Advertisement

Satisfying the Regulatory Requirements for New Antidiabetic Drugs for Type 2 Diabetes Most Expeditiously

  • J. Rick Turner
  • Dilip R. Karnad
  • Snehal Kothari
Chapter

Abstract

The regulatory landscapes for the prospective exclusion of unacceptable cardiovascular risk associated with new antidiabetic drugs for type 2 diabetes in the USA and Europe were formalized in 2008 and 2012, respectively. The FDA’s Guidance for Industry specifically addressing this landscape was issued in final format (a rare occurrence) in December 2008 (FDA 2008). The EMA’s updated general guidance document addresses this topic. Following the release of a first draft in 2010 and a revised draft in 2011 (a period for public comment followed each release), the document was finalized in May 2012 and became effective in November 2012 (EMA 2012). The first section of this chapter presents the key aspects of each document.

Keywords

Interim Analysis Statistical Analysis Plan Cardiovascular Safety Antidiabetic Therapy Group Sequential Design 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. CANVAS. CANagliflozin cardioVascular Assessment Study (2015). Available at http://clinicaltrials.gov/ct2/show/NCT01032629?term=CANVAS&rank=1. Accessed 31 Aug 2015
  2. Cox DR (1972) Regression models and life tables (with discussion). J R Stat Soc Ser B 34:187–220Google Scholar
  3. EMA (2012) Guideline on the clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus. Effective November 2012. Available at. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129256.pdf Accessed 2 Jan 2016
  4. FDA (CDER). Summary review(s) for canagliflozin. Application number: 204042Orig1s000. Available at http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000SumR.pdf. Accessed 31 Aug 2015
  5. FDA (CDER). Summary review for Linagliptin. Application number: 201280Orig1s000. Available at http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000SumR.pdf. Accessed 31 Aug 2015
  6. FDA (2008) Guidance for industry. Diabetes Mellitus—evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. December 2008. Available at. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf. Accessed 2 Jan 2016
  7. FDA (2010) Guidance for industry. Adaptive design clinical trials for drugs and biologics. February 2010 (Draft). Available at. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm201790.pdf. Accessed 31 August 2015
  8. FDA. Statistics review(s) for Empagliflozin marketing application. Available at http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204629Orig1s000StatR.pdf. Accessed 12 Dec 2015
  9. Geiger MJ, Mehta C, Turner JR et al (2015) Clinical development approaches and statistical methodologies to prospectively assess the cardiovascular risk of new antidiabetic therapies for type 2 diabetes. Ther Innov Regul Sci 49:50–64CrossRefGoogle Scholar
  10. Green JB, Bethel MA, Armstrong PW, TECOS Study Group et al (2015) Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 373:232–242PubMedCrossRefGoogle Scholar
  11. Horsdal HT, Sondergaard F, Johnsen SP, Rungby J (2011) Antidiabetic treatments and risk of hospitalization with myocardial infarction: a nationwide case-control study. Pharmacoepidemiol Drug Saf 20:331–337PubMedCrossRefGoogle Scholar
  12. Lan KKG, DeMets DL (1983) Discrete sequential boundaries for clinical trials. Biometrika 70:659–663CrossRefGoogle Scholar
  13. McMurray JJ, Gerstein HC, Holman RR, Pfeffer MA (2014) Heart failure: a cardiovascular outcome in diabetes that can no longer be ignored. Lancet Diab Endocrinol 2:843–851CrossRefGoogle Scholar
  14. O’Brien PC, Fleming TR (1979) A multiple testing procedure for clinical trials. Biometrics 35:549–556PubMedCrossRefGoogle Scholar
  15. Pfeffer MA, Claggett B, Diaz R, ELIXA Investigators et al (2015) Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 373:2247–2257PubMedCrossRefGoogle Scholar
