.4 8.0 Osteoarthritis 5.2 4.3 Asthenia 5.0 11.7 Nausea 4.9 6.0 Tremor 4.8 21.7 Hyperhidrosis 4.5 18.7 Oedema peripheral 2.9 5.0 Hypoglycaemia 2.3 18.2 Hunger 0.9 5.2 Safety population; orange highlighted: hypoglycaemia and symptoms suggestive of hypoglycaemia. AE=adverse event; bid=twice daily; glim=glimiperide; met=metformin; vilda=vildagliptin. Matthews DR et al. Diab Obes Metab 2010; 12: 780–789.
    • 144. Study purpose: to compare the effect of 52 weeks treatment with Vidagliptin 50 mg bid to gliclazide up to 320 mg daily as add-on therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy Target population: T2DM patients inadequately controlled on a stable metformin monotherapy (baseline HbA1c 7.5-11%) n=494 Gliclazide up to 320 mg# + Met‡ N** = 1007 n=513 Vildagliptin 50 mg bid + Met‡ 4 weeks 52 weeks Metformin‡ Filozof and Gautier. Diabetes Medicine. 2010; 27: 318-326. Vildagliptin vs. gliclazide as add on to metformin: study design and objective **Randomized population; ‡ met minimum dose 1500 mg/d; #Gliclazide was titrated from 80 mg initial dose to a maximum daily dose of 320 mg; Patients on gliclazide were titrated to the next dose level at weeks 4 (to 160 mg), 8 (to 240 mg), and 12 (to 320 mg), if the fasting plasma glucose was > 7 mmol/L (126 mg/dL) or fasting blood glucose was > 6.3 mmol/L (113 mg/dL) and titration was not contraindicated in the investigator’s opinion due to the risk of hypoglycemia T2DM= Type 2 diabetes mellitus; Met= metformin; HbA1c= glycosylated hemoglobin.
    • 145. Filozof and Gautier. Diabetes Medicine. 2010; 27: 318-326. Change Body weightb from BL to week 52 Glic up to 320 mg + Met Vilda 50 mg bid + Met 5 / 510 5 / 493n/N= Number of hypoglycemic events# Patients with one or more hypos (%) Incidence(%) Numberofevents 510 493N= Mean BL ~ 85 kg Glic= gliclazide; Met= metformin; Vilda= vildagliptin; BL= baseline; EP= end point; * p<0.001 Vilda vs Glic, 95% CI (-1.77, -0.79), adjusted mean change from BL to EP; b) per protocol population; c) safety population; # All hypoglycemic events: grade 1 Mean HbA1c EP Hypoglycemic eventsc Mean difference of adjusted values: 0.04% 95%CI: -0.11, 0.20 Vildagliptin provides similar HbA1c reduction as gliclazide but with a better tolerability profile -0.81% vilda + met -0.84 glic +met Non-inferior MeanHbA1c(%) 7 7.5 8 8.5 9 -4 0 4 12 16 24 32 40 52 56 Time (Week) AdjustedMeanChange inbodyweight(kg) 386 393N= 0.08 1.36 0.0 0.4 0.8 1.2 *
    • 146. Vildagliptin vs. gliclazide as add on to metformin: AEs with incidence in ≥4% in any group Safety population; orange highlighted: hypoglycaemia and symptoms suggestive of hypoglycaemia AEs= adverse events; Vilda= vildagliptin; Glic= gliclazide; Met= metformin Filozof and Gautier. Diabetes Medicine. 2010; 27: 318-326. AE preferred term, % patients Vilda 50 mg bid + Met N=510 % (n) Glic up to 320 mg + Met N=493 Any AE 61.8 (315) 61.3 (302) Nasopharyngitis 6.3 (32) 5.7 (28) Hypertension 5.7 (29) 6.3 (31) Diarrhea 5.1 (26) 5.5 (27) Headache 3.1 (16) 5.7 (28) Pain in extremity 2.7 (14) 4.5 (22) Asthenia 2.2 (11) 4.9 (24) Bronchitis 2.0 (10) 4.1 (20) Fatigue 2.0 (10) 4.1 (20) Tremor 1.8 (9) 4.9 (24) Hyperhidrosis 1.4 (7) 5.3 (26)
    • 147. Initial combination of vildagliptin and metformin: study design and objectives Primary objective: to demonstrate efficacy of single-pill combination therapy of vildagliptin and metformin compared with individual monotherapy in drug-naïve patients with T2DM in a multicenter, randomized, double-blind, active-controlled study Target population: drug-naïve patients with T2DM (HbA1c 7.5–11%) *Randomized population. HbA1c=hemoglobin A1c; met=metformin; T2DM=type 2 diabetes mellitus; vilda=vildagliptin. Bosi E, et al Diabe Obes Metab. 2009; 11: 506–515. Met 500 mg qd Met 500 mg bid Met 1000 mg AM Met 500 mg PM Metformin 1000 mg bid Vilda 50 mg qd Vildagliptin 50 mg bidn=300 n=294 Vilda / met 50/500 mg qd Low dose: vilda / met 50/500 mg bidn=290 50/1000 mg AM 50/500 mg PM High dose: vilda / met 50/1000 mg bidn=295 50/500 mg bid Screening Titration Maintenance N=1179* 2 weeks 2 weeks 2 weeks 2 weeks 18 weeks 24 weeks Vilda/met 50/500 qd
    • 148. Initial combination of vildagliptin + metformin provides significantly more HbA1c reductions than the monotherapies MeanChangeinHbA1c(%) Intention-to-treat population. HbA1c=hemoglobin A1c; HD=high dose; LD=low dose; met=metformin; vilda=vildagliptin. Bosi E, et al. Diab Obes Metab. 2009; 11: 506–515. n = 287 277 Change from Baseline to End Point Mean Baseline HbA1c ~8.6% 285 285 P <0.001 P=0.004 P <0.001 P <0.001 Vilda + HD met (50/1000 mg bid) Vilda + LD met (50/500 mg bid) Met 1000 mg bid Vilda 50 mg bid Duration: 24 weeks Vilda + met vs mono
    • 149. Initial combination of vildagliptin + metformin: robust change in FPGMeanChangeinFPG(mmol/L) P <0.001 P=0.999* P <0.001 P <0.001 Vilda + HD met (50/1000 mg bid) Vilda + LD met (50/500 mg bid) Met 1000 mg bid Vilda 50 mg bid Change from Baseline to End Point Mean baseline FPG ~10.4 mmol/L 287 277285 285n = Duration: 24 weeks vilda + met vs mono Intention-to-treat population. FPG=fasting plasma glucose; HD=high dose; LD=low dose; met=metformin; vilda=vildagliptin. Bosi E, et al. Diabetes Obes Metab. 2009; 11: 506–515; *Data on file, Novartis Pharmaceuticals, LMF237A2302.
