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Cv safety of gliptins

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Cv safety of gliptins

  1. 1. 1Viewing Gliptins – CardiologistProspectiveDr. Neeraj BhallaSenior Consultant and DirectorDeptt of Cardiology BLK Super Speciality Hospital
  2. 2. • Diabetes is a constellation of metabolicabnormalities• As there is no unifying causative mechanism ; there is no uniquetreatment for it. Treatment includes managing its components3
  3. 3. Gelfand EV et al, 2006; Vasudevan AR et al, 2005Global cardiometabolic risk (CMR)4
  4. 4. 5Impact of Hypoglycemia & weight gain in T2DM– Cardiovascular perspective
  5. 5. Hypoglycaemia& Weight gainHbA1cThe challenge of tight glucose control6
  6. 6. Hypoglycemia as a cause for cardiovascular events -Mechanisms8Desouza CV, et al.Diabetes Care. 2010;33:1389–394
  7. 7. Metabolic Syndrome facts…• The relative risk of developing diabetes , hypertensionand CVD increases with an increase in body weight1 kg weight gainCVD risk by 3.1 %Diabetes risk by 4.5-9 %Ref : Curr. Med. Chem. – Imm., Endoc. & Metab. Agents, 2001, Vol. 1, No. 1 ; IDF Defination• 78% of patients with metabolic syndrome have insulin resistance, & 48%of people with insulin resistance have metabolic syndrome.• People with metabolic syndrome are twice as likely to die from & thrice aslikely to have stroke or heart attack then people without it9
  8. 8. 10The Unmet need with current therapy for T2DM
  9. 9. Most Insulin secretagogues , including glimepiride, associated with increasedmortality & cardiovascular risk compared with metformin11Monotherapy with the most used Insulin secretagogues (ISs), including glimepiride, glibenclamide,glipizide, and tolbutamide, seems to be associated with increased mortality and cardiovascular riskcompared with metformin. Gliclazide and repaglinide appear to be associated with a lower riskthan other ISsN = 107 806 subjectsfollowed for up to 9 years(median 3.3 years)TK Schramm etal, European Heart Journal Advance Access published April 6, 2011HazardRatio(%)
  10. 10. Hypoglycemia is Common with SUs*Hypoglycemia: fingerstick blood glucose measurement 50 mg/dL (2.75 mmol/L)1. Glucovance [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2004. 2. UKPDS Group. Lancet1998; 352: 837–853. 3. Draeger KE, et al. Horm Metab Res. 1996; 28: 419–425. 4. McGavin JK, et al. Drugs 2002;62; 1357–1364. 5. Metaglip [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2002SulfonylureasGlipizide5Gliclazide4Chlorpropamide2Glyburide10510152025IncidenceofHypoglycemia(%)21.3%15.3%5%2.9%*14%11%Glibenclamide3 Glimepiride3
  11. 11. Weight Gain is a Common Side Effect of Diabetes TreatmentsTZDs4–6Metformin + TZD5,6,9Metformin + SU1–3Meglitinides4,7,8SUs1–4Metformin1–3Weight Change (kg)OAD AgentsOAD=oral antidiabetic agent; SU=sulfonylurea; TZD=thiazolidinedione.1Glucophage [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company, 2004. 2Glucovance [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company, 2004.3Metaglip [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company, 2002. 4Malone M. Ann Pharmacother. 2005; 39: 2046–2055. 5Actos [package insert].Indianapolis, Ind: Eli Lilly and Company, 2004. 6Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline, 2005. 7Starlix [package insert]. East Hanover, NJ:Novartis Pharmaceuticals Corporation; 2004. 8Prandin [package insert]. Princeton, NJ: Novo Nordisk, Inc, 2004. 9Avandamet [package insert]. Research Triangle Park, NC:GlaxoSmithKline, 2005.−5 −4 −3 −2 −1 0 1 2 3 4 5-3.8–0.5-0.4–1.70.9–4.60.3–3.0-0.3–1.90.8–2.1
  12. 12. Edema is Common with TZDs (Pioglitazone)TZDs=thiazolidinediones.1Actos [prescribing information]. Indianapolis, IN: Eli Lilly and Company, 2004.4.87.26.015.31.22.1 2.57.0024681012141618Monotherapy Combinationwith SUCombinationwithmetforminCombinationwith insulinProportionofPatients(%)Pioglitazone1Placebo or combination
  13. 13. Use of TZDs is Associated with Increased Incidence of Congestive Heart FailureNumberofCHFEventsP=0.01CHF=congestive heart failure; TZDs=thiazolidinediones.Adapted from DREAM Trial Investigators, et al. Lancet. 2006; 368: 1096–1105.HF=heart failureAdapted from Dormandy JA, et al. Lancet. 2005; 366: 1279–1289.P <0.000114205101520118051015RosiglitazonePlaceboPatientswithHF(%)PlaceboPioglitazone ≤45 mg dailyDREAM StudyPROactive Study
  14. 14. Risk of Myocardial Infarction and Death from Cardiovascular Causes withRosiglitazoneCI=confidence interval; CV=cardiovascular.Adapted from Nissen SE, Wolski K. N Engl J Med. 2007; 356: 2457–2471.Myocardial infarctionSmall trials combinedDREAMADOPTOverallDeath from CV causesSmall trials combinedDREAMADOPTOverall2.0 4.01.0Log Odds Ratio (95% CI)0.51.43 (1.03–1.98) P=0.031.45; P=0.151.65; P=0.221.33; P=0.272.40; P=0.021.20; P=0.670.80; P=0.781.64 (0.98–2.74) P=0.06
