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Dpp4i earlier the better ! (1)

This document appears to be a slide presentation given by Dr. Faraz Farishta on diabetes management. It discusses diabetes as a global health problem and challenges in achieving optimal blood sugar control, including clinical inertia. It reviews guidelines on treatment goals and limitations of conventional oral therapies. It then discusses how DPP-4 inhibitors were developed to address multiple defects in type 2 diabetes by inhibiting the breakdown of GLP-1, an incretin hormone that stimulates insulin secretion. Data is presented on the efficacy and value of the DPP-4 inhibitor vildagliptin.

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DR FARAZ FARISHTA CONSULTANT ENDOCRINOLOGIST MEDWIN HOSPITAL MD OF SPARSH ENDOCRINOLOGY & DIABETIC CENTERS PRESIDENT OF DIABETES AWARENESS FOUNDATION ASSISTANT PROFESSOR IN MIMS
Agenda  Diabetes-Global concern  Challenges associated with achieving optimal glycemic goals  Clinical inertia  Conventional management approach  What guidelines say?  What DPP4 inhibitors brought?  Vildagliptin efficacy  Vildagliptin value proposition  Summary
Diabetes is a huge and growing problem, and the costs to society are high and escalating 382 million people have diabetes By 2035, this number will rise to 592 million Ref. IDF atlas 06, 2013
Almost half of all people with diabetes live in just three countries China India USA Ref. IDF atlas 06, 2013
| Presentation Title | Presenter Name | Date | Subject | Business Use Only 5 Ref. IDF atlas 06, 2013
The ominous octet DEFRONZO, DIABETES, VOL. 58, APRIL 2009 DEFRONZO, DIABETES, VOL. 58, APRIL 2009
The natural course of HbA1c Ferrannini et al. J Clin Endocrinol Metab 2005
Hafner SM et al. JAMA 1990;263: 2893-2898 Type 2 Diabetes is a Global Cardio-metabolic Risk (CMR) The ticking clock
HbA1c=haemoglobin A1c. Diabetes Trials Unit. UKPDS Post Trial Monitoring. UKPDS 80 Slide Set. Available at: http://www.dtu.ox.ac.uk/index.php?maindoc=/ukpds/. Accessed 12 September, 2008; Holman RR, et al. N Engl J Med. 2008; 359: 1577–1589; UKPDS 33. Lancet. 1998; 352: 837–853. MedianHbA1c(%) 0 6 7 8 9 UKPDS 1998 Conventional Metformin Holman et al 2008 Legacy effect 1997 Difference in HbA1c was lost after first year but patients in the initial intensive arm still had lower incidence of any complication: • 24% reduction in microvascular complications • 15% reduction in MI • 13% reduction in all-cause mortality 2007 Achieving early glycaemic control may generate a “good legacy effect“
ADA/EASD1 AACE/ACE2 IDF3 HbA1c <7.0% (general goal) ≤6.5% <6.5% Preprandial capillary plasma glucose 70–130 mg/dL (3.9–7.2 mmol/L) <110 mg/dL (<6.0 mmol/L) <110 mg/dL (<6.0 mmol/L) Peak postprandial capillary plasma glucose <180 mg/dL (<10.0 mmol/L) <140 mg/dL (<7.7 mmol/L) <145 mg/dL (<8.0 mmol/L) ACE=American College of Endocrinology; ADA=American Diabetes Association; HbA1c=hemoglobin A1c; IDF=International Diabetes Federation. Adapted from: 1ADA / EASD consensus statement: Nathan DM, et al. Diabetes Care, 2009; 32:193–203; 2American Association of Clinical Endocrinologists, American College of Endocrinology. Endocr Pract. 2007; 13 (Suppl 1): 3–68; 3International Diabetes Federation. Global Guideline for Type 2 Diabetes. Brussels: International Diabetes Federation; 2005. Current Treatment Goals for Glycemic Control
Challenges associated with achieving optimal glycaemic goals 6.5 7.0 7.5 8.0 8.5 9.0 2001 2002 2003 2004 2005 2006 2007 3.5 4.0 4.5 5.0 5.5 6.0 2001 2002 2003 2004 2005 2006 2007 Type 1 diabetes Type 2 diabetes + insulin YearYear MeanHbA1c(%) MeanTchol(mmol/l) In patients with type 1 diabetes or type 2 diabetes on insulin, there was a 0.1% relative improvement in HbA1c vs. improvements in total cholesterol of 15% and 29%, respectively between 2001 and 2007 Currie et al. Diabetic Medicine 2010; 27:938-948
Clinical inertia in T2DM • Retrospective cohort study of over 80,000 people • Time to treatment intensification from first HbA1c above 7.5%, by number of OADs and type of intensification Khunti K, et al. Diabetes Care 1013;Epub ahead of print. *Proportion of people with HbA1c >7.5% having any intensification to their treatment at end of follow-up according to number of OADs Median: 1.5 years Median: >7.2 years Median: >6.1 years Cut-off HbA1c 7.5% (58 mmol/mol)
Clinical inertia and CV events 105477 newly diagnosed T2DM (11.3% previous CVD) 5.3 years median follow-up 6 month delay in first 2 years of treatment with HbA1c > 7.0% MI Stroke HF Any CVE All patients 1.38 (1.16-1.82) 1.07 (0.89-1.29) 1.28 (1.10-1.48) 1.25 (1.13-1.39) No Previous CVD 1.21 (1.00-1.47) 1.07 (0.87-1.31) 1.28 (1.07-1.52) 1.20 (1.07-1.35) Previous CVD 1.91 (1.40-2.60) 1.08 (0.73-1.61) 1.27 (0.95-1.70) 1.42 (1.15-1.75) Paul S et al. Poster presented at EASD 2013. Values in table correspond to HR (95% CI)
6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Consequences of delayed intervention – Interpreting the VADT results Time (years since diagnosis) HbA1c(%) Bad glycaemic “legacy” Before entering VADT intensive treatment arm After entering VADT intensive treatment arm Drive risk for complications Adapted from: Del Prato S, et al. Diabetologia 2009;52:1219-1226.
Earlier and Appropriate Intervention May Improve Patients’ Chances of Reaching Goal OAD=oral antidiabetic agent. Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355. Published Conceptual Approach HbA1cGoal Mean HbA1c of patients Duration of Diabetes OAD monotherapy Diet and exercise OAD combination OAD up-titration OAD + multiple daily insulin injections OAD + basal insulin Conventional stepwise treatment approach Earlier and more aggressive intervention approach 6 7 8 9 10
1 Gastrointestinal 2 Thiazolidinedione Adapted from DeFronzo RA. Br J Diabetes Vasc Dis. 2003;3(suppl 1):S24–S40 Conventional Oral Therapies Do Not Address the Multiple Defects in Type 2 Diabetes Sulfonylureas Glinides Impaired insulin action Inadequate glucagon suppression (-cell dysfunction) Glucose influx from GI1 tract α-Glucosidase inhibitors TZDs2 Metformin Chronic β-cell decline  Plasma glucose and disease progression Acute β-cell dysfunction unmet need unmet need
Metformin1 TZDs1-3 α-glucosidase inhibitors1 CHF=congestive heart failure; GI=gastrointestinal; SU=sulfonylurea; T2DM=type 2 diabetes mellitus; TZD=thiazolidinedione aRole uncertain 1Inzucchi SE. JAMA. 2002; 287: 360–372; 2Avandia US Prescribing Information; 3Dormandy JA, et al. Lancet. 2005; 366: 1279–1289; 4Buse JB, et al. Diabetes Care. 2004; 27: 2628–2635; 5DeFronzo RA, et al. Diabetes Care. 2005; 28: 1092–1100; 6Kendall DM, et al. Diabetes Care. 2005; 28: 1083– 1091; 7Kolterman OG, et al. Am J Health-Syst Pharm. 2005; 62: 173–181; 8Byetta US Prescribing Information. Incretin mimetics4-8 Weight gain, edema, CHF, bone fractures (pioglitazone, rosiglitazone) GI effects (flatulence, diarrhea) GI effects (nausea, diarrhea), lactic acidosis (rare) GI effects (nausea, vomiting, diarrhea), pancreatitis, hypoglycemia (in add-on to SU) SUs1 Meglitinides1 Hypoglycemia, weight gain, hyperinsulinemiaa Major Adverse Events of Traditional Treatments for T2DM- Limits Efficacy
| Presentation Title | Presenter Name | Date | Subject | Business Use Only21 What did the major guidelines say...?
