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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. Glycaemic exposure and complications of diabetes:decrease in risk for 1% reduction in HbA1c Relative risk* Microvascular complications  37% Any diabetes-related endpoint  21% Diabetes-related death  21% All-cause mortality  14% Fatal and non-fatal MI  14% 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 withmean HbA1c with no evidence of a threshold 80 Myocardial infarction Microvascular endpoints per 1000 person years (%) 60 Adjusted incidence 40 20 0 5 6 7 8 9 10 11 Mean HbA1c (%)HbA1c=haemoglobin A1c.Incidence rates and 95% confidence intervals for myocardial infarction and microvascular complications by category of mean HbA1cconcentration, adjusted for age, sex and ethnic group, expressed for white men aged 50–54 years at diagnosis and with mean durationof diabetes of 10 years.Stratton IM. et al. BMJ. 2000; 321: 405–412.
  • 7. Three studies assessed the association betweenintensive glycemic control and long-term CV complication VADT1 ACCORD2 ADVANCE3 (n=1700) (n=10250) (n=11140)HbA1c – Std vs. 8.4 vs. 6.9 7.5 vs. 6.5 7.3 vs. 6.5Intensive Non-fatal MI Non-fatal stroke Non-fatal MI Non-fatal MI CVD deathPrimary outcome Non-fatal stroke Non-fatal stroke Hospitalization for CVD death CVD death CHF RevascularizationHazard Ratio for 0.87 0.90 0.94primary outcome(95% CI) (0.730 – 1.04) (0.78 – 1.04) (0.84 – 1.06)Hazard Ratio for 1.065 (0.801 – 1.416) 1.22 (1.01 – 1.46) 0.93 (0.83 – 1.06)mortality (95% CI) * *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
  • 8. Reaching target in late stages of the disease does notreduce vascular complications VADT Primary outcome 1.0 Intensive Probability of survival 0.8 therapy 0.6 Standard therapy 0.4 0.2 0.0 0 2 4 6 8 Years No. at risk Intensive 892 774 707 639 582 510 252 62 0 Standard 899 770 693 637 570 471 240 55 0P=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 coronarydisease, and amputation for ischaemic gangrene).Duckworth W, et al. N Engl J Med. 2009; 360: 129–139.
  • 9. Achieving late glycaemic control may generatea bad legacy effect increasing risk of complications Before entering VADT After entering VADT intensive treatment arm intensive treatment arm 9.5 9.0 8.5 HbA1c (%) 8.0 Generation of a ‗bad 7.5 glycaemic legacy‘ drives risk of complications 7.0 6.5 Ideal HbA1c 6.0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Time since diagnosis (years)• Hypothetical representation of the natural history of diabetic patients in the VADT study: initial poor glycaemic control increases risk of complications later in disease courseHbA1c=haemoglobin A1c; T2DM=type 2 diabetes mellitus.Adapted from Del Prato S. Diabetologia. 2009; 52: 1219–1226.
  • 10. Early glucose control not only reducescomplications but has a long-term legacy effect After median 8.5 years‘ post-trial follow-upAggregate endpoint 1997 2007Any diabetes-related endpoint RRR = 12% 9% P= 0.029 0.040Microvascular disease RRR = 25% 24% P= 0.0099 0.001MI RRR = 16% 15% P= 0.052 0.014All-cause mortality RRR = 6% 13% P= 0.44 0.007MI=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/. Accessed12 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 generatea good legacy effect 9 Conventional Median HbA1c (%) Metformin 8 7 Legacy effect 6 0 UKPDS 1998 Holman et al 2008 1997 2007 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 mortalityHbA1c=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/. Accessed12 September, 2008; Holman RR, et al. N Engl J Med. 2008; 359: 1577–1589; UKPDS 33. Lancet. 1998; 352: 837–853.
  • 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 CVDExecutive 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 glucosehomeostasis + – Insulin* Glucose Glucagon*(plasma concentration) (plasma concentration) (plasma concentration) – +*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.
  • 15. Pancreatic islet dysfunction leads to hyperglycemia in T2DM Fewer -cells -cells Hypertrophy Insufficient Excessive Insulin Glucagon + – + ↑ Glucose↓ Glucose ↑ HGO Uptake 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. Inadequate -cell compensation for insulin resistance 95% CI Nonprogressors (n=23) Insulin secretion NGT NGT NGT NGT IGT Progressors (n=11) T2DM Resistant Insulin resistance SensitiveCI=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.
  • 17. Insulin secretion deteriorates with progressiveimpairment of glucose tolerance Hyperglycemic Clamp Plasma Glucose N=58 Insulin Response 250 500 400 Insulin (pmol/L)Glucose (mg/dL) 200 300 150 200 100 100 50 0 –20 0 20 40 60 80 100 120 140 –20 0 20 40 60 80 100 120 140 Time (min) Time (min) NGT IGT T2DM 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.
  • 18. β-cell function declines while insulin sensitivityremains stable over course of T2DM—Belfast Diet Study N=432 β-cell Function Insulin Sensitivity 80 80 60 HOMA %B 40 HOMA %S 40 20 20 0 0 0 2 4 6 0 2 4 6 Years from Diagnosis Years from Diagnosis Diet only 2–4 5–7 8–10 Years in which progression necessitated adding oral hypoglycemic* or insulinHOMA=homeostasis model assessment; T2DM=type 2 diabetes mellitus.*Tolbutamide, metformin.Adapted from Levy J, et al. Diabet Med. 1998; 15: 290–296.
  • 19. Treatment targets: deteriorating islet cell function in thesetting of insulin resistance Age,life style, environmental factors Insulin resistance Diabetes onset Islet cell function Prediabetes NGT Diabetes (IFG / IGT)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.
  • 20. 2.2) α-cells sensitivity to glucose is impaired in T2DM, resulting inexcessive glucagon secretion, leading to excess glucoseproduction from the liver
  • 21. Roles of insulin and glucagon in normal glucosehomeostasis + – Insulin* Glucose Glucagon*(plasma concentration) (plasma concentration) (plasma concentration) – +*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.
  • 22. Pancreatic islet dysfunction leads to hyperglycemia in T2DM Fewer -cells -cells Hypertrophy Insufficient Excessive Insulin Glucagon + – + ↑ Glucose↓ Glucose ↑ HGO Uptake 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. Elevated glucagon not only in T2DM but in IGT as well ( insulin / glucagon ratio) IGT T2DM 250 CHO meal Glucose 400 200mg/dL 300 mg/dL 150 Glucose NGT 200 NGT IGT 100 T2DM 100 Glucose 50 0 600 150 μU/mLpmol/L 400 Insulin NGT 100 IGT NGT 200 Insulin 50 T2DM 0 0 45 Glucagon 150 40 125 Glucagonpmol/L pg/mL 35 NGT 100 30 IGT NGT 25 T2DM 75 -60 0 60 120 180 240 300 Time (min) -60 0 60 120 180 240 Time (min) IGT=impaired glucose tolerance; NGT=normal glucose tolerance. CHO=carbohydrate; NGT=normal glucose tolerance; T2DM=type 2 diabetes mellitus. Adapted from Mitrakou A, et al. N Engl J Med. 1992; 326: 22–29. Adapted from Müller WA, et al. N Engl J Med. 1970; 283: 109–115.
  • 24. Suppression of endogenous glucose production isimpaired in T2DM Meal 18 NGT (n=12) T2DM (n=18) Endogenous Glucose 14 (µmol/min/kg) 10 6 2 –30 –15 0 30 60 90 120 150 180 210 240 270 300 Time (min)NGT=normal glucose tolerance; T2DM=type 2 diabetes mellitus.Adapted from Kelley D, et al. Metabolism. 1994; 43: 1549–1557.
  • 25. 2.3) β-cells mass progressively declines, loses sensitivity to glucoseleading to insufficient insulin secretion
  • 26. Roles of insulin and glucagon in normal glucosehomeostasis + – Insulin* Glucose Glucagon*(plasma concentration) (plasma concentration) (plasma concentration) – +*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.
  • 27. Pancreatic islet dysfunction leads to hyperglycemia in T2DM Fewer -cells -cells Hypertrophy Insufficient Excessive Insulin Glucagon + – + ↑ Glucose↓ Glucose ↑ HGO Uptake 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. Inadequate -cell compensation for insulin resistance 95% CI Nonprogressors (n=23) Insulin secretion NGT NGT NGT NGT IGT Progressors (n=11) T2DM Resistant Insulin resistance SensitiveCI=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.
  • 29. Compensatory increase in β-cell insulin secretion failsduring progression of T2DM N=149 25 Fasting Plasma Insulin (µU/mL) 20 15 10 5 0 0 60 100 140 180 220 260 260 Fasting Plasma Glucose (mg/dL)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.
  • 30. β-cell function continues to decline regardless ofintervention in T2DM Progressive Loss of β-cell Function Sulfonylurea (n=511) 100 Occurs prior to Diagnosis Diet (n=110) Metformin (n=159) 80 β-cell Function (%)* 60 40 20 0 –5 –4 –3 –2 –1 0 1 2 3 4 5 6 Years since DiagnosisT2DM=type 2 diabetes mellitus.*β-cell function measured by homeostasis model assessment (HOMA).Adapted from UKPDS Group. Diabetes. 1995; 44: 1249–1258.
  • 31. Insufficient or impaired insulin not only in T2DM but inIGT as well ( insulin / glucagon ratio) IGT T2DM 250 CHO meal Glucose 400 200mg/dL 300 mg/dL 150 Glucose NGT 200 NGT IGT 100 T2DM 100 Glucose 50 0 600 150 μU/mLpmol/L 400 Insulin NGT 100 IGT NGT 200 Insulin 50 T2DM 0 0 45 Glucagon 150 40 125 Glucagonpmol/L pg/mL 35 NGT 100 30 IGT NGT 25 T2DM 75 -60 0 60 120 180 240 300 Time (min) -60 0 60 120 180 240 Time (min) IGT=impaired glucose tolerance; NGT=normal glucose tolerance. CHO=carbohydrate; NGT=normal glucose tolerance; T2DM=type 2 diabetes mellitus. Adapted from Mitrakou A, et al. N Engl J Med. 1992; 326: 22–29. Adapted from Müller WA, et al. N Engl J Med. 1970; 283: 109–115.
  • 32. 3) Burden of T2DM 3.1) T2DM causes significant clinical complications and financial burden
  • 33. Type 2 diabetes mellitus is associated with a highand 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) 31. 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 triplebetween 2009 and 2034 Spending on people with diabetes 400 336 350 300 (US$billion) 250 171 200 150 113 100 45 165 50 68 0 2009 2034 US data Non-Medicare population Medicare-eligible populationHuang ES et al. Diabetes Care 2009; 32(12): 2225-9.
  • 35. Serious long-term complications in T2DM Brain and Cerebral Eyes Circulation (retinopathy, glaucoma, cataracts) (stroke, TIA) Heart and Coronary Circulation Kidneys (angina, MI, CHF) (nephropathy, ESRD) Peripheral Nervous System (peripheral neuropathy) Peripheral Vascular Tree (peripheral vascular disease, gangrene, amputation)CHF=congestive heart failure; ESRD=end-stage renal disease;MI=myocardial infarction; TIA=transient ischemic attack; T2DM=type 2 diabetes mellitus.Adapted from International Diabetes Federation. Complications. Available at: http://www.eatlas.idf.org/complications. Accessed April 14, 2006.
  • 36. Microvascular and macrovascular complications are the key drivers of the costs associated with type 2 diabetes Effect of Complications on Average Cost per Patient 4.0 3.5x 3.5 3.0Cost Impact Factor 2.5 2.0x 2.0 1.7x 1.5 1.0x 1.0 0.5 0.0 No Complications Microvascular Macrovascular Microvascular & Macrovascular Incremental cost due to complications Base cost without complicationsCosts were assessed retrospectively for 6 monthsSource: CODE-2 Study. Williams R et al. Diabetologia 2002; 45: S13-S17.
  • 37. Diabetes-related healthcare expenditures Breakdown of Direct Diabetes Breakdown of Costs per Patient Pharmacotherapy for Diabetes Patients 2% Anti-infectives Hospitalizations Ambulatory 6% Gastrointestinal 18% 11% Insulin 13% Oral antidiabetic 7% Cardiovascular 55% 42% and lipid lowering 21% Other medications 26% Other Source: Jonsson B et al. Diabetologia 2002; 45: S5-S12.