    • 150. Initial combination of vildagliptin and metformin: effective across the hyperglycemia spectrum (data from core study and open-label sub-study) ~9.9% 96 Change from BL to EP ~8.7% 285 Overall* >9% High BL Open-label Sub-studyb MeanChangeinHbA1c(%) ≥10% ~10. 6% 35 ~9.2% 201 >8% Subgroups by BL HbA1ca *P <0.001 vs BL; **100 mg once daily is not a recommended dosing regimen. Intent-to-treat population. aRaw mean change from baseline; bLS (least-square) mean change from baseline. BL=baseline; EP=end point; HbA1c=glycosylated hemoglobin; met=metformin; vilda=vildagliptin. Bosi E, et al. Diabetes Obes Metab. 2009; 11: 506–515; a Data on file, Novartis Pharmaceuticals, LMF237A2302 and LMF237A2302S1. Vilda 100 mg daily** + met 2000 mg daily open-label sub-study (P <0.001 vs BL)d High-dose vilda + met (50/1000 mg twice daily)c BL mean= n = >11% ~12. 1% 86 * Duration: 24 weeks Vilda + met vs mono As with traditional OADs, vildagliptin as add-on to metformin substantially reduces HbA1c in patients with high baseline levels
    • 151. 7.2) Vildagliptin significantly reduces HbA1c in patients uncontrolled with only SU or TZD
    • 152. Vildagliptin add-on to maximum-dose pioglitazone: study design and objective 4 weeks 24 weeks Pioglitazone 45 mg daily N=398* n=138: Placebo + pioglitazone 45 mg daily n=136: Vildagliptin 50 mg twice daily + pioglitazone 45 mg daily n=124: Vildagliptin 50 mg once daily + pioglitazone 45 mg daily Objective: to demonstrate that HbA1c reduction with vildagliptin (50 mg once daily or 50 mg twice daily) is superior to that with placebo after 24 weeks of treatment as add-on to pioglitazone therapy Target population: patients with T2DM inadequately controlled with prior thiazolidinedione monotherapy (HbA1c 7.5–11%) HbA1c=hemoglobin A1c; T2DM=type 2 diabetes mellitus. *Patient number refers to primary intention-to-treat population. Garber A et al. Diabetes Obes Metab. 2007; 9: 166–174.
    • 153. Vildagliptin as add-on to pioglitazone effectively decreased HbA1c levels in patients inadequately controlled with a maximum dose of TZD monotherapy HbA1c=hemoglobin A1c; PBO=placebo; pio=pioglitazone; vilda=vildagliptin. *P ≤0.001 vs PBO. Primary intention-to-treat population. Garber A et al. Diabetes Obes Metab. 2007; 9: 166–174. PBO + pio 45 mg daily (n=138) Vilda 50 mg once daily + pio (n=124) Vilda 50 mg twice daily + pio (n=136) Time (Weeks) MeanHbA1c(%) 7.4 7.6 7.8 8.0 8.2 8.4 8.6 8.8 9.0 −4 0 4 8 12 16 20 24 * * –0.5% vs PBO –0.7% vs PBO Duration: 24 weeks Add-on to pio: vilda vs PBO Add-on Treatment to Pioglitazone 45 mg Daily
    • 154. Vildagliptin add-on to glimepiride: study design and objective HbA1c=hemoglobin A1c; SU=sulfonylurea; T2DM=type 2 diabetes mellitus. *Patient number refers to primary intention-to-treat population. Garber A et al. Diabetes Obes Metab. 2008; 10: 1047–1056. 4 weeks Glimepiride 4 mg daily N=408* n=144: Placebo + glimepiride 4 mg once daily n=132: Vildagliptin 50 mg twice daily + glimepiride 4 mg once daily n=132: Vildagliptin 50 mg once daily + glimepiride 4 mg once daily 24 weeks Objective: to demonstrate superior HbA1c reduction with vildagliptin + glimepiride vs placebo + glimepiride Target population: patients with T2DM not adequately controlled with an SU; HbA1c 7.5–11%
    • 155. HbA1c=hemoglobin A1c; PBO=placebo; SU=sulfonylurea; vilda=vildagliptin. *P <0.001 vs PBO. Primary intention-to-treat population. Garber A et al. Diabetes Obes Metab. 2008; 10: 1047–1056. Vildagliptin as add-on to glimepiride produces clinically meaningful reductions in HbA1c levels in patients with T2DM not adequately treated with a sulfonylurea −0.6% vs PBO −0.7% vs PBO Time (Weeks) 7.6 7.8 8.0 8.2 8.4 8.6 8.8 9.0 −4 0 4 8 12 16 20 24 MeanHbA1c(%) PBO + glimepiride (n=144) Vilda 50 mg once daily + glimepiride (n=132) Vilda 50 mg twice daily + glimepiride (n=132) * * Duration: 24 weeks Add-on to SU: vilda vs PBO Add-on Treatment to an SU (Glimepiride 4 mg Once Daily)
    • 156. Objective: To demonstrate the efficacy of add-on therapy with vildagliptin to glimepiride in patients with type 2 diabetes inadequately controlled with prior glimepiride monotherapy Design: Randomized, double-blind, placebo-controlled, parallel-arm study Study population: patients with T2DM inadequately controlled on a stable glimepiride monotherapy (dose≥1mg/d, baseline HbA1c 7.0–10.0%) n=102 Vildagliptin 50 mg BID + Glimepiride (up to 1mg OD) 12 weeks N=202 n=100 Placebo + Glimepiride (up to 1mg OD) Glimepiride Efficacy and tolerability of vildagliptin as add-on to glimepiride in Japanese patients with Type 2 Diabetes T2DM=type 2 diabetes mellitus. Kikuchi M et al. Diab Res Clin Pract. 2010; 89:216-223. Vildagliptin 50 mg qd as add on to SU is approved in EU (SmPC). Vildagliptin as add on to SU 50 mg qd or bid is approved in Japan (Japan label).
    • 157. MeanHbA1c(%) 6.5 7.5 8.5 -2 0 2 4 8 12 Vilda+Glim Placebo+Glim 8.0 7.0 6.0 Time (week) Vildagliptin as add-on to glimepiride in Japanese patients: significant HbA1c drop -1.2 -1.0 -0.8 -0.6 -0.4 -0.2 0.0 Vilda+Glim (N=102) Placebo+Glim (N=100) - 1.00 - 0.06 LSMeanchangeinHbA1c(%) p<0.001 Mean HbA1C±SD; Full Analysis Set (FAS) population Kikuchi M et al. Diab Res Clin Pract. 2010; 89:216-223. LS (Least square) mean change ±SD; FAS population; P-value, ANCOVA Vildagliptin 50 mg qd as add on to SU is approved in EU (SmPC). Vildagliptin as add on to SU 50 mg qd or bid is approved in Japan (Japan label).
    • 158. Higher responder rates with vildagliptin as add-on to glimepiride vs placebo in Japanese patients FAS population; p-value, chi-square test; 1) Subjects with HbA1c ≤ 6.5% at endpoint / subjects with HbA1c > 6.5% at baseline (%) 2) N’ is the number of subjects with observations at both baseline and endpoint. %: percentages based on N’ Achieved HbA1c≤6.5%1,2 ≥1.0% decreasing in HbA1c2 Vilda+Glim (N=102) Placebo+Glim (N=100) Vilda+Glim (N=102) Placebo+Glim (N=100) 45.0 3.0 54.9 5.0 0 20 40 60 80 (%) 0 20 40 60 80 (%) p<0.001 p<0.001 Kikuchi M, et al. Diab Res Clin Pract 2010 89:216-223. Vildagliptin 50 mg qd as add on to SU is approved in EU (SmPC). Vildagliptin as add on to SU 50 mg qd or bid is approved in Japan (Japan label).