  16. Pocock SJ (1977) Group sequential methods in the design and analysis of clinical trials. Biometrika 64:191–199CrossRefGoogle Scholar
  17. Preiss D, Sattar N, McMurray JJ (2011) A systematic review of event rates in clinical trials in diabetes mellitus: the importance of quantifying baseline cardiovascular disease history and proteinuria and implications for clinical trial design. Am Heart J 161:210–219PubMedCrossRefGoogle Scholar
  18. Phung OJ, Schwartzman E, Allen RW, Engel SS, Rajpathak SN (2013) Sulphonylureas and risk of cardiovascular disease: systematic review and meta-analysis. Diabet Med 30:1160–1171PubMedCrossRefGoogle Scholar
  19. Roumie CL, Hung AM, Greevy RA et al (2012) Comparative effectiveness of sulfonylurea and metformin monotherapy on cardiovascular events in type 2 diabetes mellitus: a cohort study. Ann Intern Med 157:601–610PubMedPubMedCentralCrossRefGoogle Scholar
  20. Royston P, Parmar M (2011) The use of restricted mean survival time to estimate the treatment effect in randomized clinical trials when the proportional hazards assumption is in doubt. Stat Med 30:2409–2421PubMedCrossRefGoogle Scholar
  21. Sager PT, Seltzer J, Turner JR et al (2015) Cardiovascular safety outcome trials: a meeting report from the Cardiac Safety Research Consortium. Am Heart J 169:486–495PubMedCrossRefGoogle Scholar
  22. Sahlroot JT (2012) FDA experience with the diabetes guidance: statistical update. Cardiovascular Safety and State-of-the-art Development Issues, Washington, DC, 17th April 2012Google Scholar
  23. Sanofi (2014) Press release. Sanofi provides update on lixisenatide New Drug Application in U.S. 12th September 2013. Available at http://m-en.sanofi.com/Images/33756_20130912_lixisenatide_en.pdf. Accessed 3 Jan 2016
  24. Schramm TK, Gislason GH, Vaag A et al (2011) Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: a nationwide study. Eur Heart J 32:1900–1908PubMedCrossRefGoogle Scholar
  25. Scirica BM, Bhatt DL, Braunwald E, SAVOR-TIMI 53 Steering Committee and Investigators et al (2013) Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 369:1317–1326PubMedCrossRefGoogle Scholar
  26. Scirica BM, Braunwald E, Raz I, Cavender MA, SAVOR-TIMI 53 Steering Committee and Investigators et al (2014) Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial. Circulation 130:1579–1588PubMedCrossRefGoogle Scholar
  27. Sponsor’s Background Document (2015) Dapagliflozin. Prepared for the US FDA Endocrinologic & Metabolic Advisory Committee Meeting, 19th July 2011. Available at http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm262996.pdf. Accessed 31 Aug 2015
  28. Tian L, Cai T, Pfeffer MA et al (2009) Exact and efficient inference procedure for meta-analysis and its application to the analysis of independent 2x2 tables with all available data but without artificial continuity correction. Biostatistics 10:275–281PubMedCrossRefGoogle Scholar
  29. Uno H, Wittes J, Fu H, Solomon SD et al (2015) Alternatives to hazard ratios for comparing the efficacy or safety of therapies in noninferiority studies. Ann Intern Med 163:127–134PubMedPubMedCentralCrossRefGoogle Scholar
  30. White WB, Cannon CP, Heller SR, EXAMINE Investigators et al (2013) Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 369:1327–1335PubMedCrossRefGoogle Scholar
  31. Zannad F, Cannon CP, Cushman WC et al (2015) EXAMINE investigators. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet 385:2067–2076PubMedCrossRefGoogle Scholar
  32. Zhao L, Tian L, Uno H et al (2012) Utilizing the integrated difference of two survival functions to quantify the treatment contrast for designing, monitoring, and analyzing a comparative clinical study. Clin Trials 9:570–577PubMedPubMedCentralCrossRefGoogle Scholar
  33. Zinman B, Wanner C, Lachin JM, EMPA-REG OUTCOME Investigators et al (2015) Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 373:2117–2128PubMedCrossRefGoogle Scholar