  • 38. Economic burden of type 2 diabetes continues to rise in both developed countries and emerging markets• Direct costs for diabetes-related care are projected to reach USD 376 billion globally in 2010 and USD 490 billion by 2030 Estimated 2010 Total Costs Estimated 2010 Cost for Diabetes (US$ Bn) per Patient (US$) 198 7383 28 4141 22 3751 3574 17 3125 8 5 115 US UK France Germany China Japan US UK France Germany China JapanSource: IDF Diabetes Atlas 2009 www.eatlas.idf.org
  • 39. Vildagliptin is a cost effective alternative vs. pioglitazone 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“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
  • 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 Treatment difference (95% CI) Rosiglitazone vs metformin, 0.13 ( 0.22 to 0.05); P=0.002 8.0 Rosiglitazone vs glyburide, 0.42 ( 0.50 to 0.33); P <0.001 7.6 7.2 HbA1c (%) 6.8 Annualized slope (95% CI) 6.4 Rosiglitazone, 0.07 (0.06 to 0.09) Metformin, 0.14 (0.13 to 0.16)* Glyburide, 0.24 (0.23 to 0.26)* 6.0 0 0 1 2 3 4 5 Time (Years) No. of Patients 4012 3308 2991 2583 2197 822*Significant difference rosiglitazone vs other treatment groups with Hochberg adjustment.Kahn SE, et al. N Engl J Med. 2006; 355: 2427–2443.
  • 42. Most patients with T2DM do not achieve HbA1c goals Percentages of Adults reaching targets (Data from European countries) % patients reaching target A1C <6.5% 6.5<= A1C <=7.6% 7.6% < A1CReal-Life Effectiveness and Care Patterns of Diabetes Management (RECAP-DM) studyAlvarez Guisasola F. et al. Diab Metab Obes. 2008. 10 (suppl 1): 8-15
  • 43. 4.2) Mechanism of action of different anti-diabetic treatments
  • 44. Pharmacologic targets of current drugs used inthe treatment of T2DMGLP-1 analogs DPP-4 inhibitorsImprove pancreatic islet glucose sensing, Prolong GLP-1 action leading to improvedslow gastric emptying, improve satiety pancreatic islet glucose sensing, increase glucose uptake 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 -glucosidase inhibitors Delay intestinal carbohydrate Glinides absorption Increase insulin secretion from pancreatic -cellsDDP-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.
  • 45. 4.3) Use of SUs is associated with hypoglycemia and weight gain
  • 46. Sulphonylureas do not work in glucose-dependent manner increasing risk of hypoglycemia SU X Pancreatic cell K+ Pancreas Insulin Release of insulin • Increased secretion of insulin independently of glucose level • Increased risk of hypoglycemia • Chronic effect: weight gain due to defensive eating*Adapted from: Cheng AYY, et al CMAJ. 2005; 172: 213–216.* Levy AR et al. Health and Quality of Life Outcomes 2008, 6:73
  • 47. Risk of hypoglycemia with different sulfonylureas 30 25 Relative Risk (%) 20 15 10 5 0Severe hypoglycemia* Gliclazide Glipizide Glimepiride Tolbutamide Chlorpropamide Glyburiden/1000 person years = 0.85 8.70 0.86 3.50 16.00 16.00 *<50 mg/dL. Tayek J. Diabetes Obes Metab. 2008; 10: 1128–1130.
  • 48. Hypoglycemia and QoL:The impact can be substantial for both patients and caregiversShort-term consequences: unpleasant symptoms (and potential risky situations) relatedwith the actual episodeLong-term consequences: pattern of ―fear of hypoglycemia‖ with negative impact onpatients HRQOL‖ 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 havent attained clinical goals and whom intensification is likely to benefit."HRQoL=health-related quality of life.Levy AR, et al. Health Qual Life Outcomes. 2008, 6: 73.
  • 49. Weight gain is a common side effect of treatments withSU OAD Agents Weight Change (kg) -3.8–0.5 Metformin1–3 -0.4–1.7 SUs1–4 0.9–4.6 TZDs4–6 0.3–3.0 Meglitinides4,7,8 -0.3–1.9 Metformin + SU1–3 0.8–2.1 Metformin + TZD5,6,9 −5 −4 −3 −2 −1 0 1 2 3 4 5OAD=oral antidiabetic agent; SU=sulfonylurea; TZD=thiazolidinedione.1Glucophage [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company, 2004. 2Glucovance [package insert]. Princeton, NJ: Bristol-MeyersSquibb 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.
  • 50. Vildagliptin vs glimepiride as add on to metformin: No severe hypoglycemic events at 2 years Patients with one Number of Number of Discontinuation or more hypoglycemic Severe hypo due to hypoglycemic events events* hypoglycemia events (%) 16 15 20 900 838 18.2 14 14 13 800 12 Number of events Number of events Number of events 16 700 12 600 10 10 Incidence (%) 12 500 8 8 400 8 6 6 300 4 4 200 4 2.3 100 59 2 2 0 0 0 0 0 0This hypoglycemic profile was maintained in patients > 65 years Vilda 50 mg bid + Met (n=1553)Safety population; * any episode requiring the assistance of another party Glim up to 6 mg qd + Met (n=1546)Vilda= vildagliptin; Glim= glimepiride; Met= metforminMatthews DR et al Diab Obes Metab. 2010; 12:780-789
  • 51. Vildagliptin was as effective as glimepiride when added to metformin at104 weeks with no weight gain and low incidence of hypoglycemiaDuration: 104 weeks, add-on to metformin:vildagliptin vs glimepiride Hypoglycaemia 2 Patients with > 1 hypo (%) Number of hypo events Number of severe events a Discontinuations due to hypos N = 1553 1546 N = 1553 1546 N= 1553 1546 N = 1553 1546 18.2 15 16 16 13 14 No. of events 14 Incidence (%) 12 No. of events No. of events 12 10 10 8 8 6 6 4 4 2 0 2 0 59 0 0 Mean HbA1c 1 Change in body weight 3 Change from BL to EP Between-treatment Adjusted mean change in HbA1c was comparable between (BL Mean ~89kg) Difference vildagliptin and glimepiride treatment: −0.1% (0.0%) for both Adjusted mean change n = 1539 1520 in body weight (kg) 2.0 1.2 Primary objective of non-inferiority was met: 1.0 97.5% CI= (-0.00, 0.17); upper limit 0.3% 0.0 Vildagliptin 50 mg bid + met Glimepiride up to 6 mg qd +met -1.0 -0.3 -1.5 -2.0 *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. 51
  • 52. Vildagliptin: weight loss vs. glimepiride as add on to metformin at 2 years Change from BL to EP Between-treatment (BL Mean ~ 89 kg) difference N= 1539 1520 2.0 Adjusted Mean Change in 1.5 1.2 Body weight (kg) 1.0 0.5 0.0 -0.5 -0.3 -1.0 -1.5 -1.5 -2.0 * Vilda 50 mg twice daily + met Glim up to 6 mg once daily + metIntention-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
  • 53. Weight gain is a common side effect of diabetes treatments AGISEffect of Noninsulin Antidiabetic Drugs Added to Metformin Therapy on Glycemic Control, WeightGain, and Hypoglycemia in Type 2 DiabetesOlivia J. Phung; Jennifer M. Scholle; Mehak Talwar; Coleman, CI. JAMA. 2010;303(14):1410-1418
  • 54. 4.4) Use of TZDs is associated with weight gain, edema, cardiovascularrisk and bone fractures
  • 55. TZDs increase conversion from preadipocytes into adipocytes in fat tissue as wellas in the bone marrow, consequently decreasing other pathways leading toosteoblasts, erythrocytes or lymphocytes Osteoblast Preosteoblast Bone formation Mesenchymal stem cell PPARɣ Adipocyte Preadipocyte Totipotent + Stem cell TZDs Myeloid Precursors Hematopoietic Erythroid lineage Stem cell Myeloid, Monocyte, Granulocyte lineages Lymphoid Precursors T, NK, B cell lineages Preosteoclast Osteoclast*PPARγ agonists determine MSC lineage commitmenttowards adipocytes instead of osteoblasts or erythrocytesAdapted from Rosen et al. Nat Clin Pract Rheumatol 2006, 2:35-43 and Payne et al Medical Hypothesis 2007, 69:778-786.
  • 56. PROactive: incidence of edema, and magnitude ofweight gain with pioglitazone % of Edema without HF Weight Gain (kg) 25 4 3.6 21.6 P <0.0001 20 3 15 13.0 2 10 1 5 0 -0.4 0 -1 Pioglitazone <45 mg daily PlaceboHF=heart failure.Adapted from Dormandy JA, et al. Lancet. 2005; 366: 1279–1289.
  • 57. Weight gain is a common side effect of diabetes treatments AGISEffect of Noninsulin Antidiabetic Drugs Added to Metformin Therapy on Glycemic Control, WeightGain, and Hypoglycemia in Type 2 DiabetesOlivia J. Phung; Jennifer M. Scholle; Mehak Talwar; Coleman, CI. JAMA. 2010;303(14):1410-1418
  • 58. Edema is common with TZDs (pioglitazone) 18 Pioglitazone1 Proportion of Patients (%) 16 Placebo or combination 15.3 14 12 10 8 7.2 7.0 6.0 6 4.8 4 2.5 2.1 2 1.2 0 Monotherapy Combination Combination Combination with SU with with insulin metforminTZDs=thiazolidinediones.1Actos [prescribing information]. Indianapolis, IN: Eli Lilly and Company, 2004.
  • 59. Use of TZDs is associated with increased incidence ofcongestive heart failure DREAM Study PROactive Study 20 P=0.01 15 P <0.0001Number of CHF Events 14 15 Patients with HF (%) 11 10 10 8 5 5 2 0 0 Rosiglitazone Pioglitazone ≤45 mg daily Placebo PlaceboCHF=congestive heart failure; TZDs=thiazolidinediones. HF=heart failureAdapted from DREAM Trial Investigators, et al. Lancet. 2006; 368: 1096–1105. Adapted from Dormandy JA, et al. Lancet. 2005; 366: 1279–1289.
  • 60. Risk of myocardial infarction and death fromcardiovascular causes with rosiglitazone Myocardial infarction Small trials combined 1.45; P=0.15 DREAM 1.65; P=0.22 ADOPT 1.33; P=0.27 Overall 1.43 (1.03–1.98) P=0.03Death from CV causes 2.40; P=0.02 Small trials combined DREAM 1.20; P=0.67 ADOPT 0.80; P=0.78 Overall 1.64 (0.98–2.74) P=0.06 0.5 1.0 2.0 4.0 Log Odds Ratio (95% CI)CI=confidence interval; CV=cardiovascular.Adapted from Nissen SE, Wolski K. N Engl J Med. 2007; 356: 2457–2471.
  • 61. RECORD study results: secondary endpoints – cardiovascular Rosiglitazone Control (n=2220) (n=2227) Hazard ratio (95% CI) Death All cause 136 157 0.86 (0.68, 1.08); P=0.19 CV 60 71 0.84 (0.59, 1.18); P=0.32 MI 64 56 1.14 (0.80, 1.63); P=0.47 Stroke 46 63 0.72 (0.49, 1.06); P=0.10 CV death, 154 165 0.93 (0.74, 1.15); P=0.50 MI or stroke Heart failure* 61 29 2.10 (1.35, 3.27); P=0.001 0.5 1.0 2.0 3.0 4.0 *Fatal and non-fatal. CI=confidence interval; CV=cardiovascular; MI=myocardial infarction. Hazard Ratio (95% CI) Home PD et al. Lancet. 2009; 373: 2125–2135.
  • 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 wasalmost twice as high with rosiglitazone compared to metformin-treatedpatients 10 9.3 Rosiglitazone (n=1456) Metformin (n=1454) 8 Glyburide (n=1441) Patients (%) 6 * 5.6 5.1 * ** 4 3.5 3.4 3.1 * ** 1.7 1.5 2 1.3 0 Overall Lower limb Upper limb*P <0.01; **P <0.05 vs rosiglitazone (unadjusted, contingency 2 test).Kahn SE, et al. N Engl J Med. 2006; 355: 2427–2443.
  • 64. RECORD study results: increased limb fractures inpatients with rosiglitazone Rosiglitazone Active control Overall incidence of bone fractures higher with rosiglitazone (p<0.0001*) Patients (%) All Upper Distal lower All Upper Distal lower limb limb limb limb n (events) 124 68 63 36 47 16 61 50 23 19 23 11 N (patients) 1078 1075 1078 1075 1078 1075 1142 1152 1142 1152 1142 1152 Women Men*P <0.0001 Rosiglitazone vs controlHome PD, et al. Lancet. 2009; 373: 2125–2135.
  • 65. Pioglitazone has a similar risk of fractures as rosiglitazone 77% increased risk of peripheral fracture in women2Aubert RE, et al. Diabetes Obes Metab. 2010;12(8):716-721Colin R. Arch Intern Med. 2009;169(15):1395-1402.