Reference: A. Garber et. al., ENDOCRINE PRACTICE Vol 19 (Suppl 2) May/June 2013 AACE’ 2013 Treatment Algorithm
T2DM Anti-hyperglycemic Therapy: When goal is to avoid hypoglycemia Initial drug monotherapy Efficacy (! HbA1c) Hypoglycemia Weight Side effects Costs Healthy eating, weight control, increased physical activity Metformin high low risk neutral/loss GI / lactic acidosis low Metformin + Metformin + Metformin + Metformin + Metformin + Efficacy (! HbA1c) Hypoglycemia Weight Major side effect(s) Costs high low risk gain edema, HF,fx’s‡ high Thiazolidine- dione intermediate low risk neutral rare‡ high DPP-4 Inhibitor highest high risk gain hypoglycemia‡ variable Insulin (usually basal) Two drug combinations* Sulfonylurea† + Thiazolidine- dione + DPP-4 Inhibitor + GLP-1 receptor agonist + Insulin (usually basal) + Metformin + Metformin + Metformin + Metformin + Metformin + TZD DPP-4-i GLP-1-RA Insulin§ SU† DPP-4-i GLP-1-RA Insulin§ SU† SU† TZD TZD TZD DPP-4-i Insulin§ Insulin§ Insulin# (multiple daily doses) Three drug combinations More complex insulin strategies or or or or or or or or or or or or GLP-1-RA high low risk loss GI‡ high GLP-1 receptor agonist Sulfonylurea† high moderate risk gain hypoglycemia‡ low If needed to reach individualized HbA1c target after ~3 months, proceed to 2-drug combination (order not meant to denote any specific preference): If needed to reach individualized HbA1c target after ~3 months, proceed to 3-drug combination (order not meant to denote any specific preference): Diabetes Care, Diabetologia. 19 April 2012
Initial drug monotherapy Efficacy (! HbA1c) Hypoglycemia Weight Side effects Costs Healthy eating, weight control, increased physical activity Metformin high low risk neutral/loss GI / lactic acidosis low Metformin + Metformin + Metformin + Metformin + Metformin + Efficacy (! HbA1c) Hypoglycemia Weight Major side effect(s) Costs high low risk gain edema, HF,fx’s‡ high Thiazolidine- dione intermediate low risk neutral rare‡ high DPP-4 Inhibitor highest high risk gain hypoglycemia‡ variable Insulin (usually basal) Two drug combinations* Sulfonylurea† + Thiazolidine- dione + DPP-4 Inhibitor + GLP-1 receptor agonist + Insulin (usually basal) + Metformin + Metformin + Metformin + Metformin + Metformin + TZD DPP-4-i GLP-1-RA Insulin§ SU† DPP-4-i GLP-1-RA Insulin§ SU† SU† TZD TZD TZD DPP-4-i Insulin§ Insulin§ Insulin# (multiple daily doses) Three drug combinations More complex insulin strategies or or or or or or or or or or or or GLP-1-RA high low risk loss GI‡ high GLP-1 receptor agonist Sulfonylurea† high moderate risk gain hypoglycemia‡ low If needed to reach individualized HbA1c target after ~3 months, proceed to 2-drug combination (order not meant to denote any specific preference): T2DM Anti-hyperglycemic Therapy: When goal is to avoid weight gain Diabetes Care, Diabetologia. 19 April 2012
| Presentation Title | Presenter Name | Date | Subject | Business Use Only25
Concluding remarks on guidelines  In AACE/ ACE guidelines priority has been given to Incretin based therapies most likely because of glycemic control along with added benefit like weight reduction with GLP1-RA (weight neutral with DPP4-i), and extra glycemic effects like triglyceride reduction, reduced hepatic fat and reduction in systolic and diastolic blood pressure.  In ADA/EASD 2012 guidelines : guide the clinician in choosing agents which may be most appropriate under certain situations: to avoid weight gain, to avoid hypoglycemia, and to minimize costs Reference: Timothy Bailey, The American Journal of Medicine (2013) 126, S10-S20 Diabetes CDiabetes Care, Diabetologia. 19 April 2012 are, Diabetologia. 19 April 2012
GLP1 (7-36) agonist DPP4 inhibition rationale in T2DM treatment Oral glucose or mixed meal GLP1 (9-36) inactive GLP1 actions >80% of total pool Intestinal wall Ahrén et al. Diabetes Care 2003; 26: 2860–2864; Deacon et al. Diabetes 1995;44:1126–1131; Deacon, Holst. Biochem Biophys Res Commun 2002;294:1–4; Demuth et al. Biochem Biophys Res Commun 2002;296:229–232; Drucker. Diabetes Care 2003;26:2929–2940 L-cell DPP4
HGO= Hepatic Glucose Output Adapted from Unger RH. Metabolism. 1974;23:581.  Insulin  Glucagon IMPROVED GLYCEMIC CONTROL Incretin Activity Prolonged Improved islet function DPP-4 Inhibitor  Insulin  Glucagon HYPERGLYCEMIA Incretin Response Diminished Further impaired islet function T2DM DPP-4 Inhibition enhances the physiological effects of incretin hormones
Non Glucose dependent action of Sulphonylurea (Sus) Glucose dependent action of DPP4 inhibitors (DPP4i) High risk of hypoglycemia & Beta cell stress/exhaution in Sulphonylurea Lesser risk of hypoglycemia & Beta cell preservation in DPP4 inhibitors The Glucose dependent action of DPP4i Vs SUs Lesser chances of Hypoglycemia & lesser Beta cell stress
DPP4-i addresses the unmet need in the management of diabetes Adapted from Drucker. Diabetes Care 2003;26:2929–2940 Physiological levels of GLP1 – multiple effects on plasma glucose • Improves glucose uptake in fat and muscle tissue Insulin resistance • Suppresses glucagon secretion Inadequate glucagon suppression (-cell dysfunction) • Improves insulin secretion Acute β-cell function • Increases insulin biosynthesisa • Promotes β-cell differentiationa • Decreases β-cell apoptosisa Chronic β-cell function aPreclinical data. GLP1=glucagon-like peptide-1.
ED50 Insulin capacity Glucose Concentration (mmol/L) InsulinSecretoryResponse 4.5 5.0 5.5 6.0 6.5 7.0 Glucose sensitivity Can we increase insulin secretion capacity? Short-term effect Increased glucose sensitivity Glucose-dependent stimulation of insulin secretion No danger of hypoglycemia ED50 Insulin capacity Effect of GLP-1 on Insulin Response to Glucose in Patients with T2DM ED50=effective dose at 50%; GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus. Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441; Zander M, et al. Lancet. 2002;359:824–30.
Sustainability of β-cell Function: No sustainability of Glycemic Control with Sulfonylureas DeFronzo (Diabetes 2009; 58:773-795) ADA/EASD Algorithm: • As the progressive decline in beta cell function is a key factor limiting long-term glycaemic control, more consideration should be given to drugs with beta cell-preserving properties Schernthaner G et al Diabetologia (2010) 53:1258–1269
Sustainability of β-cell Function : Vildagliptin versus glimepiride over 2 years 33 Initial response was defined as a reduction from baseline in HbA1c ≥0.5% or a HbA1c ≤6.5% during the first 6 months of treatment. Sustainability was defined as the time (in days) from initial response (when the patient reached their lowest HbA1c level within the first 6 months), until an increase of >0.3% above that initial response was detected. 309 270 250 260 270 280 290 300 310 320 Vildagliptin Glimepiride Mean Sustainability of Initial Response (IR) in days Days Mathews etal, Diabetes, Obesity and Metabolism 12: 780–789, 2010
* * * 0 12 24 52 Time (Week) * * † 0 12 24 52 Time (Week) pmol/L30min/(mmol/L) 0 12 24 52 Time (Week) * * mL·min-1·m-2 0.050 0.040 0.045 0.025 0.030 0.035 300 250 275 200 225 14 10 12 6 8 Insulin Secretion Insulin Sensitivity Adaptation Index Effects of vildagliptin treatment on -cell function and insulin sensitivity over 52 Weeks Patients on Stable Metformin Therapy *P <0.05 vs placebo; †P <0.01 vs placebo. Adapted from Ahrén B, et al. Diabetes Care. 2005; 28: 1936–1940. Vildagliptin 50 mg daily / metformin Placebo / metformin nmolC-peptide·mmolglucose -1· mL-1·m-2
Efficacy as Monotherapy compared to Metformin comparable efficacy at 2 yrs At 1 yr (52 weeks) At 2 yrs (104 weeks) Intention-to-treat population. *Non-inferiority end point not met, confidence interval = 0.28–0.65 (non-inferiority margin is defined by confidence interval upper limit of 0.4%). *Not non-inferior; **P <0.001 vs metformin (Fisher’s exact test). Schweizer A, et al. Diabet Med. 2007; 24: 955–961. Göke B, et al. Horm Metab Res. 2008; 40: 892–895.
Rationale for the fixed dose combination of vildagliptin plus metformin used as initial therapy 1. The Mechanistic Rationale – • Vildagliptin offers a clinically important outcome when added to metformin with a twice daily dose regimen, taking advantage of its tight binding and slow dissociation characteristics that lead to a sustained overnight effect • Synergistic Effect – Higher intact GLP-1 levels with combination 2. The Clinical Rationale – • Equivalent or superior HbA1c lowering without the GI tolerability issues associated with higher doses of metformin • Comparable overall tolerability profile and low risk of hypoglycaemia 3. The Compliance Rationale • Single pill Combination tends to improve patient compliance.
Initial combination of Vildagliptin + Metformin Effective across the hyperglycemia spectrum 37
Preferred term, % Mono vilda n=297 Mono met n=295 Low-dose vilda + met n=290 High-dose vilda + met n=292 Diarrhoea 2.4 11 7.2 6.5 Headache 5.4 4.5 6.2 5.5 Nasopharyngitis 3.7 4.8 5.5 7.5 Dizziness 2.7 4.1 4.8 5.1 Nausea 2.4 5.8 4.8 6.5 Pain in extremity 1.7 2.4 3.1 1.4 Upper respiratory tract infection 3.4 2.7 3.1 1.4 Fatigue 2.0 5.1 2.4 2.4 Dyspepsia 1.0 1.7 2.1 3.4 Asthenia 1.3 1.4 1.4 3.1 Cough 2.7 3.1 1.4 1.7 Vomiting 0.3 2.4 1.4 3.1 Back pain 2.0 3.8 1.0 3.8 Hypertension 2.4 3.4 1.0 2.1 Abdominal pain 2.0 3.4 0.7 0.7 Constipation 3.4 1.7 0.7 2.1 High-dose vildagliptin + metformin (50/1000 mg bid); low-dose vildagliptin + metformin (50/500 mg bid). Met=metformin; vilda=vildagliptin. Data on file, Novartis Pharmaceuticals, LMF237A2302. Initial Combination of Vildagliptin + Metformin: incidence of AEs > in any group
Vildagliptin in combination with insulin 42 40% fewer incidences of hypoglycemia, no severe hypoglycemia BL=baseline; HbA1c=hemoglobin A1c. *P <0.001; **P <0.05 between groups. Fonseca V, et al. Diabetologia. 2007; 50: 1148–1155.