    • 159. 8) Vildagliptin: the power of mechanistic evidence 8.1) Vildagliptin enhances islet function by improving α- and β-cell sensitivity to glucose restoring the physiological balance between glucagon and insulin
    • 160. Acute effects of vildagliptin on insulin, glucose and glucagon levels in patients with T2DM OGTT 30 min after Single Oral Dose of Vildagliptin (100 mg qd**) OGTT=oral glucose tolerance test. *P <0.01. ** 100 mg qd is NOT an approved dose. He YL, et al. J Clin Pharmacol. 2007; 47: 633–641. Vildagliptin 100 mg once daily was used in this study. Galvus (vildagliptin) is approved for 50 mg once or twice daily in combination with metformin or a TZD, and Galvus (vildagliptin) 50 mg once daily in combination with a sulfonylurea. 7.5 12.5 17.5 22.5 Glucose (mmol/L) 0 60 80 100 120 40 20 Insulin (pmol/L) 60 80 100 120 140 Glucagon (ng/L) −90 −60 −30 0 30 60 90 120 150 180 210 240 270 300 −90 −60 −30 0 30 60 90 120 150 180 210 240 270 300 −90 −60 −30 0 30 60 90 120 150 180 210 240 270 300 Time Vildagliptin 100 mg** (n=15) Placebo (n=16) 75 g Glucose Dose
    • 161. Meal * * * * * * * * * * * * Vildagliptin 100 mg (n=16) Placebo (n=16) Acute effects of vildagliptin on GLP-1 levels in patients with T2DM: increased GLP-1 levels that persist beyond the post-meal period GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus. *P <0.05. Balas B, et al. J Clin Endocrinol Metab. 2007; 92: 1249–1255. Vildagliptin 100 mg once daily was used in this study. Galvus (vildagliptin) is approved for 50 mg once or twice daily in combination with metformin or a TZD, and Galvus (vildagliptin) 50 mg once daily in combination with a sulfonylurea. Galvus is NOT approved for 100 mg qd, 0.0 4.0 8.0 12.0 16.0 17:00 20:00 23:00 02:00 05:00 08:00 Time ActiveGLP-1(pmol/L) * 161
    • 162. Acute effects of vildagliptin on glucagon levels in patients with T2DM: decreased glucagon levels persist beyond the post-meal period Meal * * ** * * * * *P <0.05 vs placebo. Balas B, et al. J Clin Endocrinol Metab. 2007; 92: 1249–1255. Vildagliptin 100 mg once daily was used in this study. Galvus (vildagliptin) is approved for 50 mg once or twice daily in combination with metformin or a TZD, and Galvus (vildagliptin) 50 mg once daily in combination with a sulfonylurea. Galvus is NOT approved for 100 mg qd, −60 −50 −40 −30 −20 −10 0 10 20 17:00 Time DeltaGlucagon(ng/L) 20:00 23:00 02:00 05:00 08:00 Placebo (n=16) Vildagliptin 100 mg (n=16) * 162
    • 163. Acute effects of vildagliptin on endogenous glucose production (EGP) levels in patients with T2DM: decreased EGP levels persist beyond post-meal period EGP=endogenous glucose production. *P <0.05 vs placebo. Balas B, et al. J Clin Endocrinol Metab. 2007; 92: 1249–1255. Vildagliptin 100 mg once daily was used in this study. Galvus (vildagliptin) is approved for 50 mg once or twice daily in combination with metformin or a TZD, and Galvus (vildagliptin) 50 mg once daily in combination with a sulfonylurea. Galvus is NOT approved for 100 mg qd, 0 −0.3 −0.6 −0.9 −1.2 −1.5 DeltaEGP(mg/kg/min) 17:00 20:00 23:00 02:00 05:00 08:00 Time ********* * * * **************** Placebo (n=16) Vildagliptin 100 mg (n=16) Meal
    • 164. Acute effects of vildagliptin on insulin secretion rates in patients with T2DM: increased rate persists beyond the post-meal period AUC=area under the curve; ISR=insulin secretion rate. *P <0.05. ** 100 mg qd is NOT an approved dose. Balas B, et al. J Clin Endocrinol Metab. 2007; 92: 1249–1255. Vildagliptin 100 mg once daily was used in this study. Galvus (vildagliptin) is approved for 50 mg once or twice daily in combination with metformin or a TZD, and Galvus (vildagliptin) 50 mg once daily in combination with a sulfonylurea. ISR(AUC)/glucose(AUC) 100(pmol•kg-1•min-1)/(mg/dL) 0 2 4 6 8 18:00 * * * *** * * * * * * * * * * * * * * * Time 20:00 23:00 02:00 05:00 08:00 Placebo (n=16) Vildagliptin 100 mg qd** (n=16) * * Meal
    • 165. Comparison of plasma GLP-1 levels following 3 Months’ treatment with vildagliptin or sitagliptin GLP-1=glucagon-like peptide-1. *P <0.05 vs vildagliptin group, Plasma levels during 24-h sampling comprising three standardized meals after 3 months of treatment in type 2 diabetic patients. Marfella R, et al. J Diabetes Complications. 24: 79-83, 2010.. 30 25 20 15 10 5 0 -20 0 15 30 60 90 120 180 240 300 0 15 3060 90 120 180 240 300 0 15 3060 90 120 180 240 300 min Breakfast Lunch Dinner IntactGLP-1(pmol/L) Sitagliptin 100 mg once daily + metformin (N=20) Vildagliptin 50 mg twice daily + metformin (N=18) Retrospective analysis of patients on sitagliptin (N=20) or vildagliptin (N=18)
    • 166. Comparison of plasma glucagon levels following 3 Months’ treatment with vildagliptin or sitagliptin Sitagliptin 100 mg once daily + metformin (N=20) Vildagliptin 50 mg twice daily + metformin (N=18) *P <0.05 vs vildagliptin group; Plasma levels during 24-h sampling comprising three standardized meals after 3 months of treatment in type 2 diabetic patients. Marfella R, et al. J Diabetes Complications. 24: 79-83, 2009. 90 80 70 60 50 40 30 20 Breakfast Lunch Dinner PlasmaGlucagon(mg/dL) -20 0 15 30 60 90 120 180 240 300 0 15 3060 90 120 180 240 300 0 15 3060 90 120 180 240 300 min Retrospective analysis of patients on sitagliptin (N=20) or vildagliptin (N=18)
    • 167. Vildagliptin improves β-cell sensitivity to glucose Vildagliptin 50 mg once daily Placebo Mari A, et al. J Clin Endocrinol Metab. 2008; 93: 103–109. Secretionat7mMglucose (pmol/min/m2) 180 200 220 240 260 −4 0 4 8 12 16202428323640444852 Time (weeks) Basal Secretory Tone 45 50 55 60 65 70 75 −4 0 4 8 12 1620 24 2832 36 40 4448 52 Time (weeks) GlucoseSensitivity (pmol/min/m2/mM) Glucose Sensitivity
    • 168. Ahrén B, et al. J Clin Endocrinol Metab. 2009;94(4):1236–1243. Vildagliptin 100 mg once daily is NOT an approved dose. Effects of vildagliptin treatment on the sensitivity of the α-cell to glucose Time (min) −30 0 30 60 90 120 165 210 255 285 90 110 130 150 170 Dose Meal Glucagon(ng/L) 7.5 mM 5.0 mM 2.5 mM Placebo Vildagliptin 100 mg once daily
    • 169. 8.2) Vildagliptin reduces insulin resistance