  • 66. Number needed to harm via excess fractures with TZDsranges from 21 to 551-year number need to harm range from 21 - 55 Population Baseline risk Odds ratio of 1-year number Excess fractures of fractures fracture (95% CI) needed to with TZD use per per 1000 from meta- harm* (95% CI) 100 patient-years Patent-years analysis (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 28.6 2.23 (1.65-3.01) 31 (19-57) 32 (18-53) Study; mean age 65 years 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. *mean age 56 years; diabetes diagnosed within 3 years before study; no previous use of oral hypoglycemic agentLoke YK, Singh S. Furberg C. Long-term use of thiazolidinediones and fractures in type 2diabetes: a meta-analysis CMAJ Jan 6 2009 180 (1)
  • 67. In patients failing on metformin vildagliptin is the only DPP-4 inhibitor showing similar efficacy to pioglitazone at 1 year without weight gainDuration: 52 weeks add-on to metformin: vildagliptin vs pioglitazone 9.0 Change in HbA1c Change in Body Weight (Mean BL Body Weight ~91 kg) 24-week analysis 8.5 Vilda NI Mean HbA1c (%) established * Change in Body Weight (kg) 8.0 Unadjusted Mean 7.5 7.0 −4 0 4 12 16 24 32 40 52 n=293 n=277 Time (Weeks) *P <0.001 change from baseline Vildagliptin 50 mg bid + Pioglitazone 30 mg od + metformin metformin 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.
  • 68. Pioglitazone added greater body weight burden to obesepatients (BMI >35 kg/m2)Duration: 24 weeksAdd-on to met:vilda vs pio All Patients BMI >35 kg/m2 Mean BL ~91.8 kg Mean BL ~110.4 kg n= 264 246 73 70 3.0 Vilda 50 mg twice daily + met * 2.6 Body Weight (kg) to Week 24 Pio 30 mg once daily + met Adjusted Mean Change in 2.5 * 1.9 2.0 1.5 1.0 0.5 0.3 0.1 0.0BL=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.
  • 69. Vildagliptin demonstrated to be likely more cost-effective thanpioglitazone - even without considering the recent evidence on theincreased risk of fractures in men an womenVildagliptin vs pioglitazone as add-on to metformin Costs QALYs Net ICER benefit Vildagliptin Pioglitazone Diff % Vildagliptin Pioglitazone Diff % 0.001 0.01 Vildagliptin £20,222 £20,245 -£23 -0.1% 9.4541 9.4527 £50 dominates 4 % 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 treatmentQALY: quality adjusted life year; ICER: incremental cost-effectiveness ratio; net benefit: (payer acceptability threshold £20l x ΔQALYs) – Δ costs Pricingassumption: Vildagliptin at £1.20 for 100mg dailyEfficacy data based on study LAF237A2354Source: http://www.ispor.org/congresses/Greece1108/Posters2.aspxESTIMATING THE COST EFFECTIVENESS IN THE UK OF VILDAGLIPTIN COMPARED TO PIOGLITAZONE AS ADD-ON THERAPY TO METFORMIN USING THE SHEFFIELDTYPE 2 DIABETES MODEL Brennan A, Gillett M, Duenas A , University of Sheffield, Sheffield, United Kingdom
  • 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) Proportion of Length of stay per Total cost Fracture site fractures hospitalization (days) per fracture hospitalized Hip 100% 26.0 £10,760 Vertebrae 35% 15.0 £1,706 Proximal 32% 10.6 £1,112 humerus Wrist 25% 5.4 £527Data 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 forfractures 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. Womens Health Med 2006;3:149–151 .
  • 72. Fractures have significant health related quality of life impactin elderly women 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% P CI value Comparison condition Arthritis 0.12 0.11-0.12 <0.001 (n=22,331) 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); 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,
  • 73. 4.6) GLP-1 analogs are associated with gastrointestinal adverse events
  • 74. Gastrointestinal adverse events are common duringtreatment with exenatide 50 44% Exenatide (n=963) 45 Placebo (n=483) Proportion of Patients (%) 40 35 30 25 20 18% 15 13% 13% 10 6% 4% 5 0 Nausea Vomiting Diarrhea*In three 30-week placebo-controlled trials.Adapted from Byetta [prescribing information]. San Diego, CA: Amylin Pharmaceuticals Inc, 2005.
  • 75. Incidence of hypoglycemia during treatment with exenatide Exenatide 5 mcg bid 40 Exenatide 10 mcg bid 35.7% 35 Placebo Proportion of Patients (%) 30 27.8% 25 19.2% 20 14.4% 15 12.6% 10 5.3% 4.5% 5.3% 5 3.3% 0 Combination Combination Combination with with metformin with SU metformin + SU 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.
  • 76. 4.7) Hypoglycemia has clinical, social and economic consequences
  • 77. Mechanisms by which hypoglycemia may affectcardiovascular eventsIL6: interleukin 6CRP: C-reactive proteinVEGF: vascular endothelial growth factorDesouza CV et al. Hypoglycemia, Diabetes, and Cardiovascular Events. Diabetes Care 2010; 33: 1389-1394.
  • 78. Hypoglycemia consequences Hospitalization costs4 CV complications5 Weight gain by defensive eating6 Dizzy turn unconsciousness5 Hypoglycemia Seizures5 Car accident3 Increased risk of dementia1 Death2 Coma51: Whitmer RA et al 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, CMRO 26, 1333-1342, 20106. Foley J & Jordan J, Vascular Health Risk Management, 2010 6:541-548
  • 79. Hypoglycemia was a strong predictor of CV death inVADT study Risk of death Lower Higher HR (Lower CL, Upper CL) Hypoglycemia 4.042 (1.449, 11.276)* HbA1c 1.213 (1.038, 1.417)** HDL-C 0.699 (0.536, 0.910)* Age 2.090 (1.518, 2.877)*** Prior event 3.116 (1.744, 5.567)*** 0 2 4 6 8 10 12 Hazard Ratio*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.
  • 80. Hypoglycemia and QoL:The impact can be substantial for both patients and caregiversShort-term consequences: unpleasant symptoms (and potential risky situations) relatedwith the actual episodeLong-term consequences: pattern of ―fear of hypoglycemia‖ with negative impact onpatients HRQOL‖ 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 havent attained clinical goals and whom intensification is likely to benefit."HRQoL=health-related quality of life.Levy AR, et al. Health Qual Life Outcomes. 2008, 6: 73.
  • 81. Hypoglycemia increases costly hospital admissions UK Payer Perspective Costs Of Hypoglycaemia Per NHS Reference Costs HRG Name Non-elective spell % applied in Reduced Weighted Healthcare tariff (£) calculation of short stay Average (£) Resource Group reduced short stay emergency emergency tariff tariff (£) Diabetes with Hypoglycaemic Emergency 2,171 20% 434 1,824 >69 years or with cc Diabetes with Hypoglycaemic Emergency 776 50% 388 582 <70 years without ccUK 2007-08 Admitted Patient Care Mandatory TariffCc = comorbidity or complication; HRG = Healthcare resource groupGillette M, Fitzgerald P, Brennan A. Analysis of the economic impact of hypos – comparison of vildagliptin versus sulphonylurea. Modellingphase report. University of Sheffield, School of Health and Related Research. October 2009. (Prepared for Novartis)
  • 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 GLP-1: Glucagon-like Peptide-1 H A E G T F T S D V S S Y L E G Q A A G R G K V L W A I F E K GIP: Glucose-dependent Insulinotropic Peptide A Y E G T F I S D Y S I A M D K I H Q W D N K K G K Q A L L W N V F D Q K H N I T QAmino acids shown in orange are homologous with the structure of glucagon.
  • 84. GLP-1 and GIP are synthesized and secreted from thegut in response to food Intake L-cell (ileum) ProGIP Proglucagon GLP-1 [7–37] GIP [1–42] K-cell GLP-1 [7–36 NH2] (jejunum)GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1.Adapted from Drucker DJ. Diabetes Care. 2003; 26: 2929–2940.
  • 85. Incretin hormones are the body‘s natural way to maintain glycemic control Food intake Insulin secretion Insulin biosynthesis cell proliferation Pancreas cell survival cells Intestinal secretion of GLP1 (7-36) amide Action on cells Glucose sensing + GIP (1-42) and cells cellsIntestine Glucagon secretion DPP4 DPP4 inhibitors GLP-1 (9-36) amide And GIP (3-42) Blood Glucose levelAdapted from L Baggio and DJ Drucker Gastroenterology 2007 132:2131-2157And DJ Drucker The J Clin Invest 2007, 117:24-32 85
  • 86. Proof of a gastrointestinal ‗incretin effect‘: different responses to oral vs i.v. glucose Oral Glucose Tolerance Test and Matched IV Infusion 200 400Plasma Glucose (mg/dL) 50 g Glucose Plasma Insulin (pmol/L) 150 300 100 200 50 100 0 0 –30 0 30 60 90 120 150 180 210 –30 0 30 60 90 120 150 180 210 Time (min) Time (min) Oral IV N=6 IV=intravenous. Adapted from Nauck MA, et al. J Clin Endocrinol Metab. 1986; 63: 492–498.
  • 87. GLP-1 restores insulin and glucagon responses ina glucose-sensitive manner in patients with T2DMN=10 Glucose (mg/dL) C-peptide (nmol/L) Glucagon (pmol/L)300 3.0 30 GLP-1 infusion GLP-1 infusion GLP-1 infusion250 2.5 25 *200 2.0 * 20 * * * *150 1.5 15 * * * *100 * 1.0 10 * * * *50 * 0.5 5 * * * 0 0.0 0 –30 0 30 60 90 120 150 180 210 240 –30 0 30 60 90 120 150 180 210 240 –30 0 30 60 90 120 150 180 210 240 Time (min) Time (min) Time (min) GLP-1†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. PlaceboAdapted from Nauck MA, et al. Diabetologia. 1993; 36: 741–744.
  • 88. 5.2) Oral DPP-4 inhibitors enhance the physiological effects of incretinhormones such as GLP-1 and GIP
  • 89. Inhibition of DPP-4 increases active GLP-1 Meal Intestinal GLP-1 GLP-1 t½=1–2 min release Active GLP-1 DPP-4 GLP-1 inactive (>80% of pool) DPP-4DPP-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. inhibitorAdapted 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) 120 75 g Glucose 100 Vildagliptin 100 mg (n=15) (pmol/L) Insulin 80 Dose Placebo (n=16) 60 40 20 0 −90 −60 −30 0 30 60 90 120 150 180 210 240 270 300 22.5 (mmol/L) Glucose 17.5 12.5 7.5 −90 −60 −30 0 30 60 90 120 150 180 210 240 270 300 140 120 Glucagon (ng/L) 100 80OGTT=oral glucose tolerance test. 60*P <0.01. −90 −60 −30 0 30 60 90 120 150 180 210 240 270 300He YL, et al. J Clin Pharmacol. 2007; 47: 633–641. TimeVildagliptin 100 mg once daily was used in this study. Galvus (vildagliptin) is approved for 50 mg once or twice daily incombination 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,
  • 91. Acute effects of vildagliptin on GLP-1 levels in patients with T2DM:increased GLP-1 levels that persist beyond the post-meal period Meal 16.0 Vildagliptin 100 mg (n=16) * Placebo (n=16) * 12.0 *Active GLP-1 (pmol/L) * * * * * 8.0 ** * * * 4.0 0.0 17:00 20:00 23:00 02:00 05:00 08:00GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus. Time*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 aTZD, and Galvus (vildagliptin) 50 mg once daily in combination with a sulfonylurea. Galvus is NOT approved for 100 mg qd, 91
  • 92. Effects of vildagliptin and vildagliptin plus metforminon fasting GLP-1 levels Fasting Levels of Intact GLP-1 at Fasting Levels of Intact GLP-1 in Baseline and at 3 Months Vildagliptin Subgroups at 3 Months Vilda group† Placebo Vilda only Vilda + met n= 20 20 19 19 7 13 14 12 14 Intact GLP-1 (pM) 10 12 **Intact GLP-1 (pM) 10 8 * 8 6 6 4 4 2 0 2 0 Vildagliptin: 50 mg bid BL 3 months BL 3 monthsBL=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.
  • 93. 5.3) Mode of action evidence supports potential intra-class differentiationof vildagliptin vs. sitagliptin
  • 94. Vildagliptin vs Sitagliptin: what do we know so far? Chemical structures of DPP-4 inhibitors Competitive inhibitors Substrates acting as inhibitors F F NH2 O F N N N Non- N N Covalent N H covalent (cyanopyrrolidine) NC O HO CF3 Sitagliptin1 Vildagliptin2 O CN H3 C Non- N N H H NH2 covalent N O N NC Covalent O HO NH 3+ PhCO 2- (cyanopyrrolidine) Alogliptin3 Saxagliptin41Januvia 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
  • 95. Different binding kinetics within DPP-4 class Natural K1 K2 substrate: (GLP-1) + K-1 Fast + (~1 sec) GLP-1 DPP-4 DPP-4 GLP-1: DPP-4 Inactive complex GLP-1 Substrate K1 K2 acting as inhibitor: + K-1 Slow (~ 1 h) + Slow dissociation (vildagliptin, saxagliptin) Substrate-like DPP-4 Substrate-like Inactive DPP-4 enzyme blocker enzyme blocker: substrate-like DPP-4 complex enzyme blocker Competitive K1 inhibitor:(sitagliptin, alogl + K-1 iptin) Fast dissociation Inhibitor DPP-4 Inhibitor: DPP-4 complexDPP-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.