43 Vildagliptin role in hypoglycemia situations – emerging data 43
44 Possible mechanism for low risk of hypoglycemia
Response to meal (−80%) 0 400 600 1000 Response to hypoglycemia (+38%) 200 0 40 60 Placebo 10 GlucagonΔAUC0-120(ng/L*min) VildagliptinPlacebo * 800 20 30 50 Δglucagon(ng/L) ** Vildagliptin Vildagliptin inhibits glucagon at high glucose but increases glucagon at low glucose *P=0.025; **P=0.039 Ahrén, et al. J Clin Endocrinol Metab 94:1236, 2009
Vildagliptin has specific role at low glucose Increased GIP levels Increased glucose sensitivity in islet α- and β-cells Potential mechanisms to Mitigate the risk of Hypoglycaemia
Insulin Glucagon ↑ Insulin secretion ↓ Glucagon at high glucose ↑ Glucagon at low glucose GLP-1   GIP ()  Vildagliptin increases both GLP-1 and GIP and therefore lowers glucose with low risk of hypoglycemia GLP-1 and GIP: dual effects on islet hormone secretion
Cardio Vascular Renal Elderly Fasting Patients
Odds ratio [95% CI] p-value Major CV event1 0.71 [0.59, 0.86] < 0.001 Acute MI 0.64 [0.44, 0.94] 0.023 Stroke 0.77 [0.48, 1.24] 0.29 Mortality 0.60 [0.41, 0.88] 0.008 CV mortality 0.67 [0.39, 1.14] 0.14 Meta-analysis of 70 short- and medium-term trials, with 41,959 patients and mean follow-up of 44.1 weeks DPP4 inhibitor better Comparator better Cardiovascular Safety: In a large meta-analysis of CV events, DPP-4is were better than the comparator in terms of CV safety AMI, acute myocardial infarction; CV, cardiovascular; DPP4i, dipeptidyl peptidase-4 inhibitors; MACE, major CV events; MH–OR, Mantel–Haenzel odds ratio. 1.Analysis of MACE as serious adverse events supports the safety of DPP4 inhibitors, but does not demonstrate their efficacy in reducing CV risk ion a long-term basis. Monami M, et al. Diabetes Obes Metab. 2013;15:112–120. 0.0 1.0 10.0
53 Cardiac safety: Vildagliptin vs Competition Monami et al, Diabetes, Obesity and Metabolism 15: 112–120, 2013 Benefit was only significant with Vildagliptin and Saxagliptin Significant (p=0.005) 39% reduction in MACE with Vildagliptin
SAVOR-TIMI Primary End-point: Composite of CVD death, MI or ischemic stroke Secondary end-point: Primary + hospitalisation for unstable angina, coronary revascularization or HF Scirica BM et al. N Engl J Med 2013. DOI: 10.1056/NEJMoa1307684 16,492 T2DM with CVD or at risk Saxagliptin vs placebo Median follow-up 2.1 years More patients on saxagliptin had hospitalisation with HF HR 1.27 (95% CI 1.07 to 1.51)
Placebo + Current therapy Vildagliptin (50 mg qd2 or bid3) + Current therapy Run-in Double-blind Treatment 52 weeks2 weeks Screening Randomization Stable dose of current therapy1 ● This was a multi-center, randomized, double-blind clinical trial to evaluate the safety of vildagliptin versus placebo when given as monotherapy or as add-on therapy to other anti- diabetic drugs for 52 weeks in patients with T2DM and CHF (NYHA class I-III). Stratification occurred at Visit 2 for baseline CHF status (NYHA class I, II or III) 1Patients remained on their current anti-diabetic therapy (for at least 8 weeks prior to Visit 1 and on a stable dose for at least 4 weeks prior to Visit 1). 2Patients who were taking background sulfonylurea therapy were instructed to take one tablet (vildagliptin 50 mg or vildagliptin 50 mg matching placebo) before the breakfast meal every day. 3Patients who were not taking background sulfonylurea therapy were instructed to take one tablet (vildagliptin 50 mg or vildagliptin 50 mg matching placebo) before breakfast and one tablet before the evening meal every day. N=128 N=126 CHF, congestive heart failure; NYHA, New York Heart Association; T2DM, type 2 diabetes mellitus. Vildagliptin In Ventricular Dysfunction Diabetes Study
PPS: †p=0.667 (95% CI=-2.21, 3.44); FAS ‡p=0.670 (95% CI=-1.97, 3.06). Indicates non-inferiority to comparator at the 2.5% alpha level. Non-inferiority margin is -3.5. FAS, full analysis set; LVEF, left ventricular ejection fraction; PPS, per protocol set. Study 23118, Novartis Data on file, CSR Table 11-6. Primary endpoint: Change in LVEF from baseline to Week 52 endpoint . Vildagliptin Placebo Between-treatment difference Full analysis setPer protocol set 4.95 4.33 † 0.62 0 1 2 3 4 5 6 7 AdjustedmeanchangeinLVEF,% 4.06 3.51 ‡ 0.54 0 1 2 3 4 5 6 AdjustedmeanchangeinLVEF,% N= 89 90 N= 114 111
*p=0.04, indicates statistical significance at 5% level. #Full analysis set. BL, baseline. Study 23118, Novartis Data on file, CSR Table 11-8. -0.21 0.15 -0.36 *-0.6 -0.5 -0.4 -0.3 -0.2 -0.1 0 0.1 0.2 0.3 0.4 Adjustedmean(SE)changeinHbA1c,% N = 115 107 BL = 7.8 7.8 Strictly Confidential. Proprietary information of Novartis. For internal use ONLY. Secondary endpoint: Change in HbA1c from baseline to rescue-censored 52 week endpoint# Vildagliptin Placebo Between-treatment difference
Similar incidence of SAEs, discontinuations due to AEs, or death for vildagliptin and comparators n (%) Vilda 50 mg bid N=6116 Total comparators N=6210 Any AE 4225 (69.1) 4228 (69.0) Drug-related AEs 961 (15.7) 1349 (21.7) SAEs 545 (8.9) 557 (9.0) Discontinuation of study drug due to AEs 347 (5.7) 400 (6.4) Deaths 24 (0.4) 23 (0.4) AEs=adverse events; bid=twice daily; PBO=placebo; SAEs= serious adverse events; vilda=vildagliptin. All-study safety (excluding open-label) population. Schweizer A. et al, Vasc Health Risk Manag 2011(accepted version)
Renal safety of Vildagliptin- 1 year data Significant HbA1c reduction • 1 year safety study adding Vildagliptin 50mg od to background therapy in those with moderate or severe renal failure • Better HbA1c reduction of 0.6% and 0.8% with Vildagliptin in moderate and severe RI respectively Kothny et al. Diabetes Obesity Metabolism,2012
No deterioration of renal function with vildagliptin Renal impairment Moderate Severe eGFR (MDRD) (mL/min/1.73 m2) Vilda 50mg qd N=163 Placebo N=129 Vilda 50mg qd N=124 Placebo N=97 Mean Baseline 39.3 40.3 21.9 20.9 Mean Change from baseline 0.865 0.572 -1.456 -1.121 Median Change from baseline -0.068 -0.067 -1.291 -1.872 Estimated *GFR (MDRD) in patients with severe and moderate RI at 24 wks * eGFR (MDRD)= GFR estimated using the MDRD formula. Baseline eGFR is defined as the lowest of eGFR (MDRD) values before visit 2 that were calculated using the serum creatinine value before visit 2 and the age at the associated creatinine measurement date • The overall incidences of AEs, SAEs, discontinuations due to AEs and deaths were comparable between vildagliptin 50 mg qd and placebo treatment groups • No statistically significant or clinically relevant differences for events of identified risk observed for vildagliptin MDRD = Modification of Diet in Renal DiseaseLukashevich et al. Diabetes Obesity Metabolism,2011
Mechanistic basis of Vildagliptin in T2DM patients with renal impairment Yan –Ling He-Int J Clin Pharmacol Ther. 2013; 51:693–703  Only ~23% of vildagliptin is excreted unchanged by kidney (main excretion mode is hydrolysis to inactive metabolite) In Mild/Moderate/severe : similar and minimal increase in Cmax In moderate and severe RI: 1.7~2 fold increase in exposure of vildagliptin(AUC0-24hrs) Doubling of exposure (AUC) but no expected increased in concentration (Cmax) in Moderate/Severe RI Effectively with vildagliptin in RI there is, • Reduced dose frequency, dose strength unchanged, maintained 24-hour DPP4 blockage (50 mg once daily Vildagliptin in moderate/severe RI = 50 mg twice daily Vildagliptin in normal renal function) • A1c reductions with 50 mg OD similar to reduction with 50 mg BD with normal renal function • 50% reduced therapy cost In patients with moderate-severe RI with vildagliptin, How does Vildagliptin add value in terms of Renal safety to T2DM patients Reduce dose frequency by half
65 Summary and Take Home Messages • Tight glycaemic control should be targeted from the day of diagnosis • Intensive glycaemic control:  Reduces risk of micro-vascular complications  Some benefit in reducing cardiovascular events  No reductions in mortality  Clinical inertia a major issue in achieving tight targets  DPP-4 inhibitors are an important therapy option as reflected by current guidelines and clinical evidence • Vildagliptin is efficacious, weight neutral, with a low risk of hypoglycaemia as monotherapy, and in combination with other anti-diabetic agents including metformin.