    • 170. Vildagliptin treatment improves insulin sensitivity 4.0 4.5 5.0 5.5 6.0 6.5 7.0 Duration: 6 weeks Vildagliptin vs placebo GlucoseRd(mg/kg•min) Placebo (n=16) Vildagliptin 50 mg twice daily (n=16) Insulin infusion 80 mU/m2•min Mean Rd difference=0.7 mg/kg•min Rd=rate of disappearance. *P <0.05. Azuma K, et al. J Clin Endocrinol Metab. 2008; 93: 459–464. *6.1 5.4 Hyperinsulinemic Euglycemic Clamp
    • 171. * * * 0 12 24 52 Time (Week) * * † 0 12 24 52 Time (Week) pmol/L30min/(mmol/L) 0 12 24 52 Time (Week) * * mL·min-1·m-2 0.050 0.040 0.045 0.025 0.030 0.035 300 250 275 200 225 14 10 12 6 8 Insulin Secretion Insulin Sensitivity Adaptation Index Effects of vildagliptin treatment on -cell function and insulin sensitivity over 52 Weeks Patients on Stable Metformin Therapy *P <0.05 vs placebo; †P <0.01 vs placebo. Adapted from Ahrén B, et al. Diabetes Care. 2005; 28: 1936–1940. Vildagliptin 50 mg daily / metformin Placebo / metformin nmolC-peptide·mmolglucose -1· mL-1·m-2
    • 172. 8.3) Vildagliptin reduces postprandial lipids
    • 173. Vildagliptin improves postprandial lipid and lipoprotein metabolism TG=triglyceride; Vilda=vildagliptin. Matikainen N, et al. Diabetologia. 2006; 49: 2049–2057. Before vilda, Week 0 (n=13) Vilda 50 mg twice daily, Week 4 (n=15) 0.8 0.6 0.4 0.2 0.0 −1 0 1 2 3 4 5 6 7 8 0.08 0.06 0.04 0.02 0.00 −1 0 1 2 3 4 5 6 7 8 Time (h) 0.50 0.40 0.30 0.20 0.10 0.00 −1 0 1 2 3 4 5 6 7 8 Time (h) 4.0 3.5 3.0 2.5 2.0 1.5 1.0 −1 0 1 2 3 4 5 6 7 8 Plasma TG Chylomicron TG Chylomicron apo B-48 Chylomicron cholesterol mmol/L mmol/Lmmol/L mg/L
    • 174. 8.4) Vildagliptin has the potential for disease prevention and modification
    • 175. Replication -cellMass(mg) Vehicle Vildagliptin P <0.05 0.00 0.02 0.04 0.06 0.08 0.10 0.12 0.14 Vehicle BrdU-positiveCells(%) P <0.001 0 20 40 60 80 100 120 Vildagliptin ApopTag-positiveCells(%) Vehicle Vildagliptin P <0.05 0.0 0.5 1.0 1.5 2.0 2.5 Apoptosis -cell Mass Vildagliptin 60 mg/kg 21 days Vehicle Insulin Day 7 Day 21 Duttaroy A, et al. Diabetes. 2005; 54 (Suppl 1): A141. Abstract 572-P and poster presented at ADA. Effect of vildagliptin on β-cell mass in a neonatal rat pancreatic growth model
    • 176. Vildagliptin increases pancreatic beta cell mass in neonatal rats Duttaroy A. et al. European J Pharmacol. 2011; 650: 703–707 Control Vildagliptin Day 7 BrdU+ cells Day 7 Apoptag+ cells Day 21 Insulin+ cells *p<0.05; **p<0.01 Replication Apoptosis -cell Mass
    • 177. ISR/G=insulin-secretory rate relative to glucose concentration. Scherbaum WA, et al. Diabetes Obes Metab. 2008; 10: 1114–1124. Durability of β-cell function over 2 years MeanISR/G(pmol/min/m2/mM) Time (Weeks) Treatment period Wk 0–52 Treatment period Wk 56–108Washout Washout Placebo (n=40) Vildagliptin 50 mg once daily (n=49) 30 −8 0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 35 40 45 50
    • 178. * * * 0 12 24 52 Time (Week) * * † 0 12 24 52 Time (Week) pmol/L30min/(mmol/L) 0 12 24 52 Time (Week) * * mL·min-1·m-2 0.050 0.040 0.045 0.025 0.030 0.035 300 250 275 200 225 14 10 12 6 8 Insulin Secretion Insulin Sensitivity Adaptation Index Effects of vildagliptin treatment on -cell function and insulin sensitivity over 52 weeks Patients on Stable Metformin Therapy *P <0.05 vs placebo; †P <0.01 vs placebo. Adapted from Ahrén B, et al. Diabetes Care. 2005; 28: 1936–1940. Vildagliptin 50 mg daily / metformin Placebo / metformin nmolC-peptide·mmolglucose -1· mL-1·m-2
    • 179. 9) Vildagliptin shows a favorable safety and tolerability profile 9.1) Pooled analysis demonstrates that overall incidence of adverse events is similar for vildagliptin vs. comparators
    • 180. Pooled analysis: most common AEs by preferred term (occurring in >3% of patients in either group) AEs=adverse events; bid=twice daily; comp=all comparators; PBO=placebo; All-study safety (excluding open-label) population. Schweizer A. et al, Vasc Health Risk Manag 2011(accepted version) Preferred term, n (%) Vildagliptin 50 mg bid N= 6116 Total comp N=6210 Nasopharyngitis 577 (9.4) 528 (8.5) Headache 431 (7.0) 371 (6.0) Dizziness 390 (6.4) 460 (7.4) Back pain 356 (5.8) 321 (5.2) Upper respiratory tract infection 317 (5.2) 254 (4.1) Bronchitis 297 (4.9) 278 (4.5) Diarrhea 345 (5.6) 418 (6.7) Hypertension 297 (4.9) 315 (5.1) Influenza 290 (4.7) 282 (4.5) Arthralgia 289 (4.7) 236 (3.8) Nausea 247 (4.0) 268 (4.3) Pain in extremity 217 (3.5) 238 (3.8) Fatigue 210 (3.4) 253 (4.1) Cough 206 (3.4) 210 (3.4) Urinary tract infection 204 (3.3) 185 (3.0) Asthenia 198 (3.2) 306 (4.9) Tremor 184 (3.0) 471 (7.6) Oedema peripheral 180 (2.9) 219 (3.5) Hyperhidrosis 169 (2.8) 422 (6.8) Hypoglycemia 1.7 5.8
    • 181. Similar incidence of SAEs, discontinuations due to AEs, or death for vildagliptin and comparators n (%) Vilda 50 mg bid N=6116 Total comparators N=6210 Any AE 4225 (69.1) 4228 (69.0) Drug-related AEs 961 (15.7) 1349 (21.7) SAEs 545 (8.9) 557 (9.0) Discontinuation of study drug due to AEs 347 (5.7) 400 (6.4) Deaths 24 (0.4) 23 (0.4) AEs=adverse events; bid=twice daily; PBO=placebo; SAEs= serious adverse events; vilda=vildagliptin. All-study safety (excluding open-label) population. Schweizer A. et al, Vasc Health Risk Manag 2011(accepted version)
    • 182. No increased risk for hepatic AEs and SAEs vs comparators AEs=adverse events; bid=twice daily; CI=confidence interval; qd=once daily; SAEs=serious adverse events; vilda=vildagliptin. *Vs comparators (all non-vildagliptin treatment groups). All-study safety (excluding open-label) population. Vildagliptin better Vildagliptin worse Vildagliptin Reference Peto odds ratio n / N (%) n / N (%) (95% CI) Hepatic AEs Vilda 50 mg qd* 15 / 1502 (1.00) 14 / 1662 (0.84) 1.29 (0.61–2.70) Vilda 50 mg bid* 83 / 6116 (1.36) 84 / 4872 (1.72) 0.87 (0.64–1.19) Hepatic SAEs Vilda 50 mg qd* 2 / 1502 (0.13) 2 / 1662 (0.12) 1.08 (0.15–7.76) Vilda 50 mg bid* 6 / 6116 (0.10) 5 / 4872 (0.10) 1.13 (0.35–3.67) Odds Ratio 0.01 0.1 1 10 100 According to the Prescribing information, vildagliptin should not be used in patients with hepatic impairment, including patients with pre-treatment alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3x the upper limit of normal (ULN). Liver function tests should be performed prior to the initiation of treatment with vildagliptin in order to know the patient’s baseline value. Liver function should be monitored during treatment with vildagliptin at 3-month intervals during the first year and periodically thereafter. Ligueros-Saylan M, et al. Diab Obes Metab 2010 12:495-509