  15. 15. 17Cardiovascular effects of gliptins
  16. 16. Vildagliptin: less hypoglycaemia & Weight gainthan sulfonylureaHypoglycaemia0600500400300200100Ferrannini E, et al. Diabetes Obes Metab 2009; 11: 157–166Body weight889190Weight(kg)89-8 2 12 22 32 42 52Weeks39554No.hypoglycaemiceventsSafety populationGlimepiride + metformin (n=1383)Vildagliptin + metformin (n=1389)
  17. 17. Beneficial effect on Blood pressure and LipidsBL=baseline; HDL-C=high-density lipoprotein cholesterol; LDL-C=low-density lipoprotein cholesterol; BL=baseline; DBP=diastolic blood pressure; met=metformin;PBO=placebo; SBP=systolic blood pressure met=metformin; PBO=placebo; TC=total cholesterol; TG=triglycerides; vilda=vildagliptin.Primary intention-to-treat population; n refers to the patient number in the TG test. *P=0.014 vs PBO; all other values did not reach statistical significance. Bosi E, et al.Diabetes Care. 2007; 30; 890–895.
  18. 18. Cardiovascular effects of gliptinsPotentially antiatherogenic and might reduce cardiovascular complicationsAndré J. Scheen. Nat. Rev. Cardiol, January 201320
  19. 19. DPP4 inhibitors & Cardiac safetyAn overall favorable effect of DPP4i on cardiac safety23Monami etal, Current MedicalResearch & Opinion Volume 27,Number S3 2011Overall ODDS RATIO = 0.689
  20. 20. The FDA position on CV outcome studies• Sponsors should compare the incidence of important cardiovascular events occurring with the investigationalagent to incidence of same types of events occurring with control group to show that upper bound of the 2-sided95 percent confidence interval for estimated risk ratio is > 1.8.• This can be accomplished in several ways.• The integrated analysis (meta-analysis) of the phase 2 & phase 3 clinical trials can be used.• If the data from all the studies that are part of meta-analysis will not by itself be able to show that the upper bound ofthe two-sided 95 percent confidence interval for the estimated risk ratio is less than 1.8, then an additional single, largesafety trial should be conducted that alone, or added to other trials, would be able to satisfy this upper bound beforeNDA/BLA submission.24(Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf)If the premarketing application contains clinicaldata that show that the upper bound of the two-sided 95 percent confidence interval for theestimated increased risk (i.e., risk ratio) is less than1.3 and the overall risk-benefit analysis supportsapproval, a postmarketing cardiovascular trialgenerally may not be necessary
  21. 21. bid=twice daily; CI=confidence interval; CV=cardiovascular; M-H RR=Mantel-Haenszel risk ratio; qd=once daily; vilda=vildagliptin.*Vs all comparators=placebo, metformin, gliclazide, acarbose, rosiglitazone, pioglitazone and glimepiride. All-study safety population.#Guidance for Industry: Diabetes Mellitus - Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes, US Departmentof Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER), December 2008.Schweizer A, et al. Diabetes Obes Metab. 2010; 12: 485–494.Vildagliptin Reference M-H RRn / N (%) n / N (%) (95% CI)Vilda 50 mg qd* 10 / 1393 (0.72) 14 / 1555 (0.90) 0.88 (0.37–2.11)Vilda 50 mg bid* 81 / 6116 (1.32) 80 / 4872 (1.64) 0.84 (0.62–1.14)Risk ratioIncidences and odds ratios for adjudicated CVevents by treatmentVildagliptin better Vildagliptin worse0.1 1 10#Meta-analysis of vildagliptin 50 mg bid data vs all comparators according to the methodology setby the US Food and Drug Administration [50 mg bid odds ratio = 0.84 (95% CI 0.62–1.14)]Pooled Meta-analysis of 25 Phase III studies of vildagliptin shows no increasedcardiovascular risk vs comparators
  22. 22. Cardiac Safety data of gliptins1 = Schweizer A, et al. Diabetes Obes Metab. 2010; 12: 485–494. 2 = http://clinicaltrials.gov/ct2/show/NCT00894868?term=vildagliptin+%2B+heart+failure&rank=1 NCT00894868 Effect ofVildagliptin on Left Ventricular Function in Patients With Type 2 Diabetes and Congestive Heart Failure – Recruiting patients 3 = VERIFY:A Study to Compare Combination Regimen WithVildagliptin & Metformin Versus Metformin in Treatment-naïve Patients With Type 2 Diabetes Mellitus NCT015282544 = Scheen A, Expert Opin. Pharmacother. (2012) 13(1):81-99 * Based on routine search on www.clinicaltrial.gov
  23. 23. CONCLUSIONGliptins are cardiac safe unlike other OHAs-may be cardio protective
  24. 24. Thank You from Cardiology Team BLK

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