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67 Thank You
Basic Succinct Statement - GALVUS® Presentation: Tablets containing 50 mg of Vildagliptin. Indications: ♦Galvus is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus (T2DM). It is indicated: as monotherapy, IN COMBINATION: with metformin, when diet, exercise and metformin alone do not result in adequate glycemic control. with a sulphonylurea (SU), when diet, exercise and a SU alone do not result in adequate glycemic control. with a thiazolidinedione (TZD), when diet, exercise and a TZD alone do not result in adequate glycemic control. IN TRIPLE COMBINATION: with a sulphonylurea and metformin when diet and exercise plus dual therapy with these agents do not provide adequate glycemic control. ♦Galvus is also indicated in combination with insulin (with or without metformin) when diet, exercise and a stable dose of insulin do not result in adequate glycemic control. ♦Galvus is also indicated as initial combination therapy with metformin in patients with T2DM whose diabetes is not adequately controlled by diet and exercise alone. Dosage and administration: ♦Adults: The recommended dose is 50 mg or 100 mg daily for monotherapy, and for combination with metformin, with a TZD or with insulin (with or without metformin); 50 mg daily in combination with a SU; 100 mg daily for triple combination with metformin and a SU. Maximum dose is 100 mg/day (in two divided doses of 50 mg).♦Children (under 18 years of age): Not recommended. ♦Special population: In patients with moderate to severe renal impairment or End Stage Renal Disease (ESRD), the recommended dose is 50 mg once daily. Contraindications: Hypersensitivity to vildagliptin or to any of the excipients. Warnings and precautions: ♦Galvus should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. ♦Not recommended in patients with hepatic impairment including patients with a pre-treatment ALT or AST>2.5X the upper limit of normal. Liver function tests (LFT) to be performed prior to treatment initiation, at three-month intervals during the first year and periodically thereafter. Withdrawal of therapy with Galvus recommended if an increase in AST or ALT of 3X upper limit normal or greater persist. Following withdrawal of treatment with Galvus and LFT normalisation, treatment with Galvus should not be reinitiated. ♦Clinical experience in patients with NYHA functional class III treated with vildagliptin is still limited and results are inconclusive. ♦Not recommended in patients with NYHA Class IV. Women of child-bearing potential, pregnancy: Should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. Breast-feeding: Should not be used. Special excipients: Contains lactose Adverse reactions: Rare cases of angioedema. Rare cases of hepatic dysfunction (including hepatitis) ♦Monotherapy - Common: dizziness - Uncommon: headache, constipation, oedema peripheral. ♦Combination with metformin - Common: tremor, dizziness, headache. ♦Combination with a sulphonylurea - Common: tremor, headache, dizziness, asthenia. ♦Combination with a thiazolidinedione - Common: weight increase, oedema peripheral. ♦Combination with insulin - Common: headache, nausea, gastrooesophageal reflux disease, chills, decreased blood glucose – Uncommon: Diarrhoea, flatulence. ♦Combination with metformin and a sulphonylurea - Common: dizziness, tremor, asthesia, hypoglycaemia, hyperhidrosis. ♦Post-marketing experience - Rare: hepatitis (reversible with drug discontinuation) – Unknown: urticaria, pancreatitis, localized exfoliation or blisters. Interactions: ♦Vildagliptin has a low potential for drug interactions. ♦No clinically relevant interactions with other oral antidiabetics (glibenclamide, pioglitazone, metformin), amlodipine, digoxin, ramipril, simvastatin, valsartan or warfarin were observed after co-administration with vildagliptin. Packs: Box of 2 strips of 14 tablets each Note: Before prescribing, please consult full prescribing information available from Novartis Healthcare Private limited, Sandoz House, Dr. Annie Besant Road, Worli, Mumbai- 400 018, Tel: 022 2495 8888 For the use only of a registered medical practitioner or a hospital or a laboratory. India BSS dtd 27 Jan 2014 based on international BSS dtd 18 Dec 2013
Basic Succinct Statement – GalvusMet® Presentation: Tablets containing Vildagliptin/Metformin hydrochloride fixed dose combination: 50 mg/500 mg, 50 mg/850 mg, 50 mg/1,000mg. Indications: ♦Galvus Met is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus (T2DM) whose diabetes is not adequately controlled on metformin hydrochloride or vildagliptin alone or who are already treated with the combination of vildagliptin and metformin hydrochloride, as separate tablets. ♦Galvus Met is indicated in combination with a sulphonylurea (i.e., triple combination therapy) as an adjunct to diet and exercise in patients inadequately controlled with metformin and a sulphonylurea. ♦Galvus Met is indicated in combination with insulin (i.e., triple combination therapy) as an adjunct to diet and exercise to improve glycemic control in patients when stable dose of insulin and metformin alone do not provide adequate glycemic control. ♦ Galvus Met is also indicated for the treatment of Type 2 Diabetes mellitus having HbA1c > 8% where diabetes is not adequately controlled by diet and exercise alone. Dosage and administration: ♦Do not exceed the maximum recommended daily dose of vildagliptin (100 mg). ♦Should be given with meals. ♦Adults: Starting dose for patients inadequately controlled on vildagliptin or metformin hydrochloride monotherapy: 50 mg/500mg twice daily and gradually titrated after assessing adequacy of therapeutic response. ♦Starting dose for patients switching from combination therapy of vildagliptin plus metformin hydrochloride as separate tablets: 50 mg/500 mg, 50 mg/850 mg or 50 mg/1,000 mg based on the dose of vildagliptin or metformin already being taken. ♦Starting dose for treatment naïve patients: may be initiated at 50 mg/500 mg qd and gradually titrated to a maximum dose of 50 mg/1,000 mg bid after assessing adequacy of therapeutic response. ♦Use in combination with a sulphonylurea or with insulin: the dose of Galvus Met should provide vildagliptin dosed as 50 mg twice daily (100 mg total daily dose) and a dose of metformin similar to the dose already being taken. ♦Children (under 18 years of age): Not recommended. Contraindications: Known hypersensitivity to vildagliptin or metformin hydrochloride or to any of the excipients ♦renal disease or renal dysfunction ♦congestive heart failure ♦acute or chronic metabolic acidosis including diabetic ketacidosis with or without coma ♦should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials. Warnings and precautions: ♦Risk of lactic acidosis. ♦Monitoring of renal function. ♦Caution with concomitant use of medications that may affect renal function or metformin hydrochloride disposition. ♦Should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials. ♦Discontinue treatment in case of hypoxemia. ♦Temporary discontinuation in patients undergoing surgical procedure. ♦Excessive alcohol intake to be avoided. ♦Not recommended in patients with hepatic impairment including patients with a pre-treatment ALT or AST >2.5X the upper limit of normal. Liver function tests (LFT) to be performed prior to treatment initiation, at three-month intervals during the first year and periodically thereafter. Withdrawal of therapy with Galvus Met recommended if an increase in AST or ALT of 3X upper limit normal or greater persist. Following withdrawal of treatment with Galvus Met and LFT normalisation, treatment with Galvus Met should not be reinitiated. ♦Risk of decreased vitamin B12 serum levels. ♦Should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. ♦Risk of hypoglycemia. ♦May be temporarily withheld in case of loss of glycemic control. ♦Should only be used in elderly patients with normal renal function. ♦Not recommended in pediatric patients.
Women of child-bearing potential, pregnancy: Should not be used in pregnancy unless the potential benefit justifies the potential risk to the foetus. Breast-feeding: Should not be used during breast-feeding. Adverse reactions: ♦Vildagliptin: Rare cases of angioedema. Rare cases of hepatic dysfunction (including hepatitis). ♦Vildagliptin monotherapy - Common: dizziness – Uncommon: headache, constipation, oedema peripheral. ♦Metformin monotherapy – Very common: loss of appetite, nausea, vomiting, diarrhoea, abdominal pain. Common: dysgeusia. Very rare: lactic acidosis, hepatitis, skin reactions such as erythema, pruritus and urticarial, decrease of vitamin B12 absorption, liver function test abnormalities. ♦Other effects with combination of Vildagliptin and Metformin - Common: tremor, dizziness, headache. ♦Other effects with combination of Vildagliptin and Metformin with insulin – Common: headache, nausea, gastrooesophageal reflux disease, chills, blood glucose decreased– Uncommon: diarrhoea, flatulence. ♦Other effects with combination of Vildagliptin and Metformin with a sulphonylurea – Common: dizziness, tremor, asthenia, hypoglycemia, hyperhidrosis. ♦Post-marketing experience: - Rare: hepatitis (reversible with drug discontinuation) - Unknown: urticaria, pancreatitis, localized exfoliation or blisters. Interactions: ♦Interactions with Vildagliptin: low potential for drug interactions, no clinically relevant interactions with other oral antidiabetics (glibenclamide, pioglitazone, metformin), amlodipine, digoxin, ramipril, simvastatin, valsartan or warfarin were observed after co-administration with vildagliptin. ♦Interactions with metformin hydrochloride: furosemide, nifedipine, cationic drugs, drugs tending to produce hyperglycemia, alcohol. Packs: Box containing 6 strips of 10 tablets each Note: Before prescribing, consult full prescribing information available from Novartis Healthcare Private Limited, Sandoz House, Dr. Annie Besant Road, Worli, Mumbai- 400 018, Tel: 022 2495 8888 For the use only of a registered medical practitioner or a hospital or a laboratory. India BSS dtd 31 Jan 2014 based on international BSS dtd 18 Dec 2013, effective from 1 Apr 14. 2/2 Basic Succinct Statement – GalvusMet®
Disclaimer The views, opinions, ideas etc expressed therein are solely those of the author. Novartis does not certify the accuracy, completeness, currency of any information and shall not be responsible or in anyway liable for any errors, omissions or inaccuracies in such information. Novartis is not liable to you in any manner whatsoever for any decision made or action or non- action taken by you in reliance upon the information provided. Novartis does not recommend the use of its products in unapproved indications and recommends to refer to complete prescribing information prior to using any of the Novartis products.” Issued in scientific service to medical professionals For full product information please write to : Novartis Healthcare Private Limited, Sandoz House, 7th floor, Shivsagar Estate, Dr. Annie Besant Road, Worli, Mumbai, 400 018, INDIA ScientificPresentation/Galvus/CVM/279309/Aug/2014 I For use of RMP, hospital or lab only

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Dpp4i earlier the better ! (1)

  • 1.
    DR FARAZ FARISHTA CONSULTANTENDOCRINOLOGIST MEDWIN HOSPITAL MD OF SPARSH ENDOCRINOLOGY & DIABETIC CENTERS PRESIDENT OF DIABETES AWARENESS FOUNDATION ASSISTANT PROFESSOR IN MIMS
  • 2.