    • 183. No increased risk of liver enzyme (ALT / AST) elevations vs. comparators Vildagliptin better Vildagliptin worse Vildagliptin Reference Peto odds ratio n / N (%) n / N (%) (95% CI) ALT / AST >3 × ULN Vilda 50 mg qd* 6 / 1406 (0.43) 4 / 1574 (0.25) 1.60 (0.46–5.49) Vilda 50 mg bid* 51 / 5874 (0.87) 32 / 4597 (0.70) 1.24 (0.80–1.93) ALT / AST >3 × ULN and bilirubin >ULN Vilda 50 mg qd* 0 / 1400 (0.00) 1 / 1571 (0.06) 0.21 (<0.01–6.54) Vilda 50 mg bid* 5 / 5863 (0.09) 3 / 4588 (0.07) 1.19 (0.29–4.90) Odds Ratio ALT=alanine aminotransferase; AST=aspartate aminotransferase; bid=twice daily; CI=confidence interval; qd=once daily; ULN=upper limit of normal; vilda=vildagliptin. *Vs comparators (all non-vildagliptin treatment groups). All-study safety (including open-label) population. ‡Persistent elevations are those which met the criterion at consecutive on-treatment measurements or at last on-treatment visit. 0.01 0.1 1 10 100 According to the Prescribing information, vildagliptin should not be used in patients with hepatic impairment, including patients with pre-treatment alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3x the upper limit of normal (ULN). Liver function tests should be performed prior to the initiation of treatment with vildagliptin in order to know the patient’s baseline value. Liver function should be monitored during treatment with vildagliptin at 3-month intervals during the first year and periodically thereafter. Ligueros-Saylan M, et al. Diab Obes Metab 2010 12:495-509
    • 184. Low incidence of persistent markedly elevated hepatic enzymes across treatment groups Vildagliptin 50 mg qd 50 mg bid Total comp AST or ALT N= 2091 N= 5917 N=6695 ≥10 x ULN n (%) 0 1 (0.0) 2 (0.0) ≥20 x ULN n(%) 0 0 0 ALT or AST and bilirubin N= 2085 N= 5906 N= 6595 ALT or AST ≥3 xULN and bilirubin ≥2 xULN n(%) 0 3 (0.1) 3 (0.0) ALT= alanine aminotransferase; AST= aspartate aminotransferase; bid= twise a day, qd: once a day; total comp: all comparators. ULN= upper limit of normal; *Persistent elevations are defined as those not present at any pretreatment visit and meeting the criterion at consecutive on-treatment measurements or at last on-treatment visit Ligueros-Saylan M, et al. Diab Obes Metab 2010 12:495-509 Number (%) of patients with treatment-emergent, Persistent* on-treatment hepatic enzyme elevations
    • 185. Summary of hepatic safety profile of vildagliptin • There was no evidence of increased risk for hepatic AEs and SAEs with vildagliptin treatment. • There was no significant difference in ALT / AST >3x of vildagliptin vs. comparators • The incidences of markedly elevated persistent hepatic enzyme elevations (ALT/AST ≥10× or ≥20× ULN) were very low across all treatment groups and similar in the vildagliptin 50 mg bid group (1/5917 patients for ALT/AST ≥10× ULN and 0/5917 patients for ALT/AST ≥20× ULN), and the all comparators group. AEs= adverse events; ALT= alanine aminotransferase; AST= aspartate aminotransferase SAEs= serious adverse events; ULN= upper limit of normal According to the Prescribing information, vildagliptin should not be used in patients with hepatic impairment, including patients with pre-treatment alanine a minotransferase (ALT) or aspartate aminotransferase (AST)>3x ULN. Liver function should be performed prior to the initiation of treatment with vildagliptin in order to know the patient‘s baseline value. Liver function should be monitored during treatment with vildagliptin at three-month intervals during the first year and periodically thereafter. Ligueros-Saylan M, et al. Diab Obes Metab 2010 12:495-509
    • 186. Galvus labelling recommendations regarding liver monitoring • LFTs should be performed prior to the initiation of treatment with Galvus. Galvus is not recommended in patients with a pre-treatment ALT or AST >2.5X the upper limit of normal according to the BPI or above 3X according to European SmPC • LFTs should be monitored during Galvus treatment at three-month intervals during the first year and periodically thereafter • Patients who develop increased transaminase levels should be monitored with a second liver function evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the abnormality (ies) return to normal • Should an increase in AST or ALT of 3x upper limit of normal or greater persist, withdrawal of therapy with Galvus is recommended. Patients who develop jaundice or other signs suggestive of liver dysfunction should discontinue Galvus and contact their physician immediately • Following withdrawal of treatment with Galvus and LFT normaisation, vildagliptin treament should not be reinitiated. LFT: liver function test; AST= aspartate aminotransferase; ALT= alanine aminotransferase BPI: Basic prescribing information SmPC= European Summary of Product Characteristics
    • 187. No increased risk for adjudicated CCV events, relative to all comparators* AEs=adverse events; bid=twice daily; CI=confidence interval; CV=cardiovascular; M-H RR=Mantel-Haenszel risk ratio; qd=once daily; vilda=vildagliptin. *Vs comparators (all non-vildagliptin treatment groups). All-study safety population. ‡Guidance for Industry: Diabetes Mellitus - Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes, U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER), December 2008. Schweizer A, et al. Diab Obes Metab .2010 ;12:485-494. Vildagliptin All comparators M-H RR n / N (%) n / N (%) (95% CI) Vilda 50 mg qd# 10 / 1393 (0.72) 14 / 1555 (0.90) 0.88 (0.37–2.11) Vilda 50 mg bid# 81 / 6116 (1.32) 80 / 4872 (1.64) 0.84 (0.62–1.14) Risk Ratio Incidences and Odds Ratios for Adjudicated CV Events by Treatment Vildagliptin better Vildagliptin worse 0.1 1 10 #Meta-analysis of vildagliptin 50 mg bid data vs all comparators according to the methodology set by the US Food and Drug Administration‡ [50 mg bid odds ratio = 0.84 (95% CI 0.62–1.14)].