  • 96. Comparison of plasma GLP-1 levels following 3 Months‘ treatment with vildagliptin or sitagliptinRetrospective analysis of patients on Vildagliptin 50 mgsitagliptin (N=20) or vildagliptin (N=18) twice daily + metformin (N=18) 30 Sitagliptin 100 mg once daily + metformin (N=20) 25 Intact GLP-1 (pmol/L) 20 15 10 5 0 -20 0 15 30 60 90 120 180 240 300 0 15 30 60 90 120 180 240 300 0 15 30 60 90 120 180 240 300 min Breakfast Lunch Dinner 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..
  • 97. Vildagliptin Add-on to Insulin: Significant Reduction inHbA1c and Fewer Hypoglycemic EventsDuration: 24 weeksAdd-on to insulin: Add-on Treatment to Insulinvilda vs PBO Overall Mean BL = 8.4% >65 Years Mean BL = 8.4% n= 140 149 42 41 0.0 Change in HbA1c (%) -0.2 -0.1 -0.2 -0.4 -0.6 -0.5 Vilda 50 mg twice daily + insulin -0.8 * PBO + insulin -0.7 ** No. of Hypoglycemic Events No. of Severe Hypoglycemic Events * 185 No. of Severe Events 200 160 10 No. of Events 113 8 ** 120 6 6 80 4 40 2 0 0 0PBO=placebo; vilda=vildagliptin; *P <0.001; **P <0.05 between groups.Fonseca V, et al. Diabetologia. 2007; 50: 1148–1155.
  • 98. Sitagliptin in add-on to insulin setting Mean insulin dose ~50 U/day HbA1c (%) Symptomatic hypoglycaemia 8.7 18 8.6 16 8.6 Placebo 16 Sitagliptin 14 8.5 8.4 12 Patients (%) HbA1c (%) 8.3 10 8 8.2 8 8.1 8.1 6 8.0 4 7.9 2 7.8 0 Placebo Sitagliptin Placebo * Sitagliptin ** 1 severe hypo in placebo 2 severe hypos with Sitagliptin Vilsbøll T, et al. Diabetes Obes Metab 2010;12:167–177 98
  • 99. Acute effects of vildagliptin on GLP-1 levels in patients with T2DM:increased GLP-1 levels that persist beyond the post-meal period Meal 16.0 Vildagliptin 100 mg (n=16) * Placebo (n=16) * 12.0 *Active GLP-1 (pmol/L) * * * * * 8.0 ** * * * 4.0 0.0 17:00 20:00 23:00 02:00 05:00 08:00GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus. Time*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 aTZD, and Galvus (vildagliptin) 50 mg once daily in combination with a sulfonylurea. Galvus is NOT approved for 100 mg qd, 99
  • 100. Acute effects of vildagliptin on glucagon levels in patients with T2DM:decreased glucagon levels persist beyond the post-meal period Meal 20 Vildagliptin 100 mg (n=16) 10 Placebo (n=16) 0Delta Glucagon (ng/L) −10 −20 * −30 * −40 * * −50 * * * * * −60 17:00 20:00 23:00 02:00 05:00 08:00*P <0.05 vs placebo. TimeBalas 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 withmetformin or a TZD, and Galvus (vildagliptin) 50 mg once daily in combination with a sulfonylurea. Galvus is NOT approved for 100 mg qd, 100
  • 101. Acute effects of vildagliptin on endogenous glucose production (EGP)levels in patients with T2DM: decreased EGP levels persist beyondpost-meal period Meal Time 17:00 20:00 23:00 02:00 05:00 08:00 0 −0.3 Delta EGP (mg/kg/min) −0.6 * * * * * * * * * * −0.9 * * −1.2 * * * Vildagliptin 100 mg (n=16) ** * * ** * * * * * * * Placebo (n=16) −1.5EGP=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,
  • 102. 6) Vildagliptin in monotherapy settings 6.1) Vildagliptin demonstrates favorable efficacy and tolerability profile in monotherapy settings
  • 103. Vildagliptin comprehensive phase III clinicaldevelopment program Glucose Early Type 2 Advanced Diabetic intolerance Diabetes Type 2 Diabetes Complications Efficacy/safety Add-on to metformin: Moderate and in IFG in mono settings vs. vs. PBO severe renal PBO (2) - Genaral population In IGT - Chinese population impairment (ongoing) Mono vs PBO, Japan In mild vs TZD (pioglitazone) CHF (ongoing) hyperglycemia Mono long-term safety, vs SU (glim. or glicl.) Japan - Low BLHbA1c - High BL HbA1c H2H vs TZD (rosiglitazone) vs up-titration of met H2H vs met (2) Initial combination met -General population -Elderly Add-on to TZD (p incl H2H vs SU (glicl.) Japanio): - PBO controlled - Initial combo H2H vs α-GI (acarbose), China Add-on to SU (glim) Add-on to SU H2H vs α-GI (glim), Japan Asian studies (voglibose), Japan Add-on insulin
  • 104. Vildagliptin monotherapy in IGT :study design and objective 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) n=90: Vildagliptin 50 mg once daily N=179 Study Design Study Design IGT patients n=89: Placebo diagnosed by OGTT 4 weeks 12 weeksFPG=fasting plasma glucose; IGT=impaired glucose tolerance; OGTT=oral glucose tolerance test.Rosenstock J, et al. Diabetes Care. 2008; 31: 30–35.
  • 105. Vildagliptin‘s effect on GLP-1 and glucagon is fully evident in IGT populationa 12.0 Vildagliptin 50 mg once daily (n=89) b 9.0 GLP-1 Placebo (n=89) Glucose Glucose (mmol/L) Meal Meal GLP-1 (pmol/L) 8.0 8.0 4.0 7.0 0.0 6.0 –30 0 30 60 90 120 –30 0 30 60 90 120 Time (min) Time (min)c 8.0 d 26 β-cell Function Glucagon Vildagliptin 50 mg once daily (n=89) MealISR AUC0-2h / Glucose AUC0-2h 6.0 * Placebo (n=89) 24 (pmol/L•min-1•m-2•mM) Glucagon (pmol/L) 4.0 22 2.0 0.0 20 –2.0 18 –4.0 –30 0 30 60 90 120 Insulin secretion relative to glucose Time (min) Intention-to-treat population. *P=0.002 vs placebo. Rosenstock J, et al. Diabetes Care. 2008: 31: 30–35.
  • 106. Vildagliptin in T2DM patients with mild hyperglycemia:study design and objective 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 Core Extension** n=156: Vilda 50 mg once daily n=68: Vilda 50 mg once daily N=306* Washout Washout n=150: Placebo n=63: Placebo 2 weeks 52 weeks 4 weeks 52 weeks 4 weeks*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.
  • 107. Vildagliptin therapeutic effects are fully manifested in patients withmild hyperglycemia : change from baseline in HbA1c Duration: 2 years Vildagliptin vs placebo Change from BL to EP Mean Difference vs Placebo (BL Mean ~6.64%) n= 67 63 0.6 * 0.5 0.5 Mean Change in HbA1c (%) 0.4 Vildagliptin 50 mg once daily Placebo 0.3 0.2 0.1 0.1 0.0 -0.1 -0.2 -0.3 -0.4 -0.5 -0.4 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.
  • 108. Vildagliptin efficacy in mild hyperglycemia:mean HbA1c over 112 weeksDuration: 2 yearsVildagliptin Treatment period Wk 0–52 Washout Treatment period Wk 56–108 Washoutvs placebo Mean HbA1c (%)Extension intention-to-treat population.HbA1c=hemoglobin A1c. Time (Weeks)--- = washout period (52-56 weeks, 108-112 weeks);vildagliptin (n=67 at Week 0, 56 at Week 108, 51 at Week 112); Vildagliptin 50 mg once dailyplacebo (n=63 at Week 0, 47 at Week 108, 44 at Week 112).Scherbaum WA, et al. Diabetes Obes Metab. 2008; 10: 1114–1124. Placebo
  • 109. Vildagliptin efficacy in mild hyperglycemia:maintenance of effects after washoutDuration: 2 yearsVildagliptinvs placebo Change from BL to Week 112 Mean Difference vs (BL Mean ~6.64) Placebo n= 57 50 0.6 * Mean Change in HbA1c (%) 0.4 0.4 0.2 0.1 0.0 -0.2 -0.4 -0.3 Vildagliptin 50 mg once daily -0.6 PlaceboExtension 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.
  • 110. Vildagliptin dose-ranging study:study design and objective 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% n=88: Vildagliptin 50 mg once daily n=83: Vildagliptin 50 mg twice daily N=354 n=91: Vildagliptin 100 mg once daily* Drug-naïve n=92: Placebo 2 weeks 24 weeksHbA1c=hemoglobin A1c; T2DM=type 2 diabetes mellitus. *100 mg once daily is NOT an approved dosePi-Sunyer FX, et al. Diabetes Res Clin Pract. 2007; 76: 132–138.
  • 111. Vildagliptin dose-ranging study: efficacy over 24 weeks without weight gain Change in FPG from BL vs Placebo HbA1c Mean BL ~10.5 mmol/L 9.0 Change in FPG (mmol/L) 0.4 8.6 Mean HbA1c (%) 0.0 8.2 -0.4 -0.8 -0.6 7.8 -1.2 * ** -1.6 -1.3 -1.3 7.4 ** ** ** 7.0 -4 -2 0 2 4 6 8 10 12 14 16 18 20 22 24 Time (Weeks) * p=0.01 **p <0.001 vs placebo. Vildagliptin 50 mg once daily (n=84) HbA1c=hemoglobin A1c. Vildagliptin 50 mg twice daily (n=79) BL=baseline; FPG=fasting plasma glucose. Vildagliptin 100 mg once daily (n=89) Primary intention-to-treat population. Placebo (n=88) 100 mg once daily is NOT an approved dosePi-Sunyer FX, et al. Diabetes Res Clin Pract. 2007; 76: 132–138.
  • 112. Vildagliptin vs rosiglitazone: study design and objective 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% Core studya Extension studyb n=459 n=354: Vildagliptin 50 mg twice daily N=697* Drug-naïve n=238 n=179: Rosiglitazone 8 mg once daily 2 weeks 24 weeks 80 weeksHbA1c=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 oralantidiabetic agents for at least 12 weeks prior to study entry (visit 1) and no treatment with oral antidiabetic agents >3 consecutive months at anytime 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 patientstreated 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.
  • 113. Vildagliptin provides HbA1c reductions that are sustained over two years of treatment Vildagliptin vs rosiglitazone: 104 weeksa (including 80-week extension to the 24-week core study) Change in HbA1c Change in Body Weight Not NI* −4.7kg P<0.001** 14 TG TC LDL-C HDL-C Adjusted mean % change 12 10 8 6 4 2 0 Vildagliptin 50 mg bid −2 Rosiglitazone 8 mg qd −4 −6 ** ** −8*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.
  • 114. Vildagliptin vs metformin: study design and objective Objective: to demonstrate that HbA1c reduction with vildagliptin is not inferior to metformin Target population: drug-naïve patients with T2DM; HbA1c 7.5–11% Core study† Extension study†† n=526: Vildagliptin 50 mg n=300a twice daily N=780* Drug-naïve n=254: Metformin 1000 mg n=158a twice daily 2 weeks 52 weeks 52 weeksHbA1c=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 hadhad 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.
  • 115. Vildagliptin vs metformin monotherapy :HbA1c efficacy and tolerability at 2 yearsDuration: 104 weeks (including 52-week extension to the 52-week core study)Vildagliptin vs metformin Mean HbA1c (%) Gastrointestinal AE Incidence (%) 509.5 45.6 Vildagliptin 50 mg twice daily9.0 Metformin 1000 mg twice daily 408.5 ** 30 25.08.0 207.5 Not NI*7.0 106.5 0 −2 0 4 8 12 16 24 32 40 52 64 76 88 104 Time (Weeks)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.
  • 116. Vildagliptin compared to metformin in elderly treatment-naïvepatients: study design and objective 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=169 Vilda 100 mg qd N* = 335 n=166 Met up to 1500 mg daily** 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 weeksT2DM= Type 2 diabetes mellitus; Met= metformin; Vilda= vildagliptin; HbA1c= glycosylated hemoglobin.Schweizer et al Diabetes, Obesity and Metabolism 2009, 11:804-812.
  • 117. Vildagliptin in elderly patients:similar HbA1c reductions compared to metformin Change from BL to EP Between-treatment Mean BL ~ 7.7% difference N= 159 161 0.2 0.11 0.0 Adjusted Mean Change -0.2 in HbA1c (%) -0.4 -0.6 -0.64 -0.8 -0.75 Vildagliptin 100 mg once daily Metformin 1500 mg once daily -1.0 Non-inferior* Vildagliptin 100 mg qd is not approved.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. 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 Vilda 100 mg qd Met 1500 mg/daily AE preferred term, % patients N=167 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 3.0Safety populationVilda= vildagliptin; Met= metformin; AE= adverse eventsA patient with multiple occurrences of an AE under 1 treatment is counted only once in the AE categoryData on file, Novartis Pharmaceuticals, LAF237A2398.Schweizer A, et al. Diabetes Obes Metab. 2009; 11: 804–812.