    Agenda  Diabetes-Global concern Challenges associated with achieving optimal glycemic goals  Clinical inertia  Conventional management approach  What guidelines say?  What DPP4 inhibitors brought?  Vildagliptin efficacy  Vildagliptin value proposition  Summary
  • 3.
    Diabetes is ahuge and growing problem, and the costs to society are high and escalating 382 million people have diabetes By 2035, this number will rise to 592 million Ref. IDF atlas 06, 2013
  • 4.
    Almost half ofall people with diabetes live in just three countries China India USA Ref. IDF atlas 06, 2013
  • 5.
    | Presentation Title| Presenter Name | Date | Subject | Business Use Only 5 Ref. IDF atlas 06, 2013
  • 6.
    The ominous octet DEFRONZO, DIABETES,VOL. 58, APRIL 2009 DEFRONZO, DIABETES, VOL. 58, APRIL 2009
  • 7.
    The natural courseof HbA1c Ferrannini et al. J Clin Endocrinol Metab 2005
  • 8.
    Hafner SM etal. JAMA 1990;263: 2893-2898 Type 2 Diabetes is a Global Cardio-metabolic Risk (CMR) The ticking clock
  • 9.
    HbA1c=haemoglobin A1c. Diabetes TrialsUnit. UKPDS Post Trial Monitoring. UKPDS 80 Slide Set. Available at: http://www.dtu.ox.ac.uk/index.php?maindoc=/ukpds/. Accessed 12 September, 2008; Holman RR, et al. N Engl J Med. 2008; 359: 1577–1589; UKPDS 33. Lancet. 1998; 352: 837–853. MedianHbA1c(%) 0 6 7 8 9 UKPDS 1998 Conventional Metformin Holman et al 2008 Legacy effect 1997 Difference in HbA1c was lost after first year but patients in the initial intensive arm still had lower incidence of any complication: • 24% reduction in microvascular complications • 15% reduction in MI • 13% reduction in all-cause mortality 2007 Achieving early glycaemic control may generate a “good legacy effect“
  • 10.
    ADA/EASD1 AACE/ACE2 IDF3 HbA1c<7.0% (general goal) ≤6.5% <6.5% Preprandial capillary plasma glucose 70–130 mg/dL (3.9–7.2 mmol/L) <110 mg/dL (<6.0 mmol/L) <110 mg/dL (<6.0 mmol/L) Peak postprandial capillary plasma glucose <180 mg/dL (<10.0 mmol/L) <140 mg/dL (<7.7 mmol/L) <145 mg/dL (<8.0 mmol/L) ACE=American College of Endocrinology; ADA=American Diabetes Association; HbA1c=hemoglobin A1c; IDF=International Diabetes Federation. Adapted from: 1ADA / EASD consensus statement: Nathan DM, et al. Diabetes Care, 2009; 32:193–203; 2American Association of Clinical Endocrinologists, American College of Endocrinology. Endocr Pract. 2007; 13 (Suppl 1): 3–68; 3International Diabetes Federation. Global Guideline for Type 2 Diabetes. Brussels: International Diabetes Federation; 2005. Current Treatment Goals for Glycemic Control
  • 11.
    Challenges associated withachieving optimal glycaemic goals 6.5 7.0 7.5 8.0 8.5 9.0 2001 2002 2003 2004 2005 2006 2007 3.5 4.0 4.5 5.0 5.5 6.0 2001 2002 2003 2004 2005 2006 2007 Type 1 diabetes Type 2 diabetes + insulin YearYear MeanHbA1c(%) MeanTchol(mmol/l) In patients with type 1 diabetes or type 2 diabetes on insulin, there was a 0.1% relative improvement in HbA1c vs. improvements in total cholesterol of 15% and 29%, respectively between 2001 and 2007 Currie et al. Diabetic Medicine 2010; 27:938-948
  • 12.
    Clinical inertia inT2DM • Retrospective cohort study of over 80,000 people • Time to treatment intensification from first HbA1c above 7.5%, by number of OADs and type of intensification Khunti K, et al. Diabetes Care 1013;Epub ahead of print. *Proportion of people with HbA1c >7.5% having any intensification to their treatment at end of follow-up according to number of OADs Median: 1.5 years Median: >7.2 years Median: >6.1 years Cut-off HbA1c 7.5% (58 mmol/mol)
  • 13.
    Clinical inertia andCV events 105477 newly diagnosed T2DM (11.3% previous CVD) 5.3 years median follow-up 6 month delay in first 2 years of treatment with HbA1c > 7.0% MI Stroke HF Any CVE All patients 1.38 (1.16-1.82) 1.07 (0.89-1.29) 1.28 (1.10-1.48) 1.25 (1.13-1.39) No Previous CVD 1.21 (1.00-1.47) 1.07 (0.87-1.31) 1.28 (1.07-1.52) 1.20 (1.07-1.35) Previous CVD 1.91 (1.40-2.60) 1.08 (0.73-1.61) 1.27 (0.95-1.70) 1.42 (1.15-1.75) Paul S et al. Poster presented at EASD 2013. Values in table correspond to HR (95% CI)
  • 14.
    6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 1 2 34 5 6 7 8 9 10 11 12 13 14 15 16 Consequences of delayed intervention – Interpreting the VADT results Time (years since diagnosis) HbA1c(%) Bad glycaemic “legacy” Before entering VADT intensive treatment arm After entering VADT intensive treatment arm Drive risk for complications Adapted from: Del Prato S, et al. Diabetologia 2009;52:1219-1226.
  • 15.
    Earlier and AppropriateIntervention May Improve Patients’ Chances of Reaching Goal OAD=oral antidiabetic agent. Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355. Published Conceptual Approach HbA1cGoal Mean HbA1c of patients Duration of Diabetes OAD monotherapy Diet and exercise OAD combination OAD up-titration OAD + multiple daily insulin injections OAD + basal insulin Conventional stepwise treatment approach Earlier and more aggressive intervention approach 6 7 8 9 10
  • 16.
    1 Gastrointestinal 2 Thiazolidinedione Adaptedfrom DeFronzo RA. Br J Diabetes Vasc Dis. 2003;3(suppl 1):S24–S40 Conventional Oral Therapies Do Not Address the Multiple Defects in Type 2 Diabetes Sulfonylureas Glinides Impaired insulin action Inadequate glucagon suppression (-cell dysfunction) Glucose influx from GI1 tract α-Glucosidase inhibitors TZDs2 Metformin Chronic β-cell decline  Plasma glucose and disease progression Acute β-cell dysfunction unmet need unmet need
  • 17.
    Metformin1 TZDs1-3 α-glucosidase inhibitors1 CHF=congestive heart failure;GI=gastrointestinal; SU=sulfonylurea; T2DM=type 2 diabetes mellitus; TZD=thiazolidinedione aRole uncertain 1Inzucchi SE. JAMA. 2002; 287: 360–372; 2Avandia US Prescribing Information; 3Dormandy JA, et al. Lancet. 2005; 366: 1279–1289; 4Buse JB, et al. Diabetes Care. 2004; 27: 2628–2635; 5DeFronzo RA, et al. Diabetes Care. 2005; 28: 1092–1100; 6Kendall DM, et al. Diabetes Care. 2005; 28: 1083– 1091; 7Kolterman OG, et al. Am J Health-Syst Pharm. 2005; 62: 173–181; 8Byetta US Prescribing Information. Incretin mimetics4-8 Weight gain, edema, CHF, bone fractures (pioglitazone, rosiglitazone) GI effects (flatulence, diarrhea) GI effects (nausea, diarrhea), lactic acidosis (rare) GI effects (nausea, vomiting, diarrhea), pancreatitis, hypoglycemia (in add-on to SU) SUs1 Meglitinides1 Hypoglycemia, weight gain, hyperinsulinemiaa Major Adverse Events of Traditional Treatments for T2DM- Limits Efficacy
  • 18.
    | Presentation Title| Presenter Name | Date | Subject | Business Use Only21 What did the major guidelines say...?
  • 19.
    Reference: A. Garberet. al., ENDOCRINE PRACTICE Vol 19 (Suppl 2) May/June 2013 AACE’ 2013 Treatment Algorithm
  • 20.
    T2DM Anti-hyperglycemic Therapy:When goal is to avoid hypoglycemia Initial drug monotherapy Efficacy (! HbA1c) Hypoglycemia Weight Side effects Costs Healthy eating, weight control, increased physical activity Metformin high low risk neutral/loss GI / lactic acidosis low Metformin + Metformin + Metformin + Metformin + Metformin + Efficacy (! HbA1c) Hypoglycemia Weight Major side effect(s) Costs high low risk gain edema, HF,fx’s‡ high Thiazolidine- dione intermediate low risk neutral rare‡ high DPP-4 Inhibitor highest high risk gain hypoglycemia‡ variable Insulin (usually basal) Two drug combinations* Sulfonylurea† + Thiazolidine- dione + DPP-4 Inhibitor + GLP-1 receptor agonist + Insulin (usually basal) + Metformin + Metformin + Metformin + Metformin + Metformin + TZD DPP-4-i GLP-1-RA Insulin§ SU† DPP-4-i GLP-1-RA Insulin§ SU† SU† TZD TZD TZD DPP-4-i Insulin§ Insulin§ Insulin# (multiple daily doses) Three drug combinations More complex insulin strategies or or or or or or or or or or or or GLP-1-RA high low risk loss GI‡ high GLP-1 receptor agonist Sulfonylurea† high moderate risk gain hypoglycemia‡ low If needed to reach individualized HbA1c target after ~3 months, proceed to 2-drug combination (order not meant to denote any specific preference): If needed to reach individualized HbA1c target after ~3 months, proceed to 3-drug combination (order not meant to denote any specific preference): Diabetes Care, Diabetologia. 19 April 2012
  • 21.
