Hypoglycaemia and weight gain may adversely impact HbA1c control
Agents capable of triggering hypoglycemic episodes can also promote weight gain, especially as part of an intensified regimen aimed at achieving normal or near-normal glycemic levels. The weight gain may be related in part to an increase in “defensive eating” to prevent a decline from normoglycemia to hypoglycemia.Foley J, et al. Weight neutrality with the DPP-4 inhibitor, vildagliptin: Mechanistic basis and clinical experience. Vascular Health and Risk Management. 2010;6:541–548.
Hypoglycemic events may trigger inflammation by inducing the release of C-reactive protein (CRP), IL-6, and vascular endothelial growth factor (VEGF). Hypoglycemia also induces increased platelet and neutrophil activation. The sympathoadrenal response during hypoglycemia increases adrenaline secretion and may induce arrhythmias and increase cardiac workload. Underlying endothelial dysfunction 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.
Methods - All Danish residents >20 years, initiating single-agent ISs or metformin between 1997 and 2006 were followed for up to 9 years (median 3.3 years) by individual-level linkage of nationwide registers. All-cause mortality, cardiovascular mortality, and the composite of myocardial infarction (MI), stroke, and cardiovascular mortality associated with individual ISs were investigated in patients with or without previous MI by multivariable Cox proportional-hazard analyses including propensity analyses. A total of 107 806 subjects were included, of whom 9607 had previous MI.Compared with metformin, glimepiride (hazard ratios and 95% confidence intervals): 1.32 (1.24–1.40), glibenclamide: 1.19 (1.11–1.28), glipizide: 1.27 (1.17–1.38), and tolbutamide: 1.28 (1.17–1.39) were associated with increased all cause mortality in patients without previous MI. The corresponding results for patients with previous MI were as follows: glimepiride: 1.30 (1.11–1.44), glibenclamide: 1.47 (1.22–1.76), glipizide: 1.53 (1.23–1.89), and tolbutamide: 1.47 (1.17–1.84). Results for gliclazide [1.05 (0.94–1.16) and 0.90 (0.68–1.20)] and repaglinide and [0.97 (0.81–1.15) and 1.29 (0.86–1.94)] were not statistically different from metformin in both patients without and with previous MI, respectively. Results were similar for cardiovascular mortality and for the composite endpoint Conclusions - Monotherapy with the most used ISs, including glimepiride, glibenclamide, glipizide, and tolbutamide, seems to be associated with increased mortality and cardiovascular risk compared with metformin. Gliclazide and repaglinide appear to be associated with a lower risk than other ISs.
Vildagliptin Add-on to Metformin: Effect on Blood Pressure in HypertensivePatients (SBP ≥140 mmHg and DBP ≥90 mmHg)This 24-week, double-blind, randomized, multicenter, placebo-controlled study compared the effects of treatment with vildagliptin 50 mg once daily (n=143), vildagliptin 50 mg twice daily (n=143), or placebo (n=130) in patients with type 2 diabetes mellitus (T2DM) continuing a stable metformin dose regimen (mean dose 2.1 g daily) but achieving inadequate glycemic control (HbA1c 7.5–11%).1,2As hypertension is an important cardiovascular risk factor in diabetic patients, the effect of vildagliptin 50 mg twice daily on blood pressure was evaluated in a subset of patients with hypertension (systolic blood pressure [SBP] ≥140 mmHg and diastolic blood pressure [DBP] ≥90 mmHg).2Compared with placebo, vildagliptin 50 mg twice daily resulted in larger decreases in DBP (−4.0 vs −0.9) and SBP (−9.8 vs −6.3).1,2The effect seen on blood pressure needs further investigation but these reductions suggest a favorable effect of vildagliptin on blood pressure in hypertensive patients with T2DM.ReferencesBosi E, et al. Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Care 2007; 30: 890-895.Bosi E, et al. Presented at ADA Annual Meeting, June 22-26, 2007; Chicago, IL, 2165-PO.Vildagliptin Add-on to Metformin: Neutral Effect on Fasting LipidsThis 24-week, double-blind, randomized, multicenter, placebo-controlled study compared the effects of treatment with vildagliptin 50 mg once daily (n=143), vildagliptin 50 mg twice daily (n=143), or placebo (n=130) in patients with type 2 diabetes mellitus (T2DM) continuing a stable metformin dose regimen (mean dose 2.1 g daily) but achieving inadequate glycemic control (HbA1c 7.5–11%).1Change in lipid levels at 24 weeks was a secondary end point. Total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels did not change significantly over the 24-week treatment period in all treatment groups.1,2In patients receiving placebo while maintaining metforminmonotherapy, fasting triglyceride (TG) increased by 19% whereas in patients receiving vildagliptin50 mg once daily, fasting TG increased by 1% (P=0.014 vs placebo). In patients receiving vildagliptin 50 mg twice daily, fasting TG increased by 5% (P=0.052 vs placebo).Thus, vildagliptin has a neutral effect on the fasting lipid profile when added to metforminmonotherapy in patients with T2DM.ReferencesBosi E, et al. Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Care 2007; 30; 890-895.
The biggest point to consider here is that Prospective data “will evaluate efficacy/safety” however retrospective data with vildagliptin “has already proved efficacy/safety”Schweizer etal Diabetes Obes Metab. 2010 is a metaanalysis on >7500 ptsVilda pooled data is an ongoing process.. Pharmocovigilance is onging processLina, Sita & Saxa are doing prospective studies as a part of USFDA commitment.. Also worth commenting is that the study is just a non-inferiority study vs comparators and not a planned superiority study .Also USFDA states that any compound with OR < 1.3 does not need a outcome study.... We all know our OR is 0.84 which is less than 1.3. We do not need a prospective study as we already have a pooled analysis confirming an OR of 0.84Relative risk is the ratio of the chance of a disease developing among members of a population exposed to a factor compared with a similar population not exposed to the factor
No increase in cardiovascular risk—consistently adjudicated* CV events showing no increased risk relative to comparators† in more than 7500 patients‡2 [Schweitzer et al. 2010/pg 487/Col 1/Para 3/B; Fig. 1/A]No risk of weight gain—GALVUS is weight-neutral3 and weight gain itself is an independent risk factor for cardiovascular events4 [Bolli_Diabetes_Obes Metab. 2008/p86/col 1/para3] [Anderson 2001/pg 329S/col 2/para 2/A]
Cv safety of gliptins
1Viewing Gliptins – CardiologistProspectiveDr. Neeraj BhallaSenior Consultant and DirectorDeptt of Cardiology BLK Super Speciality Hospital
• Diabetes is a constellation of metabolicabnormalities• As there is no unifying causative mechanism ; there is no uniquetreatment for it. Treatment includes managing its components3
Gelfand EV et al, 2006; Vasudevan AR et al, 2005Global cardiometabolic risk (CMR)4
5Impact of Hypoglycemia & weight gain in T2DM– Cardiovascular perspective
Hypoglycaemia& Weight gainHbA1cThe challenge of tight glucose control6
Hypoglycemia as a cause for cardiovascular events -Mechanisms8Desouza CV, et al.Diabetes Care. 2010;33:1389–394
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
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(%)
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
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
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
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
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.
Cardiovascular effects of gliptinsPotentially antiatherogenic and might reduce cardiovascular complicationsAndré J. Scheen. Nat. Rev. Cardiol, January 201320
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
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
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
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
CONCLUSIONGliptins are cardiac safe unlike other OHAs-may be cardio protective