Clinical trial simulation methods for estimating the impact of DPP-4 inhibitors on cardiovascular disease

Abstract

Introduction

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of oral antidiabetic agents for the treatment of type 2 diabetes mellitus, which lower blood glucose without causing severe hypoglycemia. However, the first cardiovascular (CV) safety trials have only recently reported their results, and our understanding of these therapies remains incomplete. Using clinical trial simulations, we estimated the effectiveness of DPP-4 inhibitors in preventing major adverse cardiovascular events (MACE) in a population like that enrolled in the SAVOR-TIMI (the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus – Thrombolysis in Myocardial Infarction) 53 trial.

Methods

We used the Archimedes Model to simulate a clinical trial of individuals (N=11,000) with diagnosed type 2 diabetes and elevated CV risk, based on established disease or multiple risk factors. The DPP-4 class was modeled with a meta-analysis of HbA_1c and weight change, pooling results from published trials of alogliptin, linagliptin, saxagliptin, sitagliptin, and vildagliptin. The study treatments were added-on to standard care, and outcomes were tracked for 20 years.

Results

The DPP-4 class was associated with an HbA_1c drop of 0.66% (0.71%, 0.62%) and a weight drop of 0.14 (−0.07, 0.36) kg. These biomarker improvements produced a relative risk (RR) for MACE at 5 years of 0.977 (0.968, 0.986). The number needed to treat to prevent one occurrence of MACE at 5 years was 327 (233, 550) in the elevated CV risk population.

Conclusion

Consistent with recent trial publications, our analysis indicates that DPP-4 inhibitors do not increase the risk of MACE relative to the standard of care. This study provides insights about the long-term benefits of DPP-4 inhibitors and supports the interpretation of the published CV safety trial results.

Keywords:

• cardiovascular
• DPP-4 inhibitors
• simulation

Supplementary materials

Table S1 Characteristics of the studies included in the meta-analysis

Table S2 Baseline characteristics of the simulated cohort, based on the actual SAVOR-TIMI 53 cohort

Table S3 Sensitivity of the absolute MACE risk reduction associated with the DPP-4 inhibitor class, at 5 years, to different effect assumptions