    Initial drug monotherapy Efficacy (!HbA1c) Hypoglycemia Weight Side effects Costs Healthy eating, weight control, increased physical activity Metformin high low risk neutral/loss GI / lactic acidosis low Metformin + Metformin + Metformin + Metformin + Metformin + Efficacy (! HbA1c) Hypoglycemia Weight Major side effect(s) Costs high low risk gain edema, HF,fx’s‡ high Thiazolidine- dione intermediate low risk neutral rare‡ high DPP-4 Inhibitor highest high risk gain hypoglycemia‡ variable Insulin (usually basal) Two drug combinations* Sulfonylurea† + Thiazolidine- dione + DPP-4 Inhibitor + GLP-1 receptor agonist + Insulin (usually basal) + Metformin + Metformin + Metformin + Metformin + Metformin + TZD DPP-4-i GLP-1-RA Insulin§ SU† DPP-4-i GLP-1-RA Insulin§ SU† SU† TZD TZD TZD DPP-4-i Insulin§ Insulin§ Insulin# (multiple daily doses) Three drug combinations More complex insulin strategies or or or or or or or or or or or or GLP-1-RA high low risk loss GI‡ high GLP-1 receptor agonist Sulfonylurea† high moderate risk gain hypoglycemia‡ low If needed to reach individualized HbA1c target after ~3 months, proceed to 2-drug combination (order not meant to denote any specific preference): T2DM Anti-hyperglycemic Therapy: When goal is to avoid weight gain Diabetes Care, Diabetologia. 19 April 2012
  • 22.
    | Presentation Title| Presenter Name | Date | Subject | Business Use Only25
  • 23.
    Concluding remarks onguidelines  In AACE/ ACE guidelines priority has been given to Incretin based therapies most likely because of glycemic control along with added benefit like weight reduction with GLP1-RA (weight neutral with DPP4-i), and extra glycemic effects like triglyceride reduction, reduced hepatic fat and reduction in systolic and diastolic blood pressure.  In ADA/EASD 2012 guidelines : guide the clinician in choosing agents which may be most appropriate under certain situations: to avoid weight gain, to avoid hypoglycemia, and to minimize costs Reference: Timothy Bailey, The American Journal of Medicine (2013) 126, S10-S20 Diabetes CDiabetes Care, Diabetologia. 19 April 2012 are, Diabetologia. 19 April 2012
  • 24.
    GLP1 (7-36) agonist DPP4 inhibitionrationale in T2DM treatment Oral glucose or mixed meal GLP1 (9-36) inactive GLP1 actions >80% of total pool Intestinal wall Ahrén et al. Diabetes Care 2003; 26: 2860–2864; Deacon et al. Diabetes 1995;44:1126–1131; Deacon, Holst. Biochem Biophys Res Commun 2002;294:1–4; Demuth et al. Biochem Biophys Res Commun 2002;296:229–232; Drucker. Diabetes Care 2003;26:2929–2940 L-cell DPP4
  • 25.
    HGO= Hepatic GlucoseOutput Adapted from Unger RH. Metabolism. 1974;23:581.  Insulin  Glucagon IMPROVED GLYCEMIC CONTROL Incretin Activity Prolonged Improved islet function DPP-4 Inhibitor  Insulin  Glucagon HYPERGLYCEMIA Incretin Response Diminished Further impaired islet function T2DM DPP-4 Inhibition enhances the physiological effects of incretin hormones
  • 26.
    Non Glucose dependentaction of Sulphonylurea (Sus) Glucose dependent action of DPP4 inhibitors (DPP4i) High risk of hypoglycemia & Beta cell stress/exhaution in Sulphonylurea Lesser risk of hypoglycemia & Beta cell preservation in DPP4 inhibitors The Glucose dependent action of DPP4i Vs SUs Lesser chances of Hypoglycemia & lesser Beta cell stress
  • 27.
    DPP4-i addresses theunmet need in the management of diabetes Adapted from Drucker. Diabetes Care 2003;26:2929–2940 Physiological levels of GLP1 – multiple effects on plasma glucose • Improves glucose uptake in fat and muscle tissue Insulin resistance • Suppresses glucagon secretion Inadequate glucagon suppression (-cell dysfunction) • Improves insulin secretion Acute β-cell function • Increases insulin biosynthesisa • Promotes β-cell differentiationa • Decreases β-cell apoptosisa Chronic β-cell function aPreclinical data. GLP1=glucagon-like peptide-1.
  • 28.
    ED50 Insulin capacity Glucose Concentration (mmol/L) InsulinSecretoryResponse 4.55.0 5.5 6.0 6.5 7.0 Glucose sensitivity Can we increase insulin secretion capacity? Short-term effect Increased glucose sensitivity Glucose-dependent stimulation of insulin secretion No danger of hypoglycemia ED50 Insulin capacity Effect of GLP-1 on Insulin Response to Glucose in Patients with T2DM ED50=effective dose at 50%; GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus. Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441; Zander M, et al. Lancet. 2002;359:824–30.
  • 29.
    Sustainability of β-cellFunction: No sustainability of Glycemic Control with Sulfonylureas DeFronzo (Diabetes 2009; 58:773-795) ADA/EASD Algorithm: • As the progressive decline in beta cell function is a key factor limiting long-term glycaemic control, more consideration should be given to drugs with beta cell-preserving properties Schernthaner G et al Diabetologia (2010) 53:1258–1269
  • 30.
    Sustainability of β-cellFunction : Vildagliptin versus glimepiride over 2 years 33 Initial response was defined as a reduction from baseline in HbA1c ≥0.5% or a HbA1c ≤6.5% during the first 6 months of treatment. Sustainability was defined as the time (in days) from initial response (when the patient reached their lowest HbA1c level within the first 6 months), until an increase of >0.3% above that initial response was detected. 309 270 250 260 270 280 290 300 310 320 Vildagliptin Glimepiride Mean Sustainability of Initial Response (IR) in days Days Mathews etal, Diabetes, Obesity and Metabolism 12: 780–789, 2010
  • 31.
    * * * 012 24 52 Time (Week) * * † 0 12 24 52 Time (Week) pmol/L30min/(mmol/L) 0 12 24 52 Time (Week) * * mL·min-1·m-2 0.050 0.040 0.045 0.025 0.030 0.035 300 250 275 200 225 14 10 12 6 8 Insulin Secretion Insulin Sensitivity Adaptation Index Effects of vildagliptin treatment on -cell function and insulin sensitivity over 52 Weeks Patients on Stable Metformin Therapy *P <0.05 vs placebo; †P <0.01 vs placebo. Adapted from Ahrén B, et al. Diabetes Care. 2005; 28: 1936–1940. Vildagliptin 50 mg daily / metformin Placebo / metformin nmolC-peptide·mmolglucose -1· mL-1·m-2
  • 32.
    Efficacy as Monotherapycompared to Metformin comparable efficacy at 2 yrs At 1 yr (52 weeks) At 2 yrs (104 weeks) Intention-to-treat population. *Non-inferiority end point not met, confidence interval = 0.28–0.65 (non-inferiority margin is defined by confidence interval upper limit of 0.4%). *Not non-inferior; **P <0.001 vs metformin (Fisher’s exact test). Schweizer A, et al. Diabet Med. 2007; 24: 955–961. Göke B, et al. Horm Metab Res. 2008; 40: 892–895.
  • 33.
    Rationale for thefixed dose combination of vildagliptin plus metformin used as initial therapy 1. The Mechanistic Rationale – • Vildagliptin offers a clinically important outcome when added to metformin with a twice daily dose regimen, taking advantage of its tight binding and slow dissociation characteristics that lead to a sustained overnight effect • Synergistic Effect – Higher intact GLP-1 levels with combination 2. The Clinical Rationale – • Equivalent or superior HbA1c lowering without the GI tolerability issues associated with higher doses of metformin • Comparable overall tolerability profile and low risk of hypoglycaemia 3. The Compliance Rationale • Single pill Combination tends to improve patient compliance.
  • 34.
    Initial combination ofVildagliptin + Metformin Effective across the hyperglycemia spectrum 37
  • 35.
    Preferred term, % Monovilda n=297 Mono met n=295 Low-dose vilda + met n=290 High-dose vilda + met n=292 Diarrhoea 2.4 11 7.2 6.5 Headache 5.4 4.5 6.2 5.5 Nasopharyngitis 3.7 4.8 5.5 7.5 Dizziness 2.7 4.1 4.8 5.1 Nausea 2.4 5.8 4.8 6.5 Pain in extremity 1.7 2.4 3.1 1.4 Upper respiratory tract infection 3.4 2.7 3.1 1.4 Fatigue 2.0 5.1 2.4 2.4 Dyspepsia 1.0 1.7 2.1 3.4 Asthenia 1.3 1.4 1.4 3.1 Cough 2.7 3.1 1.4 1.7 Vomiting 0.3 2.4 1.4 3.1 Back pain 2.0 3.8 1.0 3.8 Hypertension 2.4 3.4 1.0 2.1 Abdominal pain 2.0 3.4 0.7 0.7 Constipation 3.4 1.7 0.7 2.1 High-dose vildagliptin + metformin (50/1000 mg bid); low-dose vildagliptin + metformin (50/500 mg bid). Met=metformin; vilda=vildagliptin. Data on file, Novartis Pharmaceuticals, LMF237A2302. Initial Combination of Vildagliptin + Metformin: incidence of AEs > in any group
  • 36.
    Vildagliptin in combinationwith insulin 42 40% fewer incidences of hypoglycemia, no severe hypoglycemia BL=baseline; HbA1c=hemoglobin A1c. *P <0.001; **P <0.05 between groups. Fonseca V, et al. Diabetologia. 2007; 50: 1148–1155.
  • 37.
    43 Vildagliptin role inhypoglycemia situations – emerging data 43
  • 38.
    44 Possible mechanism forlow risk of hypoglycemia
  • 39.