  • 119. Long term efficacy and safety of vildagliptin vs SU:study design and objective 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 Vildagliptin 50 mg bid N* = 1092 n=546 Gliclazide up to 320 mg daily 2 weeks 104 weeks*Randomized populationT2DM= 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
  • 120. Vildagliptin vs gliclazide in monotherapy setting: less weight gain and less hypoglycemia despite the unmet non inferiority HbA1c Change(a) Body weight Change(a) Hypoglycemia(b) from BL to EP from BL to EPAdjusted Mean Change Mean Change in Body % patients with mild in HbA1c (%) hypoglycemia † weight (kg) Vilda 50 mg bid Glic up to 320 mg dailya: per protocolepopulation; b: safety population 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 41:909 120
  • 121. Vildagliptin vs acarbose in Chinese population:study design and objective 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=441 Vildagliptin 50 mg bid N=661* Drug naïve n=220 Acarbose ≤100 mg tid 2 weeks 24 weeks* Randomized population.HbA1c=glycosylated hemoglobin; T2DM=type 2 diabetes mellitusPan C. et al. Diabeteic Medicine. 2008. 25:435-441
  • 122. Vildagliptin is as effective as acarbose but with half theincidence of gastrointestinal side effects Change from BL to EP* Gastrointestinal adverse events (BL Mean ~8.6) n= 441 220 n= 440 220 0 30 25.5 Mean Change in HbA1c (%) 25 (% patients reporting GI adverse events) 20 -0.5 15 *** 12.3 10 -1 5 0 -1.4 -1.3 -1.5 NI Vildagliptin 50 mg bid Acarbose ≤100 mg tidChange in HbA1c is expressed for ITT population. Gastrointestinal adverse events reports from the safety population; ***p<0.001 vs acarboseBL=core baseline; CI=confidence interval; EP=study end point; HbA1c=glycosylated hemoglobinNI: Non-inferiority of vildagliptin as compared to acarbose demonstrated; 95% CI (-0.32, -0.10); statistical significance for non-inferiority margindefined by CI upper limit of 0.4%.Pan C. et al. Diabeteic Medicine. 2008. 25:435-441
  • 123. Vildagliptin monotherapy vs voglibose in Japanese population: study design and objective 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=188 Vildagliptin 50 mg BID N=380 Drug-naïve n=192 Voglibose 0.2 mg TID 2 weeks 12 weeksT2DM=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).Iwamoto Y et al. Diab Obes Metab 2010, 12:700-708.
  • 124. Vildagliptin monotherapy is superior to voglibose monotherapy in Japanese populationAt 12 weeks treatment Change from BL to Wk 12 Target HbA1c Reduction Mean BL ~ 7.5 % ≤6.5% ≥ 1.0% n= 188 192 n 65 65 71 72 0 Adjusted Mean Change in % patients reaching target -0.2 HbA1c (%) -0.4 -0.38 -0.6 -0.8 -1 -0.95 * Vildagliptin 50 mg bid •p< 0.001 vs voglibose Voglibose 0.2 mg tidVildagliptin monotherapy is not approved in EU, please refer to your local label (SmPC).Vildagliptin monotherapy is approved in Japan (Japan label). Iwamoto Y et al. Diab Obes Metab 2010, 12:700-708.
  • 125. Better GI tolerability with vildagliptin monotherapy vs voglibose monotherapy in Japanese population Vildagliptin 50 md BID Voglibose 0.2 mg TID % patients (n=188) (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**P=0.002 vs voglibose. Vildagliptin monotherapy is not approved in EU, please refer to your local label (SmPC).AE=adverse event; DC=discontinuation. Vildagliptin monotherapy is approved in Japan (Japan label).Iwamoto Y et al. Diab Obes Metab 2010, 12:700-708.
  • 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 metforminon fasting GLP-1 levels Fasting Levels of Intact GLP-1 at Fasting Levels of Intact GLP-1 in Baseline and at 3 Months Vildagliptin Subgroups at 3 Months Vilda group† Placebo Vilda only Vilda + met n= 20 20 19 19 7 13 14 12 14 Intact GLP-1 (pM) 10 12 **Intact GLP-1 (pM) 10 8 * 8 6 6 4 4 2 0 2 Vildagliptin dosing: 50 mg bid 0 BL 3 months BL 3 monthsBL=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.
  • 128. Vildagliptin add-on to metformin: significantly lowersHbA1c over 52 weeksDuration: 52 weeksVilda add-on to met Vilda 50 mg daily + met (extension, ITT n=42) PBO + met (extension, ITT n=29) Vilda 50 mg daily + met (core, ITT n=56) 8.4 PBO + met (core, ITT n=51) 8.0 HbA1c (%) P <0.0001 –1.1 0.2% 7.6 P <0.0001 7.2 6.8 −4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Weekn 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.
  • 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% n=143: Vildagliptin 50 mg once daily + metformin N=416* n=143: Vildagliptin 50 mg twice daily + metformin Metformin >1500 mg n=130: Placebo + metformin (monotherapy, stable dose) 4 weeks 24 weeksHbA1c=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.
  • 130. Vildagliptin produces clinically meaningful, dose related decreases in A1C and FPG as add-on therapy to metformin. Add-on Treatment to Metformin (2.1 g Mean Daily) Reduction in HbA1c Reduction in FPGDuration: 24 weeks Duration: 24 weeksVildagliptin add-on Vildagliptin add-onto metformin to metformin 11 8.6 8.4 Mean FPG (mmol/L) Mean HbA1c (%) 8.2 10 8.0 −0.8 vs placebo −0.7% vs placebo ** 7.8 * 9 7.6 −1.1% vs −1.7 vs 7.4 placebo placebo *** 7.2 * 8 −4 0 4 8 12 16 20 24 −4 0 4 8 12 16 20 24 Time (Weeks) Time (Weeks) Vildagliptin 50 mg once daily + metformin (n=143) FPG=fasting plasma glucose; HbA1c=hemoglobin A1c. Vildagliptin 50 mg twice daily + metformin (n=143) *P <0.001; **P=0.003 vs placebo; ***P <0.001 vs placebo. Placebo + metformin (n=130) Primary intention-to-treat population. Bosi E, et al. Diabetes Care. 2007; 30: 890–895.
  • 131. Vildagliptin: enhances β-cell function and improves PPGwhen metformin alone is not sufficientDuration: 24 weeks β-cell Function 2-h PPGVilda add-on to met Placebo-adjusted Placebo-adjusted values values 10.0 0.0 8.0 Adjusted Mean Change in Adjusted Mean Change in ISR AUC / Glucose AUC * * 2-h PPG (mmol/L) 6.0 -1.0 5.7 5.2 4.0 -1.9 -2.0 -2.3 2.0 * -3.0 * 0.0AUC=area under the curve; ISR=insulin secretion rate; Vilda 50 mg once daily + met (n=53)met=metformin; PBO=placebo; PPG=postprandial glucose; vilda=vildagliptin.*P ≤0.001 vs PBO. Vilda 50 mg twice daily + met (n=57)Bosi E, et al. Diabetes Care. 2007; 30: 890–895.
  • 132. Vildagliptin: efficacious in elderly and obese patientsand those with poorly controlled T2DMDuration: 24 weeksVilda add-on to met Add-on Treatment to Metformin (2.1 g Mean Daily) >65 years BL BMI >30 kg/m2 BL HbA1c Mean BL ~8.3% Mean BL ~8.3% >9% n= 20 22 103 86 29 29 Change from BL in HbA1c (%) Vilda 50 mg twice daily + met PBO + metBL=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.
  • 133. Vildagliptin add on to metformin in Chinese patients : Study design and objective 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= 148 Vildagliptin 50 mg qd + Metformin‡ N = 438 n= 146 Vildagliptin 50 mg bid + Metformin‡ Metformin n=144 Placebo + Metformin ‡ 2 weeks 24 weeks ‡ metformin dose >= 1500 mg dailyData on file LAF237A23140
  • 134. Vildagliptin add on to metformin in Chinese patients : significant improvement in HbA1c, FPP and PPG Change in FPG (mmol/L) from baseline to endpoint HbA1c reduction BL 8.72 8.78 8.76 N=147 N=145 N=144 Adjusted mean change ** * ** * Change in 2h prandial glucose from baseline to end point BL 12.29 13.49 13.13 Adjusted change in 2-hr prandial N=40 N=46 N=44 glucose (mmol/L) Vilda 50 mg qd * P<0.001 vs. Placebo ** P=0.001 vs. Placebo Vilda 50 mg bid *** P<0.05 vs Placebo placeboNote: 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 ***
  • 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 n/N= 67/147 73 / 145 48/144 38/147 43/145 29/144 70 ** % patients reaching target 60 * 53.7 48.9 50 40 34.8 *** **** 29.7 30 26.2 20.1 20 10 0 vilda 50 qd + met vilda 50 mg bid + met Placebo*p =0.018 vs placebo; ** p=0.002 vs placebo; *** p=0.222 vs placebo; ****p=0.061Data on file LAF237A23140, Table 11-6
  • 136. Vildagliptin add on to metformin in Chinese patients : % patients reporting AEs (≥ 2.5% in any group) Preferred term Vilda 50 Vilda 50 Placebo mg qd* mg bid 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 2.8Safety population**Vildagliptin 100 mg once daily is not a therapeutic dose according to the Basic Prescribing Information documentData on file LAF237A23140 Table 12-3
  • 137. Vildagliptin vs pioglitazone as add-on to metformin:study design and objectivePrimary objective: to compare efficacy and safety of vildagliptin 50 mg twicedaily 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 metforminmonotherapy (baseline HbA1c 7.5–11%) Double-blind1 Single-blind2 n=295: Vildagliptin 50 mg twice daily + metformin N=576* n=281: Pioglitazone 30 mg once daily + metformin Metformin ≥1500 mg 4 weeks 24 weeks Interim 28 weeks analysisHbA1c=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. In patients uncontrolled with metformin vildaglipitnachieves similar HbA1c drop compared with pioglitazoneDuration: 24 weeks Add-on Treatment to Metformin (2.0 g Mean Daily)Add-on to met:vilda vs pio Overall HbA1c >9% Mean BL ~8.4% Mean BL ~9.7% n= 264 246 63 58 0.0 -0.2 Change in HbA1c (%) -0.4 Adjusted Mean -0.6 -0.8 -1.0 -0.9 -1.0 -1.2 -1.4 Non-inferior* -1.6 -1.5 -1.5 -1.8 Vilda 50 mg twice daily + met Pio 30 mg once daily + metBL=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.
  • 139. In patients uncontrolled with metformin vildagliptin is the only DPP-4 inhibitor showing similar efficacy to pioglitazone at 1 year without weight gainDuration: 52 weeks add-on to metformin: vildagliptin vs pioglitazone 9.0 Change in HbA1c Change in Body Weight (Mean BL Body Weight ~91 kg) 24-week analysis 8.5 Vilda NI Mean HbA1c (%) established * Change in Body Weight (kg) 3.0 2.6 2.5 Unadjusted Mean 8.0 2.0 1.5 7.5 1.0 0.5 0.2 0.0 7.0 n=293 n=277 −4 0 4 12 16 24 32 40 52 Time (Weeks) *P <0.001 change from baseline Vildagliptin 50 mg bid + Pioglitazone 30 mg od + metformin metformin 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.
  • 140. Vildagliptin vs. glimepiride as add-on to metformin:study design and objectiveStudy purpose: To demonstrate long-term efficacy and safety of add-on therapy withvildagliptin vs glimepiride in patients with T2DM inadequately controlled with ongoingmetformin monotherapyInterim analysis: To demonstrate non-inferiority of vildagliptin vs glimepiride at 1 yearTarget population: Patients with T2DM inadequately controlled on stable metforminmonotherapy (metformin minimum dose 1500 mg/day; baseline HbA1c 6.5–8.5%) n=1396: Vildagliptin 50 mg twice daily + metformin N=2789* n=1393: Glimepiride up to 6 mg once daily + metformin Metformin 1-year interim analysis 4 weeks 104 weeksHbA1c=haemoglobin A1c; SU=sulfonylurea; T2DM=type 2 diabetes mellitus.* Randomised population.Ferrannini E et al. Diabetes Obes Metab 2009; 11: 157–166.