References

• PratleyRENauckMBaileyTLiraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycaemic control with metformin: a 26-week, randomised, parallel-group, open-label trialLancet201037597241447145620417856
   PubMed Web of Science ®Google Scholar
• BergenstalRMWyshamCMacConellLEfficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trialLancet2010376973943143920580422
   PubMed Web of Science ®Google Scholar
• RisticSByiersSFoleyHolmesDImproved glycaemic control with dipeptidyl peptidase-4 inhibition in patients with type 2 diabetes: vildagliptin (LAF237) dose responseDiabetes Obes Metab20057669269816219012
   PubMed Web of Science ®Google Scholar
• Pi-SunyerFXSchweizerAMillsDDejagerSEfficacy and tolerability of vildagliptin monotherapy in drug-naıve patients with type 2 diabetesDiabetes Res Clin Pract200776113213817223217
   PubMed Web of Science ®Google Scholar
• SchweizerACouturierAFoleyJEDejagerSComparison between vildagliptin and metformin to sustain reductions in HbA1c over 1 year in drug-naïve patients with Type 2 diabetesDiabetic Med200724995596117509069
   PubMed Web of Science ®Google Scholar
• DejagerSRazacSFoleyJESchweizerAVildagliptin in drug-naïve patients with type 2 diabetes: a 24-Week, double-blind, randomized, placebo-controlled, multiple-dose studyHorm Metab Res200739321822317373638
   PubMed Web of Science ®Google Scholar
• Rosen stockJKimSWBaronMAEfficacy and tolerability of initial combination therapy with vildagliptin and pioglitazone compared with component monotherapy in patients with type 2 diabetesDiabetes Obes Metab20079217518517300593
   PubMed Web of Science ®Google Scholar
• GarberAJSchweizerABaronMARochotteEDejagerSVildagliptin in combination with pioglitazone improves glycaemic control in patients with type 2 diabetes failing thiazolidinedione monotherapy: a randomized, placebo-controlled studyDiabetes Obes Metab20079216617417300592
   PubMed Web of Science ®Google Scholar
• RosenstockJBaronMADejagerSMillsDSchweizerAComparison of vildagliptin and rosiglitazone monotherapy in patients with Type 2 diabetesDiabetes Care200730221722317259484
   PubMed Web of Science ®Google Scholar
• BosiECamisascaRPColloberCRochotteEGarberAJEffects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metforminDiabetes Care200730489089517277036
   PubMed Web of Science ®Google Scholar
• GarberAJFoleyJEBanerjiMAEffects of vildagliptin on glucose control in patients with type 2 diabetes inadequately controlled with a sulphonylureaDiabetes Obes Metab200810111047105618284434
   PubMed Web of Science ®Google Scholar
• BolliGDottaFRochotteECohenSEEfficacy and tolerability of vildagliptin vs. pioglitazone when added to metformin: a 24-week, randomized, double-blind studyDiabetes Obes Metab2008101829018034842
   PubMed Web of Science ®Google Scholar
• PanCYangWBaronaJPComparison of vildagliptin and acarbose monotherapy in patients with Type 2 diabetes: a 24-week, double-blind, randomized trialDiabetic Med200825443544118341596
   PubMed Web of Science ®Google Scholar
• FerranniniEFonsecaVZinmanBFifty-two-week efficacy and safety of vildagliptin vs. glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapyDiabetes Obes Metab200911215716619125777
   PubMed Web of Science ®Google Scholar
• GoodmanMThurstonHPenmanJEfficacy and tolerability of vildagliptin in patients with type 2 diabetes inadequately controlled with metformin monotherapyHorm Metab Res200941536837319221978
   PubMed Web of Science ®Google Scholar
• BosiEDottaFJiaYGoodmanMVildagliptin plus metformin combination therapy provides superior glycaemic control to individual monotherapy in treatment-naive patients with type 2 diabetes mellitusDiabetes Obes Metab200911550651519320662
   PubMed Web of Science ®Google Scholar
• SchweizerADejagerSBosiEComparison of vildagliptin and metformin monotherapy in elderly patients with type 2 diabetes: a 24-week, double-blind, randomized trialDiabetes Obes Metab200911880481219476473
   PubMed Web of Science ®Google Scholar
• FilozofCGautierJFA comparison of efficacy and safety of vildagliptin and gliclazide in combination with metformin in patients with Type 2 diabetes inadequately controlled with metformin alone: a 52-week, randomized studyDiabetic Med201027331832620536495