    Response to meal(−80%) 0 400 600 1000 Response to hypoglycemia (+38%) 200 0 40 60 Placebo 10 GlucagonΔAUC0-120(ng/L*min) VildagliptinPlacebo * 800 20 30 50 Δglucagon(ng/L) ** Vildagliptin Vildagliptin inhibits glucagon at high glucose but increases glucagon at low glucose *P=0.025; **P=0.039 Ahrén, et al. J Clin Endocrinol Metab 94:1236, 2009
  • 40.
    Vildagliptin has specificrole at low glucose Increased GIP levels Increased glucose sensitivity in islet α- and β-cells Potential mechanisms to Mitigate the risk of Hypoglycaemia
  • 41.
    Insulin Glucagon ↑ Insulinsecretion ↓ Glucagon at high glucose ↑ Glucagon at low glucose GLP-1   GIP ()  Vildagliptin increases both GLP-1 and GIP and therefore lowers glucose with low risk of hypoglycemia GLP-1 and GIP: dual effects on islet hormone secretion
  • 42.
  • 43.
    Odds ratio [95% CI] p-value MajorCV event1 0.71 [0.59, 0.86] < 0.001 Acute MI 0.64 [0.44, 0.94] 0.023 Stroke 0.77 [0.48, 1.24] 0.29 Mortality 0.60 [0.41, 0.88] 0.008 CV mortality 0.67 [0.39, 1.14] 0.14 Meta-analysis of 70 short- and medium-term trials, with 41,959 patients and mean follow-up of 44.1 weeks DPP4 inhibitor better Comparator better Cardiovascular Safety: In a large meta-analysis of CV events, DPP-4is were better than the comparator in terms of CV safety AMI, acute myocardial infarction; CV, cardiovascular; DPP4i, dipeptidyl peptidase-4 inhibitors; MACE, major CV events; MH–OR, Mantel–Haenzel odds ratio. 1.Analysis of MACE as serious adverse events supports the safety of DPP4 inhibitors, but does not demonstrate their efficacy in reducing CV risk ion a long-term basis. Monami M, et al. Diabetes Obes Metab. 2013;15:112–120. 0.0 1.0 10.0
  • 44.
    53 Cardiac safety: Vildagliptinvs Competition Monami et al, Diabetes, Obesity and Metabolism 15: 112–120, 2013 Benefit was only significant with Vildagliptin and Saxagliptin Significant (p=0.005) 39% reduction in MACE with Vildagliptin
  • 45.
    SAVOR-TIMI Primary End-point: Compositeof CVD death, MI or ischemic stroke Secondary end-point: Primary + hospitalisation for unstable angina, coronary revascularization or HF Scirica BM et al. N Engl J Med 2013. DOI: 10.1056/NEJMoa1307684 16,492 T2DM with CVD or at risk Saxagliptin vs placebo Median follow-up 2.1 years More patients on saxagliptin had hospitalisation with HF HR 1.27 (95% CI 1.07 to 1.51)
  • 46.
    Placebo + Currenttherapy Vildagliptin (50 mg qd2 or bid3) + Current therapy Run-in Double-blind Treatment 52 weeks2 weeks Screening Randomization Stable dose of current therapy1 ● This was a multi-center, randomized, double-blind clinical trial to evaluate the safety of vildagliptin versus placebo when given as monotherapy or as add-on therapy to other anti- diabetic drugs for 52 weeks in patients with T2DM and CHF (NYHA class I-III). Stratification occurred at Visit 2 for baseline CHF status (NYHA class I, II or III) 1Patients remained on their current anti-diabetic therapy (for at least 8 weeks prior to Visit 1 and on a stable dose for at least 4 weeks prior to Visit 1). 2Patients who were taking background sulfonylurea therapy were instructed to take one tablet (vildagliptin 50 mg or vildagliptin 50 mg matching placebo) before the breakfast meal every day. 3Patients who were not taking background sulfonylurea therapy were instructed to take one tablet (vildagliptin 50 mg or vildagliptin 50 mg matching placebo) before breakfast and one tablet before the evening meal every day. N=128 N=126 CHF, congestive heart failure; NYHA, New York Heart Association; T2DM, type 2 diabetes mellitus. Vildagliptin In Ventricular Dysfunction Diabetes Study
  • 47.
    PPS: †p=0.667 (95%CI=-2.21, 3.44); FAS ‡p=0.670 (95% CI=-1.97, 3.06). Indicates non-inferiority to comparator at the 2.5% alpha level. Non-inferiority margin is -3.5. FAS, full analysis set; LVEF, left ventricular ejection fraction; PPS, per protocol set. Study 23118, Novartis Data on file, CSR Table 11-6. Primary endpoint: Change in LVEF from baseline to Week 52 endpoint . Vildagliptin Placebo Between-treatment difference Full analysis setPer protocol set 4.95 4.33 † 0.62 0 1 2 3 4 5 6 7 AdjustedmeanchangeinLVEF,% 4.06 3.51 ‡ 0.54 0 1 2 3 4 5 6 AdjustedmeanchangeinLVEF,% N= 89 90 N= 114 111
  • 48.
    *p=0.04, indicates statisticalsignificance at 5% level. #Full analysis set. BL, baseline. Study 23118, Novartis Data on file, CSR Table 11-8. -0.21 0.15 -0.36 *-0.6 -0.5 -0.4 -0.3 -0.2 -0.1 0 0.1 0.2 0.3 0.4 Adjustedmean(SE)changeinHbA1c,% N = 115 107 BL = 7.8 7.8 Strictly Confidential. Proprietary information of Novartis. For internal use ONLY. Secondary endpoint: Change in HbA1c from baseline to rescue-censored 52 week endpoint# Vildagliptin Placebo Between-treatment difference
  • 49.
    Similar incidence ofSAEs, discontinuations due to AEs, or death for vildagliptin and comparators n (%) Vilda 50 mg bid N=6116 Total comparators N=6210 Any AE 4225 (69.1) 4228 (69.0) Drug-related AEs 961 (15.7) 1349 (21.7) SAEs 545 (8.9) 557 (9.0) Discontinuation of study drug due to AEs 347 (5.7) 400 (6.4) Deaths 24 (0.4) 23 (0.4) AEs=adverse events; bid=twice daily; PBO=placebo; SAEs= serious adverse events; vilda=vildagliptin. All-study safety (excluding open-label) population. Schweizer A. et al, Vasc Health Risk Manag 2011(accepted version)
  • 50.
    Renal safety ofVildagliptin- 1 year data Significant HbA1c reduction • 1 year safety study adding Vildagliptin 50mg od to background therapy in those with moderate or severe renal failure • Better HbA1c reduction of 0.6% and 0.8% with Vildagliptin in moderate and severe RI respectively Kothny et al. Diabetes Obesity Metabolism,2012
  • 51.
    No deterioration ofrenal function with vildagliptin Renal impairment Moderate Severe eGFR (MDRD) (mL/min/1.73 m2) Vilda 50mg qd N=163 Placebo N=129 Vilda 50mg qd N=124 Placebo N=97 Mean Baseline 39.3 40.3 21.9 20.9 Mean Change from baseline 0.865 0.572 -1.456 -1.121 Median Change from baseline -0.068 -0.067 -1.291 -1.872 Estimated *GFR (MDRD) in patients with severe and moderate RI at 24 wks * eGFR (MDRD)= GFR estimated using the MDRD formula. Baseline eGFR is defined as the lowest of eGFR (MDRD) values before visit 2 that were calculated using the serum creatinine value before visit 2 and the age at the associated creatinine measurement date • The overall incidences of AEs, SAEs, discontinuations due to AEs and deaths were comparable between vildagliptin 50 mg qd and placebo treatment groups • No statistically significant or clinically relevant differences for events of identified risk observed for vildagliptin MDRD = Modification of Diet in Renal DiseaseLukashevich et al. Diabetes Obesity Metabolism,2011
  • 52.
    Mechanistic basis ofVildagliptin in T2DM patients with renal impairment Yan –Ling He-Int J Clin Pharmacol Ther. 2013; 51:693–703  Only ~23% of vildagliptin is excreted unchanged by kidney (main excretion mode is hydrolysis to inactive metabolite) In Mild/Moderate/severe : similar and minimal increase in Cmax In moderate and severe RI: 1.7~2 fold increase in exposure of vildagliptin(AUC0-24hrs) Doubling of exposure (AUC) but no expected increased in concentration (Cmax) in Moderate/Severe RI Effectively with vildagliptin in RI there is, • Reduced dose frequency, dose strength unchanged, maintained 24-hour DPP4 blockage (50 mg once daily Vildagliptin in moderate/severe RI = 50 mg twice daily Vildagliptin in normal renal function) • A1c reductions with 50 mg OD similar to reduction with 50 mg BD with normal renal function • 50% reduced therapy cost In patients with moderate-severe RI with vildagliptin, How does Vildagliptin add value in terms of Renal safety to T2DM patients Reduce dose frequency by half
  • 53.
    65 Summary and TakeHome Messages • Tight glycaemic control should be targeted from the day of diagnosis • Intensive glycaemic control:  Reduces risk of micro-vascular complications  Some benefit in reducing cardiovascular events  No reductions in mortality  Clinical inertia a major issue in achieving tight targets  DPP-4 inhibitors are an important therapy option as reflected by current guidelines and clinical evidence • Vildagliptin is efficacious, weight neutral, with a low risk of hypoglycaemia as monotherapy, and in combination with other anti-diabetic agents including metformin.
  • 54.
  • 55.
  • 56.