    • 188. The incidence of SYE-adjusted* adjudicated CCV events was similar with vildagliptin relative to comparators SYE-adjustedIncidence* ACS=acute coronary syndrome; CCV=cardiovascular and cerebrovascular; SYE=subject-year exposure; TIA=transient ischemic attack; vilda=vildagliptin. *SYE-adjusted rates calculated as number of patients having events per 100 subject-years of exposure. Schweizer A, et al. Diab Obes Metab .2010;12:485-494
    • 189. Vildagliptin not associated with increased risk for infections Vildagliptin All Peto odds ratio comparators n / N (%) n / N (%) (95% CI) Infections / infestations Vilda 50 mg qd* 356 / 1502 (23.07) 432 / 1662 (26.0) 0.88 (0.75–1.04) Vilda 50 mg bid* 2099 / 6116 (34.3) 1697 / 4872 (34.8) 1.04 (0.96–1.13) Vildagliptin better Vildagliptin worse Odds Ratio bid=twice daily; CI=confidence interval; qd=once daily; vilda=vildagliptin. *Vs comparators (all non-vildagliptin treatment groups). All-study safety (excluding open-label) population. Ligueros-Saylan M, et al. Diab Obes Metab 2010 ;12:495-509 0.1 1 10
    • 190. No increased risk for pancreatitis-related AEs Vildagliptin All comparators Peto odds ratio n / N (%) n / N (%) (95% CI) Pancreatitis events Vilda 50 mg qd* 2 / 1502 (0.13) 4 / 1662 (0.24) 0.76 (0.15–3.89) Vilda 50 mg bid* 7 / 6116 (0.11) 9 / 4872 (0.18) 0.70 (0.26–1.88) Odds Ratio Vildagliptin better Vildagliptin worse AEs=adverse events; bid=twice daily; CI=confidence interval; qd=once daily; vilda=vildagliptin. *Vs comparators (all non-vildagliptin treatment groups). All-study safety (excluding open-label) population. Ligueros-Saylan M, et al. Diab Obes Metab 2010 ;12:495-509 0.01 0.1 1 10 100
    • 191. Vildagliptin All Comparators Peto odds ratio n / N (%) n / N (%) (95% CI) Selected Skin-related AEs Vilda 50 mg qd 19/1502 (1.26) 11/1662 (0.66) 1.93 (0.93-3.99) Vilda 50 mg bid 89/6116 (1.47) 71/4872 (1.46) 1.10 (0.80–1.51) Selected Skin-related SAEs Vilda 50 mg qd 0/1502 (0.00) 1/1662 (0.06) 0.23 (<0.01–7.11) Vilda 50 mg bid 6/6116 (0.10) 7/4872 (0.14) 0.84 (0.29–2.49) 0.01 100 Vildagliptin worse Odds Ratio Vildagliptin better 0.1 1 10 No increased risk of skin-related AEs and SAEs with vildagliptin vs all comparators Odds ratios for selected skin and vascular- related AEs and SAEs in the all controlled studies (excluding open-label) safety population. (Vilda= vildagliptin; All comparators= all non-Vilda treatment groups, that is placebo and active comparators. n = number of patients experiencing an AE, N = total number of patients). Test for heterogeneity of selected skin- and/ or vascular – related AEs: Q = 9.58, p = 0.653 and I2 = 0.00 (vildagliptin 50 mg qd); Q= 10.79, p= 0.702 and I2 = 0.00 (vildagliptin 50 mg bid). Test for heterogeneity of selected skin- and/ or vascular – related SAEs: Q = 0.20, p = 0.999 and I2 = 0.00 (vildagliptin 50 mg qd); Q= 10.31, p= 0.739and I2 = 0.00 (vildagliptin 50 mg bid). Ligueros-Saylan M, et al. Diab Obes Metab 2010 ;12:495-509
    • 192. 9.2) Mild renal impairment does not affect vildagliptin’s safety compared to patients with normal renal function
    • 193. 50 mg qd 1338 50 mg bid 4232 comparators 4217 65.6 8.1 68.4 7.5 70.3 11.6 68.7 7.9 70.1 11.2 4.2 58.7 0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0 90.0 100.0 Normal renal Function %ofAEorSAE Mild renal Function n = Vildagliptin 50 mg qd All comparators Vildagliptin 50 mg bid Ligueros-Saylan M, et al. Diab Obes Metab 2010 12:495-509 Normal Renal function: GFR (MDRD) > 80 (ml/min) x (1.73 m2) Mild renal impairment: GFR (MDRD) ≥ 50 but ≤ 80 (ml/min) x (1.73 m2) Any AE Any SAE Any AE Any SAE 50 mg qd 665 50 mg bid 1802 comparators 1918 all studies [excluding open-label] safety population Mild renal impairment does not adversely affect the safety of vildagliptin relative to patients with normal renal function Pooled safety data
    • 194. 9.3) Overall incidence of edema is similar to all comparators
    • 195. The incidence and odds ratios of selected edema-related AEs were similar with vildagliptin relative to comparators Vildagliptin Comparators Peto OR n / N (%) n / N (%) (95% CI) Vilda 50 mg bid 189 / 6116 (3.09) 211/ 4872 (4.33) 0.72 (0.59–0.88) Risk Ratio Incidences and odds ratios for selected edema-related events by treatment Vildagliptin better Vildagliptin worse 0.1 1 10 All studies [excluding open-label] safety population Schweizer A. et al, Vasc Health Risk Manag 2011(accepted version) Pooled safety data
    • 196. 9.4) No change in bone markers has been observed with vildagliptin treatment
    • 197. Vildagliptin does not increase fasting parameters of bone metabolism and calcium homeostasis Diamant M, et al. Poster Presentation 0706-P. Presented at: 70th Scientific Sessions of the American Diabetes Association 2010. Baseline Endpoint LSM Change Between- group difference P-value Calcium (mmol/L) Placebo 2.32 ± 0.07 2.32 ± 0.08 –0.004 ± 0.012 0.000 ± 0.017 0.981Vildagliptin 2.33 ± 0.07 2.33 ± 0.07 –0.005 ± 0.011 Phosphate (mmol/L) Placebo 0.97 ± 0.16 1.01 ± 0.19 0.037 ± 0.024 0.010 ± 0.033 0.762Vildagliptin 1.00 ± 0.15 1.04 ± 0.15 0.047 ± 0.023 Alkaline phosphatase (IU/L) Placebo 7.04 ± 15.5 66.8 ± 14.2 –3.31 ± 5.24 7.14 ± 7.20 0.327Vildagliptin 66.5 ± 18.6 70.6 ± 36.3 3.83 ± 4.91 Since nutrient intake plays an important role in maintaining bone health, mediated by ensuing pancreatic islet and incretin response, this study explored effects of vildagliptin on (postprandial) markers of bone metabolism in patients with T2D and mild hyperglycemia
    • 198. 9.5) Hypoglycemia risk is consistently low with vildagliptin
    • 199. 0.6 0.8 0.3 9.2 0 0 2 4 6 8 10 12 14 Incidence(%) n = 2 23 1 189 0 N= 340 3021 354 2045 280 Low risk of hypoglycemic events in add-on metformin trials in vildagliptin treated patients Vildagliptin 50 mg qd + met Vildagliptin 50 mg bid + met Placebo + met SU + met Pioglitazone* + met Hypoglycemia Incidence in Add-on Metformin bid=twice daily; glim=glimepiride; met=metformin; pio=pioglitazone; qd=once daily. Up to 24-week add-on to metformin population. SU: glimepiride and gliclazide. *Pioglitazone 30 mg once daily. Data on file, Novartis Pharmaceuticals.