  • 141. In patients uncontrolled with metformin monotherapy vildagliptin is aseffective as glimepiride over 1 year with low incidence of hypoglycaemiaand no weight gainDuration: 52 weeks, add-on to metformin: vildagliptin vs glimepiride Incidence of hypoglycaemia b Mean HbA1c reduction a Patients with Number of Number of severe hypoglycaemic events hypoglycaemic 7.5 1 hypos (%) events c n = 1389 1383 1389 1383 1389 1383 7.3 554 Mean HbA1c (%) 7.1 16.2 NI: 97.5% CI (0.02, 0.16) Incidence (%) 6.9 No. of events −0.4% No. of events 6.7 −0.5% 6.5 0.0 -8 -4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 1.7 39 Time (weeks) Vildagliptin 50 mg twice daily + metformin Change in body weight a Glimepiride up to 6 mg once daily + metformin (BL mean ~88.8kg) BL=baseline; CI=confidence interval Adjusted mean change in body weight (kg) from BL 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. n= 1117 1071 Ferrannini E et al. Diab Obes Metab 2009; 11: 157–166.
  • 142. Vildagliptin was as effective as glimepiride when added to metformin at 104weeks with no weight gain and low incidence of hypoglycemiaDuration: 104 weeks, add-on to metformin:vildagliptin vs glimepiride Hypoglycaemia 2 Patients with > 1 hypo (%) Number of hypo events Number of severe events a Discontinuations due to hypos N = 1553 1546 N = 1553 1546 N= 1553 1546 N = 1553 1546 18.2 15 16 16 13 14 No. of events 14 Incidence (%) 12 No. of events No. of events 12 10 10 8 8 6 6 4 4 2 0 2 0 59 0 0 Mean HbA1c 1 Change in body weight 3 Change from BL to EP Between-treatment Adjusted mean change in HbA1c was comparable between (BL Mean ~89kg) Difference vildagliptin and glimepiride treatment: −0.1% (0.0%) for both Adjusted mean change n = 1539 1520 in body weight (kg) 2.0 1.2 Primary objective of non-inferiority was met: 1.0 97.5% CI= (-0.00, 0.17); upper limit 0.3% 0.0 Vildagliptin 50 mg bid + met Glimepiride up to 6 mg qd +met -1.0 -0.3 -1.5 -2.0 *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.
  • 143. Vildagliptin vs. glimepiride as add-on to metformin: AEs with incidence 5% in any group Vilda 50 Glim up Vilda 50 mg Glim up to AE preferred AE preferred term, mg bid + to 6 mg + bid + met 6 mg + met term, % % patients met met n=1553 n=1546 patients n=1553 n=1546 Any AE 83.1 86.4 Cough 6.2 5.4 Nasopharyngitis 14.7 13.6 Pain in extremity 5.7 6.3 Headache 9.6 9.2 Fatigue 5.4 8.0 Back pain 9.4 9.5 Osteoarthritis 5.2 4.3 Bronchitis 9.1 7.3 Asthenia 5.0 11.7 Dizziness 8.2 16.0 Nausea 4.9 6.0 Arthralgia 7.8 6.3 Tremor 4.8 21.7 Influenza 7.6 6.4 Hyperhidrosis 4.5 18.7 Diarrhoea 7.4 7.3 Oedema 2.9 5.0 Hypertension 6.7 8.1 peripheral Upper respiratory Hypoglycaemia 2.3 18.2 6.6 5.2 tract infection Hunger 0.9 5.2Safety 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. Vildagliptin vs. gliclazide as add on to metformin:study design and objective 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=513 Vildagliptin 50 mg bid + Met‡ N** = 1007 n=494 Gliclazide up to 320 mg# + Met‡ Metformin‡ 4 weeks 52 weeks**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 (to160 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 (113mg/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.Filozof and Gautier. Diabetes Medicine. 2010; 27: 318-326.
  • 145. Vildagliptin provides similar HbA1c reduction as gliclazidebut with a better tolerability profile Mean HbA1c Change Body weightb from BL to week 52 N= 386 393 9 Adjusted Mean Change 1.36 Mean BL ~ 85 kg in body weight (kg) -0.81% vilda + met Mean HbA1c (%) 8.5 -0.84 glic +met 1.2 Non-inferior 0.8 8 0.4 * 0.08 7.5 0.0 EP 7 -4 0 4 12 16 24 32 40 52 56 Hypoglycemic eventsc Time (Week) Patients with one Number of Mean difference of adjusted values: or more hypos (%) hypoglycemic events# 0.04% 95%CI: -0.11, 0.20 n/N= 5 / 510 5 / 493 N= 510 493 Vilda 50 mg bid + Met Glic up to 320 mg + Met Number of events Incidence (%)Glic= gliclazide; Met= metformin; Vilda= vildagliptin; BL= baseline; EP=end point; * p<0.001 Vilda vs Glic, 95% CI (-1.77, -0.79), adjusted meanchange from BL to EP; b) per protocol population; c) safety population;# All hypoglycemic events: grade 1Filozof and Gautier. Diabetes Medicine. 2010; 27: 318-326.
  • 146. Vildagliptin vs. gliclazide as add on to metformin: AEs with incidence in ≥4% in any group Vilda 50 mg bid + Met Glic up to 320 mg + Met AE preferred term, % patients N=510 N=493 % (n) 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)Safety population; orange highlighted: hypoglycaemia and symptoms suggestive of hypoglycaemiaAEs= adverse events; Vilda= vildagliptin; Glic= gliclazide; Met= metforminFilozof and Gautier. Diabetes Medicine. 2010; 27: 318-326.
  • 147. Initial combination of vildagliptin and metformin:study design and objectivesPrimary objective: to demonstrate efficacy of single-pill combination therapy ofvildagliptin and metformin compared with individual monotherapy in drug-naïve patientswith T2DM in a multicenter, randomized, double-blind, active-controlled studyTarget population: drug-naïve patients with T2DM (HbA1c 7.5–11%) Screening Titration Maintenance n=300 Vildagliptin 50 mg bid Vilda 50 mg qd n=294 Met 1000 mg AM Metformin 1000 mg bid Met 500 mg qd Met 500 mg bid Met 500 mg PM N=1179* n=290 Low dose: vilda / met 50/500 mg bid Vilda / met 50/500 mg qd n=295 50/1000 mg AM High dose: vilda / met 50/1000 mg bid Vilda/met 50/500 qd 50/500 mg bid 50/500 mg PM 2 weeks 2 weeks 2 weeks 2 weeks 18 weeks 24 weeks *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.
  • 148. Initial combination of vildagliptin + metformin providessignificantly more HbA1c reductions than the monotherapiesDuration: 24 weeksVilda + met vs mono Change from Baseline to End Point Mean Baseline HbA1c ~8.6% n= 287 285 277 285 Mean Change in HbA1c (%) P <0.001 P=0.004 Vilda 50 mg bid P <0.001 Met 1000 mg bid P <0.001 Vilda + LD met (50/500 mg bid)Intention-to-treat population. Vilda + HD met (50/1000 mg bid)HbA1c=hemoglobin A1c; HD=high dose; LD=low dose; met=metformin; vilda=vildagliptin.Bosi E, et al. Diab Obes Metab. 2009; 11: 506–515.
  • 149. Initial combination of vildagliptin + metformin:robust change in FPGDuration: 24 weeksvilda + met vs mono Change from Baseline to End Point Mean baseline FPG ~10.4 mmol/L n= 287 285 277 285 Mean Change in FPG (mmol/L) P <0.001 P=0.999* Vilda 50 mg bid P <0.001 Met 1000 mg bid P <0.001Intention-to-treat population. Vilda + LD met (50/500 mg bid)FPG=fasting plasma glucose; HD=high dose; LD=low dose; met=metformin; vilda=vildagliptin. Vilda + HD met (50/1000 mg bid)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 corestudy and open-label sub-study)Duration: 24 weeksVilda + met vs mono Change from BL to EP High BL Open-label Overall* Subgroups by BL HbA1ca Sub-study b >8% >9% ≥10% >11% BL mean= ~8.7% ~9.2% ~9.9% ~10. 6% ~12. 1% n= 285 201 96 35 86Mean Change in HbA1c (%) High-dose vilda + met (50/1000 mg twice daily)c * Vilda 100 mg daily** + met 2000 mg *P <0.001 vs BL; **100 mg once daily is not a recommended dosing regimen. daily open-label sub-study (P <0.001 Intent-to-treat population. aRaw mean change from baseline; vs BL)d bLS (least-square) mean change from baseline. BL=baseline; EP=end point; HbA1c=glycosylated hemoglobin; met=metformin; vilda=vildagliptin. As with traditional OADs, vildagliptin as add-on Bosi E, et al. Diabetes Obes Metab. 2009; 11: 506–515; to metformin substantially reduces HbA1c in a Data on file, Novartis Pharmaceuticals, LMF237A2302 and LMF237A2302S1. patients with high baseline levels
  • 151. 7.2) Vildagliptin significantly reduces HbA1c in patients uncontrolled withonly SU or TZD
  • 152. Vildagliptin add-on to maximum-dose pioglitazone:study design and objective 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%) n=124: Vildagliptin 50 mg once daily + pioglitazone 45 mg daily N=398* n=136: Vildagliptin 50 mg twice daily + pioglitazone 45 mg daily Pioglitazone 45 mg daily n=138: Placebo + pioglitazone 45 mg daily 4 weeks 24 weeksHbA1c=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 levelsin patients inadequately controlled with a maximum dose of TZDmonotherapy Duration: 24 weeks Add-on Treatment to Pioglitazone 45 mg Daily Add-on to pio: vilda vs PBO 9.0 Vilda 50 mg once daily + pio (n=124) 8.8 Vilda 50 mg twice daily + pio (n=136) 8.6 PBO + pio 45 mg daily (n=138) Mean HbA1c (%) 8.4 8.2 8.0 * 7.8 –0.5% vs PBO 7.6 –0.7% vs PBO 7.4 −4 0 4 8 12 16 20 * 24 Time (Weeks) 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.
  • 154. Vildagliptin add-on to glimepiride:study design and objective 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% n=132: Vildagliptin 50 mg once daily + glimepiride 4 mg once daily N=408* n=132: Vildagliptin 50 mg twice daily + glimepiride 4 mg once daily Glimepiride 4 mg daily n=144: Placebo + glimepiride 4 mg once daily 4 weeks 24 weeksHbA1c=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.
  • 155. Vildagliptin as add-on to glimepiride produces clinically meaningfulreductions in HbA1c levels in patients with T2DM not adequately treatedwith a sulfonylurea Duration: 24 weeks Add-on Treatment to an SU (Glimepiride 4 mg Once Daily) Add-on to SU: vilda vs PBO 9.0 Vilda 50 mg once daily + glimepiride (n=132) Vilda 50 mg twice daily + glimepiride (n=132) 8.8 PBO + glimepiride (n=144) 8.6 Mean HbA1c (%) 8.4 8.2 * 8.0 −0.6% vs PBO 7.8 −0.7% vs PBO 7.6 * −4 0 4 8 12 16 20 24 Time (Weeks) 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.
  • 156. Efficacy and tolerability of vildagliptin as add-on to glimepiride in Japanese patients with Type 2 Diabetes 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) N=202 Glimepiride n=100 Placebo + Glimepiride (up to 1mg OD) 12 weeksVildagliptin 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).T2DM=type 2 diabetes mellitus.Kikuchi M et al. Diab Res Clin Pract. 2010; 89:216-223.
  • 157. Vildagliptin as add-on to glimepiride in Japanese patients:significant HbA1c drop Vilda+Glim Placebo+Glim (N=102) (N=100) LS Mean change in HbA1c (%) Vilda+Glim 0.0 8.5 Placebo+Glim -0.2 - 0.06 8.0 Mean HbA1c (%) -0.4 7.5 -0.6 7.0 -0.8 - 1.00 6.5 -1.0 p<0.001 6.0 -1.2 -2 0 2 4 8 12 Time (week) LS (Least square) mean change ±SD; FAS population; P-value, ANCOVA Mean HbA1C±SD; Full Analysis Set (FAS) populationVildagliptin 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).Kikuchi M et al. Diab Res Clin Pract. 2010; 89:216-223.
  • 158. Higher responder rates with vildagliptin as add-on to glimepiride vs placebo in Japanese patients (%) (%) 80 Achieved 80 ≥1.0% decreasing HbA1c≤6.5%1,2 in HbA1c2 p<0.001 p<0.001 60 60 54.9 45.0 40 40 20 20 3.0 5.0 0 0 Vilda+Glim Placebo+Glim Vilda+Glim Placebo+Glim (N=102) (N=100) (N=102) (N=100)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’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).Kikuchi M, et al. Diab Res Clin Pract 2010 89:216-223.
  • 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**) 120 75 g Glucose 100 Vildagliptin 100 mg** (n=15) (pmol/L) Insulin 80 Dose Placebo (n=16) 60 40 20 0 −90 −60 −30 0 30 60 90 120 150 180 210 240 270 300 22.5 (mmol/L) Glucose 17.5 12.5 7.5 −90 −60 −30 0 30 60 90 120 150 180 210 240 270 300 140 120 Glucagon (ng/L) 100 80OGTT=oral glucose tolerance test. 60*P <0.01. −90 −60 −30 0 30 60 90 120 150 180 210 240 270 300** 100 mg qd is NOT an approved dose.He YL, et al. J Clin Pharmacol. 2007; 47: 633–641. TimeVildagliptin 100 mg once daily was used in this study. Galvus (vildagliptin) is approved for 50 mg once or twice daily incombination with metformin or a TZD, and Galvus (vildagliptin) 50 mg once daily in combination with a sulfonylurea.