    Basic Succinct Statement- GALVUS® Presentation: Tablets containing 50 mg of Vildagliptin. Indications: ♦Galvus is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus (T2DM). It is indicated: as monotherapy, IN COMBINATION: with metformin, when diet, exercise and metformin alone do not result in adequate glycemic control. with a sulphonylurea (SU), when diet, exercise and a SU alone do not result in adequate glycemic control. with a thiazolidinedione (TZD), when diet, exercise and a TZD alone do not result in adequate glycemic control. IN TRIPLE COMBINATION: with a sulphonylurea and metformin when diet and exercise plus dual therapy with these agents do not provide adequate glycemic control. ♦Galvus is also indicated in combination with insulin (with or without metformin) when diet, exercise and a stable dose of insulin do not result in adequate glycemic control. ♦Galvus is also indicated as initial combination therapy with metformin in patients with T2DM whose diabetes is not adequately controlled by diet and exercise alone. Dosage and administration: ♦Adults: The recommended dose is 50 mg or 100 mg daily for monotherapy, and for combination with metformin, with a TZD or with insulin (with or without metformin); 50 mg daily in combination with a SU; 100 mg daily for triple combination with metformin and a SU. Maximum dose is 100 mg/day (in two divided doses of 50 mg).♦Children (under 18 years of age): Not recommended. ♦Special population: In patients with moderate to severe renal impairment or End Stage Renal Disease (ESRD), the recommended dose is 50 mg once daily. Contraindications: Hypersensitivity to vildagliptin or to any of the excipients. Warnings and precautions: ♦Galvus should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. ♦Not recommended in patients with hepatic impairment including patients with a pre-treatment ALT or AST>2.5X the upper limit of normal. Liver function tests (LFT) to be performed prior to treatment initiation, at three-month intervals during the first year and periodically thereafter. Withdrawal of therapy with Galvus recommended if an increase in AST or ALT of 3X upper limit normal or greater persist. Following withdrawal of treatment with Galvus and LFT normalisation, treatment with Galvus should not be reinitiated. ♦Clinical experience in patients with NYHA functional class III treated with vildagliptin is still limited and results are inconclusive. ♦Not recommended in patients with NYHA Class IV. Women of child-bearing potential, pregnancy: Should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. Breast-feeding: Should not be used. Special excipients: Contains lactose Adverse reactions: Rare cases of angioedema. Rare cases of hepatic dysfunction (including hepatitis) ♦Monotherapy - Common: dizziness - Uncommon: headache, constipation, oedema peripheral. ♦Combination with metformin - Common: tremor, dizziness, headache. ♦Combination with a sulphonylurea - Common: tremor, headache, dizziness, asthenia. ♦Combination with a thiazolidinedione - Common: weight increase, oedema peripheral. ♦Combination with insulin - Common: headache, nausea, gastrooesophageal reflux disease, chills, decreased blood glucose – Uncommon: Diarrhoea, flatulence. ♦Combination with metformin and a sulphonylurea - Common: dizziness, tremor, asthesia, hypoglycaemia, hyperhidrosis. ♦Post-marketing experience - Rare: hepatitis (reversible with drug discontinuation) – Unknown: urticaria, pancreatitis, localized exfoliation or blisters. Interactions: ♦Vildagliptin has a low potential for drug interactions. ♦No clinically relevant interactions with other oral antidiabetics (glibenclamide, pioglitazone, metformin), amlodipine, digoxin, ramipril, simvastatin, valsartan or warfarin were observed after co-administration with vildagliptin. Packs: Box of 2 strips of 14 tablets each Note: Before prescribing, please consult full prescribing information available from Novartis Healthcare Private limited, Sandoz House, Dr. Annie Besant Road, Worli, Mumbai- 400 018, Tel: 022 2495 8888 For the use only of a registered medical practitioner or a hospital or a laboratory. India BSS dtd 27 Jan 2014 based on international BSS dtd 18 Dec 2013
  • 57.
    Basic Succinct Statement– GalvusMet® Presentation: Tablets containing Vildagliptin/Metformin hydrochloride fixed dose combination: 50 mg/500 mg, 50 mg/850 mg, 50 mg/1,000mg. Indications: ♦Galvus Met is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus (T2DM) whose diabetes is not adequately controlled on metformin hydrochloride or vildagliptin alone or who are already treated with the combination of vildagliptin and metformin hydrochloride, as separate tablets. ♦Galvus Met is indicated in combination with a sulphonylurea (i.e., triple combination therapy) as an adjunct to diet and exercise in patients inadequately controlled with metformin and a sulphonylurea. ♦Galvus Met is indicated in combination with insulin (i.e., triple combination therapy) as an adjunct to diet and exercise to improve glycemic control in patients when stable dose of insulin and metformin alone do not provide adequate glycemic control. ♦ Galvus Met is also indicated for the treatment of Type 2 Diabetes mellitus having HbA1c > 8% where diabetes is not adequately controlled by diet and exercise alone. Dosage and administration: ♦Do not exceed the maximum recommended daily dose of vildagliptin (100 mg). ♦Should be given with meals. ♦Adults: Starting dose for patients inadequately controlled on vildagliptin or metformin hydrochloride monotherapy: 50 mg/500mg twice daily and gradually titrated after assessing adequacy of therapeutic response. ♦Starting dose for patients switching from combination therapy of vildagliptin plus metformin hydrochloride as separate tablets: 50 mg/500 mg, 50 mg/850 mg or 50 mg/1,000 mg based on the dose of vildagliptin or metformin already being taken. ♦Starting dose for treatment naïve patients: may be initiated at 50 mg/500 mg qd and gradually titrated to a maximum dose of 50 mg/1,000 mg bid after assessing adequacy of therapeutic response. ♦Use in combination with a sulphonylurea or with insulin: the dose of Galvus Met should provide vildagliptin dosed as 50 mg twice daily (100 mg total daily dose) and a dose of metformin similar to the dose already being taken. ♦Children (under 18 years of age): Not recommended. Contraindications: Known hypersensitivity to vildagliptin or metformin hydrochloride or to any of the excipients ♦renal disease or renal dysfunction ♦congestive heart failure ♦acute or chronic metabolic acidosis including diabetic ketacidosis with or without coma ♦should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials. Warnings and precautions: ♦Risk of lactic acidosis. ♦Monitoring of renal function. ♦Caution with concomitant use of medications that may affect renal function or metformin hydrochloride disposition. ♦Should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials. ♦Discontinue treatment in case of hypoxemia. ♦Temporary discontinuation in patients undergoing surgical procedure. ♦Excessive alcohol intake to be avoided. ♦Not recommended in patients with hepatic impairment including patients with a pre-treatment ALT or AST >2.5X the upper limit of normal. Liver function tests (LFT) to be performed prior to treatment initiation, at three-month intervals during the first year and periodically thereafter. Withdrawal of therapy with Galvus Met recommended if an increase in AST or ALT of 3X upper limit normal or greater persist. Following withdrawal of treatment with Galvus Met and LFT normalisation, treatment with Galvus Met should not be reinitiated. ♦Risk of decreased vitamin B12 serum levels. ♦Should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. ♦Risk of hypoglycemia. ♦May be temporarily withheld in case of loss of glycemic control. ♦Should only be used in elderly patients with normal renal function. ♦Not recommended in pediatric patients.
  • 58.
    Women of child-bearingpotential, pregnancy: Should not be used in pregnancy unless the potential benefit justifies the potential risk to the foetus. Breast-feeding: Should not be used during breast-feeding. Adverse reactions: ♦Vildagliptin: Rare cases of angioedema. Rare cases of hepatic dysfunction (including hepatitis). ♦Vildagliptin monotherapy - Common: dizziness – Uncommon: headache, constipation, oedema peripheral. ♦Metformin monotherapy – Very common: loss of appetite, nausea, vomiting, diarrhoea, abdominal pain. Common: dysgeusia. Very rare: lactic acidosis, hepatitis, skin reactions such as erythema, pruritus and urticarial, decrease of vitamin B12 absorption, liver function test abnormalities. ♦Other effects with combination of Vildagliptin and Metformin - Common: tremor, dizziness, headache. ♦Other effects with combination of Vildagliptin and Metformin with insulin – Common: headache, nausea, gastrooesophageal reflux disease, chills, blood glucose decreased– Uncommon: diarrhoea, flatulence. ♦Other effects with combination of Vildagliptin and Metformin with a sulphonylurea – Common: dizziness, tremor, asthenia, hypoglycemia, hyperhidrosis. ♦Post-marketing experience: - Rare: hepatitis (reversible with drug discontinuation) - Unknown: urticaria, pancreatitis, localized exfoliation or blisters. Interactions: ♦Interactions with Vildagliptin: low potential for drug interactions, no clinically relevant interactions with other oral antidiabetics (glibenclamide, pioglitazone, metformin), amlodipine, digoxin, ramipril, simvastatin, valsartan or warfarin were observed after co-administration with vildagliptin. ♦Interactions with metformin hydrochloride: furosemide, nifedipine, cationic drugs, drugs tending to produce hyperglycemia, alcohol. Packs: Box containing 6 strips of 10 tablets each Note: Before prescribing, consult full prescribing information available from Novartis Healthcare Private Limited, Sandoz House, Dr. Annie Besant Road, Worli, Mumbai- 400 018, Tel: 022 2495 8888 For the use only of a registered medical practitioner or a hospital or a laboratory. India BSS dtd 31 Jan 2014 based on international BSS dtd 18 Dec 2013, effective from 1 Apr 14. 2/2 Basic Succinct Statement – GalvusMet®
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    Disclaimer The views, opinions,ideas etc expressed therein are solely those of the author. Novartis does not certify the accuracy, completeness, currency of any information and shall not be responsible or in anyway liable for any errors, omissions or inaccuracies in such information. Novartis is not liable to you in any manner whatsoever for any decision made or action or non- action taken by you in reliance upon the information provided. Novartis does not recommend the use of its products in unapproved indications and recommends to refer to complete prescribing information prior to using any of the Novartis products.” Issued in scientific service to medical professionals For full product information please write to : Novartis Healthcare Private Limited, Sandoz House, 7th floor, Shivsagar Estate, Dr. Annie Besant Road, Worli, Mumbai, 400 018, INDIA ScientificPresentation/Galvus/CVM/279309/Aug/2014 I For use of RMP, hospital or lab only