    • 200. Vildagliptin resulted in a significantly lower incidence of hypoglycaemia than glimepiride at 52 weeks (interim analysis) Number of Hypoglycaemic Events Severe Events (Grade 2 and Suspected Grade 2) Patients with >1 Hypos (%) 1389 Glimepiride up to 6 mg once daily + metformin Vildagliptin 50 mg twice daily + metformin 1383 1389 1383 1389 1383n = Duration: 52 weeks Add-on to met: vilda vs glim Incidence(%) No.ofEvents No.ofEvents glim=glimepiride; met=metformin; vilda=vildagliptin. Safety population. Ferrannini E, et al. Diabetes Obes Metab. 2009; 11: 157–166.
    • 201. Vildagliptin vs glimepiride as add on to metformin: No severe hypoglycemic events at 2 years Safety population; * any episode requiring the assistance of another party Vilda= vildagliptin; Glim= glimepiride; Met= metformin Matthews DR et al Diab Obes Metab. 2010; 12:780-789 Glim up to 6 mg qd + Met (n=1546) Vilda 50 mg bid + Met (n=1553) Number of hypoglycemic events Number of Severe hypo events* Patients with one or more hypoglycemic events (%) 2.3 18.2 0 4 8 12 16 20 59 838 0 100 200 300 400 500 600 700 800 900 0 15 0 2 4 6 8 10 12 14 16 Incidence(%) Numberofevents Numberofevents This hypoglycemic profile was maintained in patients > 65 years Discontinuation due to hypoglycemia 13 0 2 4 6 8 10 12 14 0 Numberofevents
    • 202. Fewer hypoglycemic events in vildagliptin add-on to insulin compared with insulin alone Add-on Treatment to InsulinDuration: 24 weeks Add-on to insulin: vilda vs PBO PBO + insulin Vilda 50 mg twice daily + insulin PBO=placebo; vilda=vildagliptin; *P <0.001; **P <0.05 between groups. Fonseca V, et al. Diabetologia. 2007; 50: 1148–1155. 0 0 No. of Events No. of Severe Events 40 80 120 160 200 2 4 6 8 10 No.ofSevereEvents 113 185 0 6 * ** No.ofEvents
    • 203. 9.6) Overall vildagliptin causes no weight gain and shows greater benefits on weight in obese patients
    • 204. -0.3 -1.1 1.6 1.7 -2 -1 0 1 2 Weight loss relative to rosiglitazone BL=baseline; BMI=body mass index. *P <0.001 vs rosiglitazone. Primary intention-to-treat population. Rosenstock J, et al. Diabetes Care. 2007; 20: 217–223. * Overall BMI >35 kg/m2 n = 459 238 132 76 BL (kg)= 91 93 111 112 WeightchangefromBL(kg) * +2.8 kg difference Duration: 24 weeks Vildagliptin vs rosiglitazone monotherapy Rosiglitazone 8 mg once daily Vildagliptin 50 mg twice daily
    • 205. Vildagliptin: similar effect on weight as metformin Intention-to-treat population. Schweizer A, et al. Diabet Med. 2007; 24: 955–961. Vildagliptin 50 mg twice daily (n=511) Metformin 1000 mg twice daily (n=249) Duration: 52 weeks; Vildagliptin vs metformin monotherapy 80 85 90 95 100 −4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Time (Weeks) MeanBodyWeight(kg)
    • 206. Initial combination of vildagliptin + metformin: change in body weight 276 258271 275n = MeanChangeinBodyWeight(kg) Change from Baseline to End Point Mean Baseline Body Weight ~88.3 kg Duration: 24 weeks Vilda + met vs mono Vilda + HD met (50/1000 mg bid) Vilda + LD met (50/500 mg bid) Met 1000 mg bid Vilda 50 mg bid Intention-to-treat population. HD=high dose; LD=low dose; met=metformin; vilda=vildagliptin. Bosi E, et al. Diabetes Obes Metab. 2009; 11: 506–515.
    • 207. Vildagliptin: weight loss compared to glimepiride in add-on to metformin at 52 weeks Time (Weeks) −1.8 kg difference Vildagliptin 50 mg twice daily + metformin Glimepiride up to 6 mg once daily + metformin Duration: 52 weeks Add-on to met: vilda vs glim Add-on Treatment to Metformin (~1.9 g Mean Daily) BodyWeight(kg) glim=glimepiride; met=metformin; vilda=vildagliptin. Vildagliptin (n=1396); glimepiride (n=1393). Ferrannini E, et al. Diabetes Obes Metab. 2009; 11: 157–166. Data on file, Novartis Pharmaceuticals, LAF237A2308.
    • 208. -0.3 -1.5 1.2 -2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0 Change from BL to EP (BL Mean ~ 89kg) Between-treatment difference Vildagliptin: weight loss compared to glimepiride in add-on to metformin at 2 years Intent to treat (ITT) population; * p=<0.001 BL= baseline; Vilda= vildagliptin; Glim= glimiperide; Met= metformin; EP= week 104 endpoint Matthews DR et al Diabetes Obes Metab 2010; 12: 780–789 AdjustedMeanChangein Bodyweight(kg) 1539 1520N= * Glim up to 6 mg qd + Met Vilda 50 mg bid + Met Duration: 2 years Add-on to met: vilda vs glim
    • 209. AdjustedMeanChangein bodyweight(kg) 386 Change from BL to Wk 52 Mean BL ~ 85 kg Glic up to 320 mg + Met Vilda 50 mg bid + Met 393N= Between-treatment difference Per protocol (PP) population; * p<0.001 Vilda vs Glic, 95% CI (-1.77, -0.79) Glic= gliclazide; Met= metformin; Vilda= vildagliptin; BL= baseline; EP= end point Adjusted mean change from BL to EP and p-value were from an ANCOVA model containing terms for treatment, baseline and pooled center. Filozof et al Diabetes Medicine 2010 (27) 318-326. * 0.08 -1.28 1.36 -1.6 -1.2 -0.8 -0.4 0.0 0.4 0.8 1.2 Vildagliptin: weight loss compared to gliclazide in add-on to metformin at 52 weeks Duration: 52 weeks Add-on to met: vilda vs glic
    • 210. 10) Special Populations 10.1) Vildagliptin demonstrates significant efficacy and favorable safety in elderly patients
    • 211. Elderly: Background information  Fast growing segment of patients with T2DM  Management of T2DM in the elderly is particularly challenging :  High prevalence of CV risk factors and comorbidities as CHF, geriatric syndromes (e.g. frailty, cognitive disorders), as well as social isolation and depression.  Polypharmacy can be high with potential increased risk of drug interactions.  Very heterogeneous population (e.g. diabetes duration, coexisting disorders and treatments )  Therapeutic goals are unclear due to lack of data with specific focus in this population mainly in very elderly 211
    • 212. Hypoglycemia in the elderly  More common among elderly patients  Generally unrecognized, symptoms (disorientation, confusion or other neuroglycopenic symptoms) can be confused with concomitant medical conditions  Unawareness of hypoglycemia increase the risk of future severe events  It is often more severe and can precipitate serious events such as falls and hip fractures.  Among older people hypoglycemia is associated with higher risk of dementia
    • 213. Very elderly (≥ 75years) data from pooled analysis  Efficacy data were collected from randomized, double-blind, controlled, parallel group studies with duration ≥ 24 weeks  Only studies with the approved vildagliptin dose of 50 mg bid. It included 7 monotherapy and 3 add-on to metformin studies  Safety profile was oserved from a pool of 38 PhII and III studies which include monotherapy and add-on therapy  AEs, SAEs, discontinuation due to AE, hepatic- related AEs , the analysis was performed only in double-blind studies  Safety on persistent treatment-emergent transaminase elevations was analysed including open-label studies (no bias expected) Schweizer A. et al, Diabetes, Obesity and Metabolism 13: 55–64, 2011.