   PubMed Web of Science ®Google Scholar
• CharbonnelBKarasikALiuJWuMMeiningerGEfficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin aloneDiabetes Care200629122638264317130197
   PubMed Web of Science ®Google Scholar
• RazIHanefeldMXuLCariaCWilliams-HermanDKhatamiHEfficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitusDiabetologia200649112564257117001471
   PubMed Web of Science ®Google Scholar
• RosenstockJBrazgRAndryukPJLuKSteinPEfficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group studyClin Ther200628101556156817157112
   PubMed Web of Science ®Google Scholar
• AschnerPKipnesMSLuncefordJKSanchezMMickelCWilliams-HermanDEEffect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetesDiabetes Care200629122632263717130196
   PubMed Web of Science ®Google Scholar
• HermansenKKipnesMLuoEFanurikDKhatamiHSteinPEfficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metforminDiabetes Obes Metab20079573374517593236
   PubMed Web of Science ®Google Scholar
• GoldsteinBJFeinglosMNLuncefordJKJohnsonJWilliams-HermanDEEffect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetesDiabetes Care20073081979198717485570
   PubMed Web of Science ®Google Scholar
• HanefeldMHermanGAWuMMickelCSanchezMSteinPPOnce-daily sitagliptin, a dipeptidyl peptidase-4 inhibitor, for the treatment of patients with type 2 diabetesCurr Med Res Opin20072361329133917559733
   PubMed Web of Science ®Google Scholar
• NauckMAMeiningerGShengDTerranellaLSteinPPEfficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trialDiabetes Obes Metab20079219420517300595
   PubMed Web of Science ®Google Scholar
• ScottRWuMSanchezMSteinPEfficacy and tolerability of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy over 12 weeks in patients with type 2 diabetesInt J Clin Pract200761117118017156104
   PubMed Web of Science ®Google Scholar
• ScottRLoeysTDaviesMJEngelSSEfficacy and safety of sitagliptin when added to ongoing metformin therapy in patients with type 2 diabetesDiabetes Obes Metab2008101095996918201203
   PubMed Web of Science ®Google Scholar
• RazIChenYWuMEfficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetesCurr Med Res Opin200824253755018194595
   PubMed Web of Science ®Google Scholar
• NonakaKKakikawaTSatoAEfficacy and safety of sitagliptin monotherapy in Japanese patients with type 2 diabetesDiabetes Res Clin Pract200879229129817933414
   PubMed Web of Science ®Google Scholar
• MohanVYangWSonHYEfficacy and safety of sitagliptin in the treatment of patients with type 2 diabetes in China, India, and KoreaDiabetes Res Clin Pract200983110611619097665
   PubMed Web of Science ®Google Scholar
• DerosaGMaffioliPSalvadeoSAEffects of sitagliptin or metformin added to pioglitazone monotherapy in poorly controlled type 2 diabetes mellitus patientsMetabolism201059688789520015525
   PubMed Web of Science ®Google Scholar
• RigbySPHandelsmanYLaiYLAbbySLTaoBJonesMREffects of colesevelam, rosiglitazone, or sitagliptin on glycemic control and lipid profile in patients with type 2 diabetes mellitus inadequately controlled by metformin monotherapyEndocr Pract2010161536319789153
   PubMed Web of Science ®Google Scholar
• SeckTNauckMShengDSitagliptin Study 024 Group. Safety and efficacy of treatment with sitagliptin or glipizide in patients with type 2 diabetes inadequately controlled on metformin: a 2-year studyInt J Clin Pract201064556257620456211
   PubMed Web of Science ®Google Scholar
• AschnerPKatzeffHLGuoHSitagliptin Study 049 Group. Efficacy and safety of monotherapy of sitagliptin compared with metformin in patients with type 2 diabetesDiabetes Obes Metab201012325226120070351
   PubMed Web of Science ®Google Scholar
• ArechavaletaRSeckTChenYEfficacy and safety of treatment with sitagliptin or glimepiride in patients with type 2 diabetes inadequately controlled on metformin monotherapy: a randomized, double-blind, non-inferiority trialDiabetes Obes Metab201113216016821199268
   PubMed Web of Science ®Google Scholar
• ScheenAJCharpentierGOstgrenCJHellqvistAGause-NilssonIEfficacy and safety of saxagliptin in combination with metformin compared with sitagliptin in combination with metformin in adult patients with type 2 diabetes mellitusDiabetes Metab Res Rev201026754054920824678
   PubMed Web of Science ®Google Scholar