  • 161. Acute effects of vildagliptin on GLP-1 levels in patients with T2DM:increased GLP-1 levels that persist beyond the post-meal period Meal 16.0 Vildagliptin 100 mg (n=16) * Placebo (n=16) * 12.0 *Active GLP-1 (pmol/L) * * * * * 8.0 ** * * * 4.0 0.0 17:00 20:00 23:00 02:00 05:00 08:00GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus. Time*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 aTZD, and Galvus (vildagliptin) 50 mg once daily in combination with a sulfonylurea. Galvus is NOT approved for 100 mg qd, 161
  • 162. Acute effects of vildagliptin on glucagon levels in patients with T2DM:decreased glucagon levels persist beyond the post-meal period Meal 20 Vildagliptin 100 mg (n=16) 10 Placebo (n=16) 0Delta Glucagon (ng/L) −10 −20 * −30 * −40 * * −50 * * * * * −60 17:00 20:00 23:00 02:00 05:00 08:00*P <0.05 vs placebo. TimeBalas 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 withmetformin or a TZD, and Galvus (vildagliptin) 50 mg once daily in combination with a sulfonylurea. Galvus is NOT approved for 100 mg qd, 162
  • 163. Acute effects of vildagliptin on endogenous glucose production (EGP)levels in patients with T2DM: decreased EGP levels persist beyondpost-meal period Meal Time 17:00 20:00 23:00 02:00 05:00 08:00 0 −0.3 Delta EGP (mg/kg/min) −0.6 * * * * * * * * * * −0.9 * * −1.2 * * * Vildagliptin 100 mg (n=16) ** * * ** * * * * * * * Placebo (n=16) −1.5EGP=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,
  • 164. Acute effects of vildagliptin on insulin secretion rates in patients with T2DM: increased rate persists beyond the post-meal period Meal 8 Vildagliptin 100 mg qd** (n=16) 100 (pmol•kg-1•min-1)/(mg/dL) ** Placebo (n=16) ISR (AUC) / glucose (AUC) * 6 ** ** * * * * * * * * * * * * * * * * 4 2 0 18:00 20:00 23:00 02:00 05:00 08:00AUC=area under the curve; ISR=insulin secretion rate. Time*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 incombination with metformin or a TZD, and Galvus (vildagliptin) 50 mg once daily in combination with a sulfonylurea.
  • 165. Comparison of plasma GLP-1 levels following 3 Months‘ treatment with vildagliptin or sitagliptinRetrospective analysis of patients on Vildagliptin 50 mgsitagliptin (N=20) or vildagliptin (N=18) twice daily + metformin (N=18) 30 Sitagliptin 100 mg once daily + metformin (N=20) 25 Intact GLP-1 (pmol/L) 20 15 10 5 0 -20 0 15 30 60 90 120 180 240 300 0 15 30 60 90 120 180 240 300 0 15 30 60 90 120 180 240 300 min Breakfast Lunch Dinner 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..
  • 166. Comparison of plasma glucagon levels following 3 Months‘ treatment with vildagliptin or sitagliptinRetrospective analysis of patients on Vildagliptin 50 mgsitagliptin (N=20) or vildagliptin (N=18) twice daily + metformin (N=18) 90 Sitagliptin 100 mg once daily + metformin (N=20) Plasma Glucagon (mg/dL) 80 70 60 50 40 30 20 -20 0 15 30 60 90 120 180 240 300 0 15 30 60 90 120 180 240 300 0 15 30 60 90 120 180 240 300 min Breakfast Lunch Dinner *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.
  • 167. Vildagliptin improves β-cell sensitivity to glucose Glucose Sensitivity Basal Secretory Tone 75 260 Secretion at 7 mM glucose 70 Glucose Sensitivity (pmol/min/m2/mM) 240 (pmol/min/m2) 65 60 220 55 200 50 45 180 −4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 −4 0 4 8 12 162024283236 40444852 Time (weeks) Time (weeks) Vildagliptin 50 mg once daily PlaceboMari A, et al. J Clin Endocrinol Metab. 2008; 93: 103–109.
  • 168. Effects of vildagliptin treatment on the sensitivity of theα-cell to glucose 170 Meal 7.5 mM 5.0 mM 2.5 mM Dose 150 Glucagon (ng/L) 130 110 90 −30 0 30 60 90 120 165 210 255 285 Time (min)Ahrén B, et al. J Clin Endocrinol Metab. 2009;94(4):1236–1243. Vildagliptin 100 mg once dailyVildagliptin 100 mg once daily is NOT an approved dose. Placebo
  • 169. 8.2) Vildagliptin reduces insulin resistance
  • 170. Vildagliptin treatment improves insulin sensitivityDuration: 6 weeksVildagliptin vs Hyperinsulinemic Euglycemic Clampplacebo 7.0 6.5 * Insulin infusion 80 mU/m2•min Glucose Rd (mg/kg•min) 6.1 Mean Rd difference=0.7 mg/kg•min 6.0 5.5 5.4 Vildagliptin 50 mg twice daily (n=16) Placebo (n=16) 5.0 4.5 4.0Rd=rate of disappearance.*P <0.05.Azuma K, et al. J Clin Endocrinol Metab. 2008; 93: 459–464.
  • 171. Effects of vildagliptin treatment on -cell function andinsulin sensitivity over 52 Weeks Patients on Stable Metformin Therapy Insulin Insulin Adaptation Secretion Sensitivity Index nmolC-peptide · mmolglucose-1 · 0.050 300 14pmol/L 30 min/(mmol/L) † * * * * mL · min-1 · m -2 0.045 * 275 * 12 * mL-1 · m-2 0.040 250 10 0.035 225 8 0.030 0.025 200 6 0 12 24 52 0 12 24 52 0 12 24 52 Time (Week) Time (Week) Time (Week) Vildagliptin 50 mg daily / metformin Placebo / metformin*P <0.05 vs placebo; †P <0.01 vs placebo.Adapted from Ahrén B, et al. Diabetes Care. 2005; 28: 1936–1940.
  • 172. 8.3) Vildagliptin reduces postprandial lipids
  • 173. Vildagliptin improves postprandial lipid and lipoproteinmetabolism Plasma TG Chylomicron TG 4.0 0.8 Before vilda, Week 0 (n=13) 3.5 Vilda 50 mg twice daily, 0.6 Week 4 (n=15) 3.0 mmol/L mmol/L 2.5 0.4 2.0 0.2 1.5 1.0 0.0 −1 0 1 2 3 4 5 6 7 8 −1 0 1 2 3 4 5 6 7 8 Chylomicron apo B-48 Chylomicron cholesterol 0.08 0.50 0.40 0.06 mmol/L mg/L 0.30 0.04 0.20 0.02 0.10 0.00 0.00 −1 0 1 2 3 4 5 6 7 8 −1 0 1 2 3 4 5 6 7 8 Time (h) Time (h)TG=triglyceride; Vilda=vildagliptin.Matikainen N, et al. Diabetologia. 2006; 49: 2049–2057.
  • 174. 8.4) Vildagliptin has the potential for disease prevention and modification
  • 175. Effect of vildagliptin on β-cell mass in a neonatal rat pancreatic growth model Insulin Vildagliptin Vehicle 60 mg/kg 21 days Replication Apoptosis -cell Mass ApopTag-positive Cells (%)BrdU-positive Cells (%) 120 2.5 0.14 P <0.05 -cell Mass (mg) 100 P <0.001 0.12 2.0 80 0.10 1.5 0.08 60 P <0.05 1.0 0.06 40 0.04 20 0.5 0.02 0 0.0 0.00 Vehicle Vildagliptin Vehicle Vildagliptin Vehicle Vildagliptin Day 7 Day 21 Duttaroy A, et al. Diabetes. 2005; 54 (Suppl 1): A141. Abstract 572-P and poster presented at ADA.
  • 176. Vildagliptin increases pancreatic beta cell mass in neonatal rats Replication Control Vildagliptin Day 7 BrdU+ cells Apoptosis Day 7 Apoptag+ cells -cell Mass Day 21 Insulin+ cells*p<0.05; **p<0.01Duttaroy A. et al. European J Pharmacol. 2011; 650: 703–707
  • 177. Durability of β-cell function over 2 years Treatment period Wk 0–52 Washout Treatment period Wk 56–108 Washout 50 Mean ISR/G (pmol/min/m2/mM) 45 40 35 30 −8 0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 Time (Weeks) Vildagliptin 50 mg once daily (n=49) Placebo (n=40)ISR/G=insulin-secretory rate relative to glucose concentration.Scherbaum WA, et al. Diabetes Obes Metab. 2008; 10: 1114–1124.
  • 178. Effects of vildagliptin treatment on -cell function andinsulin sensitivity over 52 weeks Patients on Stable Metformin Therapy Insulin Insulin Adaptation Secretion Sensitivity Index nmolC-peptide · mmolglucose-1 · 0.050 300 14pmol/L 30 min/(mmol/L) † * * * * mL · min-1 · m -2 0.045 * 275 * 12 * mL-1 · m-2 0.040 250 10 0.035 225 8 0.030 0.025 200 6 0 12 24 52 0 12 24 52 0 12 24 52 Time (Week) Time (Week) Time (Week) Vildagliptin 50 mg daily / metformin Placebo / metformin*P <0.05 vs placebo; †P <0.01 vs placebo.Adapted from Ahrén B, et al. Diabetes Care. 2005; 28: 1936–1940.
  • 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) Preferred term, n (%) Vildagliptin 50 mg bid Total comp N= 6116 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 5.8AEs=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)
  • 181. Similar incidence of SAEs, discontinuations due to AEs,or death for vildagliptin and comparators Vilda Total n (%) 50 mg bid comparators N=6116 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 347 (5.7) 400 (6.4) study drug due to AEs 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 vscomparators Vildagliptin Reference Peto odds ratio 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)AEs=adverse events; bid=twice daily; CI=confidence interval; qd=once daily; 0.01 0.1 1 10 100SAEs=serious adverse events; vilda=vildagliptin. *Vs comparators Vildagliptin better Vildagliptin worse(all non-vildagliptin treatment groups). All-study safety (excluding open-label) population.According to the Prescribing information, vildagliptin should not be used in patients withhepatic 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 shouldbe 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) elevationsvs. comparators Odds Ratio Vildagliptin Reference Peto odds ratio n / N (%) n / N (%) (95% CI)ALT / AST >3 ULNVilda 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 >ULNVilda 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)ALT=alanine aminotransferase; AST=aspartate aminotransferase; bid=twice daily; CI=confidenceinterval; qd=once daily; ULN=upper limit of normal; vilda=vildagliptin.*Vs comparators (all non-vildagliptin treatment groups). All-study safety (including open-label) 0.01 0.1 1 10 100population. ‡Persistent elevations are those which met the criterion at consecutive on-treatment Vildagliptin better Vildagliptin worsemeasurements or at last on-treatment visit.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 shouldbe 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 withvildagliptin 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 hepaticenzymes across treatment groups Number (%) of patients with treatment-emergent, Persistent* on-treatment hepatic enzyme elevations 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 0 3 (0.1) 3 (0.0) bilirubin ≥2 xULN n(%)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 measurementsor at last on-treatment visitLigueros-Saylan M, et al. Diab Obes Metab 2010 12:495-509
  • 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 aminotransferaseSAEs= serious adverse events; ULN= upper limit of normalAccording 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 ULN. Liver function should be performed prior to the initiation of treatment with vildagliptinin 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 recommendedin patients with a pre-treatment ALT or AST >2.5X the upper limit of normal according to the BPI or above3X according to European SmPC• LFTs should be monitored during Galvus treatment at three-month intervals during the first year andperiodically thereafter• Patients who develop increased transaminase levels should be monitored with a second liver functionevaluation to confirm the finding and be followed thereafter with frequent liver function tests until theabnormality (ies) return to normal• Should an increase in AST or ALT of 3x upper limit of normal or greater persist, withdrawal of therapywith Galvus is recommended. Patients who develop jaundice or other signs suggestive of liver dysfunctionshould discontinue Galvus and contact their physician immediately• Following withdrawal of treatment with Galvus and LFT normaisation, vildagliptin treamentshould not be reinitiated.LFT: liver function test; AST= aspartate aminotransferase; ALT= alanine aminotransferaseBPI: Basic prescribing informationSmPC= European Summary of Product Characteristics
  • 187. No increased risk for adjudicated CCV events, relative to all comparators* Incidences and Odds Ratios for Adjudicated CV Events by Treatment Risk Ratio 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) 0.1 1 10 Vildagliptin better Vildagliptin worse #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)]. 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.