    • 214. Age ≥ 75 years Vilda 50 mg bid n=132 Age ≥ 75 years Comparators n=169 Age < 75 years Vilda 50 mg bid n=5984 Age < 75 years Comparators n=6041 Age (years) 76.9 77.0 54.9 55.9 Male (%) 42.4 55.0 55.3 54.7 Caucasian (%) 84.8 79.3 72.6 72.5 Mean BMI (kg/m2) 29.4 28.9 31.5 31.3 Mean HbA1c % 8.3 7.9 8.3 8.0 FPG (mmol/L) 9.9 8.8 10.1 9.8 Duration of T2DM (years) 6.3 5.9 4.1 4.5 GFR, # (% pts) normal mild ( ≥50, <80) moderate (≥30, <50) severe (<30) 27.3 62.1 10.6 0.0 34.9 58.0 6.5 0.6 70.1 28.7 1.0 0.1 68.8 30.1 1.0 0.0 High CV R status* (%) 31.8 36.1 15.0 15.2 * History of prior CCV events in the SMQs ‘ischaemic heart disease, cardiac failure, ischaemic cerebrovascular conditions and/or embolic/thrombotic events arterial‘ Data presented are for patients in “all studies“ (excluding open-label studies) safety population # MDRD = mL/min per 1.73m2 Very elderly patients pooled analysis: Demographics and baseline characteristics Schweizer A et al. Diab Obes Metab 2010;13(1):55–64
    • 215. -0.9-0.9 -1.1 -1.8 -1.6 -1.4 -1.2 -1.0 -0.8 -0.6 -0.4 -0.2 0.0 Vildagliptin: significant HbA1c drop from baseline in the very elderlyChangeinHbA1c(%)frombaseline Add-on therapy studies n = BL (%)= 2303 8.7 62 8.3 910 8.4 25 8.5 * * * * *<0.05 vs baseline (within group) Age < 75 y ≥ 75 y ≥ 75 y Age < 75 y -1.2 Monotherapy studies Schweizer A et al. Diab Obes Metab 2010;13(1):55–64 Efficacy pool: All randomized, double-blind, controlled, parallel group studies with duration ≥ 24 and with patients ≥ 75years. Only studies with the approved dose of 50 mg bid. It included 7 monotherapy and 3 add-on to metformin studies. Pooled analysis at 24 weeks 50 mg bid
    • 216. -0.0 -0.9 -0.2 -1.8 -1.6 -1.4 -1.2 -1.0 -0.8 -0.6 -0.4 -0.2 0.0 Vildagliptin: no clinically significant body weight changeChangeinbodyweight(%)from baseline Add-on therapy studies n = BL (kg)= 2299 86.1 62 74.9 914 89.0 25 82.8 * * *<0.05 vs baseline (within group) At 24 weeks treatment 50 mg bid Age < 75 y ≥ 75 y ≥ 75 y Age < 75 y -0.4 Monotherapy studies Schweizer A et al. Diab Obes Metab 2010;13(1):55–64
    • 217. Vildagliptin: lower AEs, SAEs, and drug-related AEs in the very elderly Age ≥ 75 years Vilda 50 mg bid n=132 Age ≥ 75 years Comparators n=169 Age < 75 years Vilda 50 mg bid n=5984 Age < 75 years Comparators n=6041 Any AEs SYE-adj n (%) 133.9 86 (65.2) 200.6 114 (67.5) 147.9 4139 (69.2) 177.3 4174 (69.1) Drug-related AEs SYE-adj n (%) 14.5 18 (13.6) 21.8 24 (14.2) 14.9 943 (15.8) 26.0 1325 (21.9) SAEs SYE-adj n (%) 8.8 12 (9.1) 16.5 19 (11.2) 7.8 533 (8.9) 8.9 538 (8.9) Discontinuation due to AEs SYE-adj n (%) 7.2 10 (7.6) 7.5 9 (5.3) 4.7 337 (5.6) 6.1 391 (6.5) Deaths SYE-adj n (%) 0.0 0 (0.0) 1.7 2 (1.2) 0.3 24 (0.4) 0.3 21 (0.3) SYE-adj: SYE-adjusted Safety pool: A pool of 38 PhII and III studies (monotherapy and add-on therapy) Comparators group includes active comparator or placebo Schweizer A et al. Diab Obes Metab 2010;13(1):55–64
    • 218. Monotherapy studies pool Add on therapy studies pool n = BL 62 8.3 25 8.5 ChangeinHbA1c (%)frombaseline Mono > 75 Add on > 75*<0.05 vs baseline (within group) * Body Weight: At 24 weeks treatment n = BL 62 74.9 25 82.8 * * Monotherapy studies pool Add on therapy studies pool ChangeinBody Weight(kg)from baseline Very elderly patients pooled analysis: change in HbA1c and body weight at 24 weeks treatment, and hypoglycemic events HbA1c Reduction: At 24 weeks treatment Hypoglycemic events Monotherapy studies pool Add on therapy studies pool Any events 0.0 0.0 Severe events 0.0 0.0  OR No hypoglycemic events, including severe events was reported in elderly patients with monotherapy and add-on therapy Schweizer A. et al, Diabetes, Obesity and Metabolism 13: 55–64, 2011. Pooled analysis at 24 weeks; 50 mg bid
    • 219. Vildagliptin (Galvus) in Taiwan  適應症: 第二型糖尿病  用法、用量: 宜用於已使用metformin或SU或TZD且血糖控制不佳者 與metformin 、TZD 合併使用 ---- 50 mg BID 與SU合併使用 ---- 50 mg QD  特殊族群: 1. 輕度腎功能不全(肌酸酐清除率> 50 ml/min)無需調整劑量 中度或重度腎功能不全以及必須接受洗腎之末期腎臟疾病(ESRD)患者而言 ,不建議使用Galvus 。 2. 不建議使用於肝功能不全的患者,包括治療前ALT或AST >2.5 X ULN者在 使用Galvus治療的第一年內,建議每三個月需進行一次肝功能測試,直至 一年,之後建議定期監測,且當病人有噁心、嘔吐、倦怠、上腹不適、黃 疸等可能為肝傷害之症狀或證後發生時,宜檢測肝生化值(ALT)。患者的 肝臟轉胺酶濃度若增加,則應進行第二次肝功能監測加以確認,並應持續 進行肝功能測試追蹤,直至恢復正常為止。若病患之AST或ALT值持續超 過2.5 x ULN或更高, 則建議病患退出Galvus治療。患者若出現黃疸或其 他肝功能異常徵兆,應停止使用Galvus。在退出Galvus治療與肝功能回復 正常值之後, 不應再度使用Galvus。

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