• RosenstockJSankohSListJFGlucose-lowering activity of the dipeptidyl peptidase-4 inhibitor saxagliptin in drug-naive patients with type 2 diabetesDiabetes Obes Metab200810537638618355324
   PubMed Web of Science ®Google Scholar
• DeFronzoRAHissaMNGarberAJThe efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin aloneDiabetes Care20093291649165519478198
   PubMed Web of Science ®Google Scholar
• HollanderPLiJAllenEChenRSaxagliptin added to a thiazolidinedione improves glycemic control in patients with type 2 diabetes and inadequate control on thiazolidinedione aloneJ Clin Endocrinol Metab200994124810481919864452
   PubMed Web of Science ®Google Scholar
• RosenstockJAguilar-SalinasCKleinENepalSListJChenREffect of saxagliptin monotherapy in treatment-naïve patients with type 2 diabetesCurr Med Res Opin200925102401241119650754
   PubMed Web of Science ®Google Scholar
• ChacraARTanGHApanovitchARavichandranSListJChenRSaxagliptin added to a submaximal dose of sulphonilurea improves glucaemic control compared with uptritation of sulphonylurea in patients with type 2 diabetes: a randomized controlled trialIntern J Clin Pract200963913951406
   PubMed Web of Science ®Google Scholar
• GökeBGallwitzBErikssonJHellqvistAGause-NilssonISaxagliptin is non-inferior to glipizide in patients with type 2 diabetes mellitus inadequately controlled on metformin alone: a 52-week randomised controlled trialInt J Clin Pract201064121619163120846286
   PubMed Web of Science ®Google Scholar
• DeFronzoRAFleckPRWilsonCAMekkiQEfficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes and inadequate glycemic control: a randomized, double-blind, placebo-controlled studyDiabetes Care200831122315231718809631
   PubMed Web of Science ®Google Scholar
• NauckMAEllisGCFleckPRWilsonCAMekkiQEfficacy and safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a multicentre, randomised, double-blind, placebo-controlled studyInt J Clin Pract2009631465519125992
   PubMed Web of Science ®Google Scholar
• PratleyREKipnesMSFleckPRWilsonCMekkiQEfficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes inadequately controlled by glyburide monotherapyDiabetes Obes Metab200911216717619125778
   PubMed Web of Science ®Google Scholar
• PratleyREReuschJEFleckPRWilsonCAMekkiQEfficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin added to pioglitazone in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled studyCurr Med Res Opin200925102361237119650752
   PubMed Web of Science ®Google Scholar
• RosenstockJInzucchiSESeufertJFleckPRWilsonGAMekkiQInitial combination therapy with alogliptin and pioglitazone in drug-naïve patients with type 2 diabetesDiabetes Care201033112406240820724648
   PubMed Web of Science ®Google Scholar
• Del PratoSBarnettAHHuismanHNeubacherDWoerleHJDugiKAEffect of linagliptin monotherapy on glycaemic control and markers of β-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trialDiabetes Obes Metab201113325826721205122
   PubMed Web of Science ®Google Scholar
• TaskinenMRRosenstockJTamminenIKubiakRPatelSDugiKAWoerleHJSafety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled studyDiabetes Obes Metab2011131657421114605
   PubMed Web of Science ®Google Scholar
• ForstTUhlig-LaskeBRingAGraefe-ModyUFriedrichCHerbachKWoerleHJDugiKALinagliptin (BI 1356), a potent and selective DPP-4 inhibitor, is safe and efficacious in combination with metformin in patients with inadequately controlled Type 2 diabetesDiabetic Medicine201027121409141921059094
   PubMed Web of Science ®Google Scholar

Acknowledgments

The authors thank Tina Yeung and Swathi Guda for their assistance with the research work. We presented the work as a poster at the 16th ISPOR Annual European Congress in Dublin, in 2013.

Disclosure

This research was sponsored by Novartis Pharma AG and conducted by Archimedes, Inc. as consultants for Novartis. Charles Andy Schuetz was an employee of Archimedes, Inc., at that time. Siew Hwa Ong is an employee of Novartis Pharma AG. Matthias Blüher has received honoraria as a speaker from AstraZeneca, Bayer, Boehringer-Ingelheim, Lilly, Novartis, Novo Nordisk, Sanofi, MSD, and Pfizer, and also as part of an advisory board for AstraZeneca, Boehringer-Ingelheim, Lilly, Novartis, Novo Nordisk, Sanofi.