  • 188. The incidence of SYE-adjusted* adjudicated CCV events was similar with vildagliptin relative to comparators SYE-adjusted Incidence*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 forinfections Odds Ratio Vildagliptin All Peto odds ratio comparators n / N (%) n / N (%) (95% CI)Infections / infestationsVilda 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) 0.1 1 10 Vildagliptin better Vildagliptin worsebid=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
  • 190. No increased risk for pancreatitis-related AEs Odds Ratio Vildagliptin All comparators Peto odds ratio n / N (%) n / N (%) (95% CI)Pancreatitis eventsVilda 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) 0.01 0.1 1 10 100 Vildagliptin better Vildagliptin worseAEs=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
  • 191. No increased risk of skin-related AEs and SAEs with vildagliptin vs allcomparators Odds Ratio 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 0.1 1 10 100 Vildagliptin better Vildagliptin worse 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 comparedto patients with normal renal function
  • 193. Mild renal impairment does not adversely affect the safety ofvildagliptin relative to patients with normal renal functionPooled safety data Normal renal Mild renal Function Function n= 50 mg qd 50 mg bid comparators 50 mg qd 50 mg bid comparators 1338 4232 4217 665 1802 1918 100.0 90.0 Any AE Any SAE Any AE Any SAE 80.0 70.3 70.1 % of AE or SAE 68.4 68.7 65.6 70.0 58.7 60.0 50.0 40.0 30.0 20.0 11.6 11.2 7.5 7.9 8.1 10.0 4.2 0.0 Vildagliptin 50 mg qd Normal Renal function: GFR (MDRD) > 80 (ml/min) x (1.73 m 2) Mild renal impairment: GFR (MDRD) ≥ 50 but ≤ 80 (ml/min) x (1.73 m 2) Vildagliptin 50 mg bid all studies [excluding open-label] safety population Ligueros-Saylan M, et al. Diab Obes Metab 2010 12:495-509 All comparators
  • 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 comparatorsPooled safety data Incidences and odds ratios for selected edema-related events by treatment Risk Ratio 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) 0.1 1 10 Vildagliptin better Vildagliptin worseAll studies [excluding open-label] safety populationSchweizer A. et al, Vasc Health Risk Manag 2011(accepted version)
  • 196. 9.4) No change in bone markers has been observed with vildagliptintreatment
  • 197. Vildagliptin does not increase fasting parameters of bone metabolism and calcium homeostasis Between- group Baseline Endpoint LSM Change difference P-value Calcium (mmol/L) Placebo 2.32 0.07 2.32 0.08 –0.004 0.012 Vildagliptin 2.33 0.07 2.33 0.07 –0.005 0.011 0.000 0.017 0.981 Phosphate (mmol/L) Placebo 0.97 0.16 1.01 0.19 0.037 0.024 Vildagliptin 1.00 0.15 1.04 0.15 0.047 0.023 0.010 0.033 0.762 Alkaline phosphatase (IU/L) Placebo 7.04 15.5 66.8 14.2 –3.31 5.24 Vildagliptin 66.5 18.6 70.6 36.3 3.83 4.91 7.14 7.20 0.327 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 hyperglycemiaDiamant M, et al. Poster Presentation 0706-P. Presented at: 70th Scientific Sessions of the American Diabetes Association 2010.
  • 198. 9.5) Hypoglycemia risk is consistently low with vildagliptin
  • 199. Low risk of hypoglycemic events in add-on metformin trialsin vildagliptin treated patients Vildagliptin 50 mg qd + met Hypoglycemia Incidence Vildagliptin 50 mg bid + met in Add-on Metformin Placebo + met SU + met 14 Pioglitazone* + met 12 Incidence (%) 10 9.2 8 6 4 2 0.6 0.8 0.3 0 0 n= 2 23 1 189 0 N= 340 3021 354 2045 280 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 ofhypoglycaemia than glimepiride at 52 weeks (interim analysis)Duration: 52 weeksAdd-on to met: Number of Severe Events Patients withvilda vs glim Hypoglycaemic (Grade 2 and >1 Hypos (%) Suspected Grade 2) Events n= 1389 1383 1389 1383 1389 1383 Incidence (%) No. of Events No. of Events Vildagliptin 50 mg twice daily + metformin glim=glimepiride; met=metformin; vilda=vildagliptin. Safety population. Glimepiride up to 6 mg once daily + metformin 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 Patients with one Number of Discontinuation or more Number of Severe hypoglycemic due to hypoglycemic hypo events* events hypoglycemia events (%) 16 15 20 900 838 18.2 14 14 13 800 Number of events Number of events 16 12 Number of events 700 12 Incidence (%) 600 10 10 12 500 8 8 400 6 8 6 300 4 4 200 4 2.3 2 100 59 2 0 0 0 0 0 0This hypoglycemic profile was maintained in patients > 65 years Vilda 50 mg bid + Met (n=1553)Safety population; * any episode requiring the assistance of another party Glim up to 6 mg qd + Met (n=1546)Vilda= vildagliptin; Glim= glimepiride; Met= metforminMatthews DR et al Diab Obes Metab. 2010; 12:780-789
  • 202. Fewer hypoglycemic events in vildagliptin add-on toinsulin compared with insulin aloneDuration: 24 weeksAdd-on to insulin: Add-on Treatment to Insulinvilda vs PBO No. of Events No. of Severe Events * 185 No. of Severe Events 200 160 10 No. of Events 113 8 ** 120 6 6 80 4 40 2 0 0 0 Vilda 50 mg twice daily + insulin PBO + insulinPBO=placebo; vilda=vildagliptin; *P <0.001; **P <0.05 between groups.Fonseca V, et al. Diabetologia. 2007; 50: 1148–1155.
  • 203. 9.6) Overall vildagliptin causes no weight gain and shows greater benefitson weight in obese patients
  • 204. Weight loss relative to rosiglitazoneDuration: 24 weeks Overall BMI >35 kg/m2Vildagliptinvs rosiglitazonemonotherapy n= 459 238 132 76 BL (kg)= 91 93 111 112 2 1.7 1.6 Weight change from BL (kg) 1 +2.8 kg difference 0 -0.3 -1 * -1.1 * -2 Vildagliptin 50 mg twice dailyBL=baseline; BMI=body mass index. Rosiglitazone 8 mg once daily*P <0.001 vs rosiglitazone. Primary intention-to-treat population.Rosenstock J, et al. Diabetes Care. 2007; 20: 217–223.
  • 205. Vildagliptin: similar effect on weight as metforminDuration: 52 weeks; Vildagliptin vs metformin monotherapy 100 Vildagliptin 50 mg twice daily (n=511) Metformin 1000 mg twice daily (n=249) 95 Mean Body Weight (kg) 90 85 80 −4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Time (Weeks) Intention-to-treat population. Schweizer A, et al. Diabet Med. 2007; 24: 955–961.
  • 206. Initial combination of vildagliptin + metformin:change in body weightDuration: 24 weeksVilda + met vs mono Change from Baseline to End Point Mean Baseline Body Weight ~88.3 kg n= 276 271 258 275 Mean Change in Body Weight (kg) Vilda 50 mg bid Met 1000 mg bid Vilda + LD met (50/500 mg bid)Intention-to-treat population. Vilda + HD met (50/1000 mg bid)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 inadd-on to metformin at 52 weeksDuration: 52 weeks Add-on Treatment to Metformin (~1.9 g Mean Daily)Add-on to met:vilda vs glim Body Weight (kg) −1.8 kg difference Time (Weeks) Vildagliptin 50 mg twice daily + metforminglim=glimepiride; met=metformin; vilda=vildagliptin.Vildagliptin (n=1396); glimepiride (n=1393). Glimepiride up to 6 mg once daily + metforminFerrannini E, et al. Diabetes Obes Metab. 2009; 11: 157–166.Data on file, Novartis Pharmaceuticals, LAF237A2308.
  • 208. Vildagliptin: weight loss compared to glimepiride in add-onto metformin at 2 years Duration: 2 years Add-on to met: Between-treatment vilda vs glim Change from BL to EP (BL Mean ~ 89kg) difference N= 1539 1520 2.0 Adjusted Mean Change in 1.5 1.2 Body weight (kg) 1.0 0.5 0.0 -0.5 -0.3 -1.0 -1.5 -1.5 -2.0 * Vilda 50 mg bid + MetIntent to treat (ITT) population; * p=<0.001 Glim up to 6 mg qd + MetBL= baseline; Vilda= vildagliptin; Glim= glimiperide; Met= metformin; EP= week 104 endpointMatthews DR et al Diabetes Obes Metab 2010; 12: 780–789
  • 209. Vildagliptin: weight loss compared to gliclazide in add-on to metformin at 52 weeks Duration: 52 weeks Add-on to met: vilda vs glic Change from BL to Wk 52 Between-treatment Mean BL ~ 85 kg difference N= 386 393 Adjusted Mean Change in 1.36 1.2 body weight (kg) 0.8 0.4 0.08 0.0 -0.4 -0.8 -1.2 -1.28 -1.6 Vilda 50 mg bid + Met * Glic up to 320 mg + MetPer 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 pointAdjusted 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.
  • 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. Very elderly patients pooled analysis: Demographics and baseline characteristics Age ≥ 75 years Age ≥ 75 years Age < 75 years Age < 75 years Vilda 50 mg bid Comparators Vilda 50 mg bid Comparators n=132 n=169 n=5984 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 6.3 5.9 4.1 4.5 (years) GFR, # (% pts) 27.3 34.9 70.1 68.8 normal 62.1 58.0 28.7 30.1 mild ( ≥50, <80) 10.6 6.5 1.0 1.0 moderate (≥30, <50) 0.0 0.6 0.1 0.0 severe (<30) 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 1.73m2Schweizer A et al. Diab Obes Metab 2010;13(1):55–64
  • 215. Vildagliptin: significant HbA1c drop from baseline in the very elderlyPooled analysis at 24 weeks50 mg bid Monotherapy Add-on therapy studies studies n= 2303 62 910 25 BL (%)= 8.7 8.3 8.4 8.5 0.0 Change in HbA1c (%) from baseline -0.2 -0.4 -0.6 -0.8 -1.0 -0.9 -0.9 -1.2 * * -1.1 -1.2 -1.4 * * Age < 75 y -1.6 ≥ 75 y Age < 75 y -1.8 ≥ 75 yEfficacy pool: All randomized, double-blind, controlled, parallel group studies with duration ≥ 24 and with patients ≥ 75years. Only *<0.05 vs baseline (within group)studies with the approved dose of 50 mg bid. It included 7 monotherapy and 3 add-on to metformin studies.Schweizer A et al. Diab Obes Metab 2010;13(1):55–64
  • 216. Vildagliptin: no clinically significant body weight changeAt 24 weeks treatment 50 mg bid Add-on therapy Monotherapy studies studies n= 2299 62 914 25 BL (kg)= 86.1 74.9 89.0 82.8 0.0 -0.0 -0.2 Change in body weight (%) from -0.2 -0.4 -0.4 -0.6 * -0.8 baseline -0.9 -1.0 -1.2 * Age < 75 y -1.4 ≥ 75 y Age < 75 y -1.6 ≥ 75 y -1.8*<0.05 vs baseline (within group)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 Age ≥ 75 years Age < 75 years Age < 75 years Vilda 50 mg bid Comparators Vilda 50 mg bid Comparators n=132 n=169 n=5984 n=6041Any AEs SYE-adj 133.9 200.6 147.9 177.3n (%) 86 (65.2) 114 (67.5) 4139 (69.2) 4174 (69.1)Drug-related AEs SYE-adj 14.5 21.8 14.9 26.0n (%) 18 (13.6) 24 (14.2) 943 (15.8) 1325 (21.9)SAEs SYE-adj 8.8 16.5 7.8 8.9n (%) 12 (9.1) 19 (11.2) 533 (8.9) 538 (8.9)Discontinuation due toAEs SYE-adj 7.2 7.5 4.7 6.1n (%) 10 (7.6) 9 (5.3) 337 (5.6) 391 (6.5)Deaths SYE-adj 0.0 1.7 0.3 0.3n (%) 0 (0.0) 2 (1.2) 24 (0.4) 21 (0.3)SYE-adj: SYE-adjustedSafety 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. Very elderly patients pooled analysis: change in HbA1c and body weight at 24 weeks treatment, and hypoglycemic eventsPooled analysis at 24 weeks; 50 mg bid HbA1c Reduction: At 24 weeks treatment Body Weight: At 24 weeks treatment Monotherapy Add on therapy Monotherapy Add on therapy studies pool studies pool studies pool studies pool n= 62 25 n= 62 25 BL 8.3 8.5 BL 74.9 82.8 Weight (kg) from (%) from baseline Change in HbA1c Change in Body baseline * * * *<0.05 vs baseline (within group) Mono > 75 Add on > 75 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.
  • 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。