Further Reading

  1. Abbas AS, Dehbi HM, Ray KK (2016) Cardiovascular and non-cardiovascular safety of dipeptidyl peptidase-4 inhibition: a meta-analysis of randomized controlled cardiovascular outcome trials. Diabetes Obes Metab 18:295–299PubMedCrossRefGoogle Scholar
  2. Al-Tabakha MM (2015) Future prospect of insulin inhalation for diabetic patients: the case of Afrezza versus Exubera. J Control Release 215:25–38PubMedCrossRefGoogle Scholar
  3. Ard J, Cannon A, Lewis CE, Satiety Clinical Adiposity – Liraglutide Evidence in Non-diabetic Diabetic Individuals (SCALE) Study Groups et al (2016) The efficacy and safety of liraglutide 3.0 mg for weight management are similar across races: subgroup analysis across SCALE and phase 2 randomized trials. Diabetes Obes Metab 18:430–435PubMedCrossRefGoogle Scholar
  4. Azimova K, San Juan Z, Mukherjee D (2014) Cardiovascular safety profile of currently available diabetic drugs. Ochsner J 14:616–632PubMedPubMedCentralGoogle Scholar
  5. Bekiari E, Rizava C, Athanasiadou E et al (2015) Systematic review and meta-analysis of vildagliptin for treatment of type 2 diabetes. Endocrine 52(3):458–480 [Epub ahead of print]PubMedCrossRefGoogle Scholar
  6. Bentley-Lewis R, Aguilar D, Riddle MC, ELIXA Investigators et al (2015) Rationale, design, and baseline characteristics in evaluation of LIXisenatide in acute coronary syndrome, a long-term cardiovascular end point trial of lixisenatide versus placebo. Am Heart J 169:631–638.e7PubMedCrossRefGoogle Scholar
  7. Bhatt HB (2015) Thoughts on the progression of type 2 diabetes drug discovery. Expert Opin Drug Discov 10:107–110PubMedCrossRefGoogle Scholar
  8. Boyle LD, Wilding JP (2014) A safety evaluation of canagliflozin: a first-in-class treatment for type 2 diabetes. Expert Opin Drug Saf 13:1535–1544PubMedCrossRefGoogle Scholar
  9. Cameron FJ, Wherrett DK (2015) Care of diabetes in children and adolescents: controversies, changes, and consensus. Lancet 385:2096–2106PubMedCrossRefGoogle Scholar
  10. Cefalu WT, Buse JB, Del Prato S et al (2014) Beyond metformin: safety considerations in the decision-making process for selecting a second medication for type 2 diabetes management: reflections from a diabetes care editors’ expert forum. Diabetes Care 37:2647–2659PubMedPubMedCentralCrossRefGoogle Scholar
  11. Cernea S, Cahn A, Raz I (2016) Saxagliptin for the treatment of diabetes: a focus on safety. Expert Opin Drug Saf 15:696–707Google Scholar
  12. Chatterjee S, Davies MJ (2015) Current management of diabetes mellitus and future directions in care. Postgrad Med J 91:612–621PubMedCrossRefGoogle Scholar
  13. Cho YM (2015) Cardiovascular effects of the incretin-based therapy: the good, the bad, or the ugly? J Diab Investig 6:597–599CrossRefGoogle Scholar
  14. Dailey G (2015) Empagliflozin for the treatment of type 2 diabetes mellitus: an overview of safety and efficacy based on Phase 3 trials. J Diabetes 7:448–461PubMedCrossRefGoogle Scholar
  15. Deacon CF, Lebovitz HE (2016) A comparative review of DPP-4 inhibitors and sulphonylureas. Diabetes Obes Metab 18:333–347PubMedCrossRefGoogle Scholar
  16. Doggrell SA, Dimmitt SB (2016) Sitagliptin and other ‘gliptins’- why prescribe them? Expert Opin Pharmacother 17:757–760PubMedCrossRefGoogle Scholar
  17. Erdmann E, Califf R, Gerstein HC et al (2015) Effects of the dual peroxisome proliferator-activated receptor activator aleglitazar in patients with type 2 diabetes mellitus or prediabetes. Am Heart J 170:117–122PubMedCrossRefGoogle Scholar
  18. Ferdinand KC, Botros FT, Atisso CM, Sager PT (2016) Cardiovascular safety for once-weekly dulaglutide in type 2 diabetes: a pre-specified meta-analysis of prospectively adjudicated cardiovascular events. Cardiovasc Diabetol 15:38PubMedPubMedCentralCrossRefGoogle Scholar
  19. Fiorentino TV, Sesti G (2015) Lessons learned from cardiovascular outcome clinical trials with dipeptidyl peptidase 4 (DPP-4) inhibitors. Endocrine. [Epub ahead of print]Google Scholar
  20. Gallwitz B (2016) Novel therapeutic approaches in diabetes. Endocr Dev 31:43–56PubMedCrossRefGoogle Scholar
  21. Ghosal S, Sinha B (2016) Gliptins and cardiovascular outcomes: a comparative and critical analysis after TECOS. J Diab Res 2016:1643496Google Scholar
  22. Ghosh RK, Bandyopadhyay D, Hajra A, Biswas M, Gupta A (2016) Cardiovascular outcomes of sodium-glucose cotransporter 2 inhibitors: a comprehensive review of clinical and preclinical studies. Int J Cardiol 212:29–36PubMedCrossRefGoogle Scholar
  23. Gilbert RE, Krum H (2015) Heart failure in diabetes: effects of anti-hyperglycaemic drug therapy. Lancet 385:2107–2117PubMedCrossRefGoogle Scholar
  24. Giorda CB, Picariello R, Tartaglino B et al (2015) Hospitalisation for heart failure and mortality associated with dipeptidyl peptidase 4 (DPP-4) inhibitor use in an unselected population of subjects with type 2 diabetes: a nested case-control study. BMJ Open 5:e007959PubMedPubMedCentralCrossRefGoogle Scholar
  25. Green JB (2014) Understanding the type 2 diabetes mellitus and cardiovascular disease risk paradox. Postgrad Med 126:190–204PubMedCrossRefGoogle Scholar
  26. Green JB, Bethel MA, Paul SK et al (2013) Rationale, design, and organization of a randomized, controlled Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) in patients with type 2 diabetes and established cardiovascular disease. Am Heart J 166:983–989.e7PubMedCrossRefGoogle Scholar
  27. Gunton JE, Cheung NW, Davis TM, Zoungas S, Colagiuri S, Australian Diabetes Society (2014) A new blood glucose management algorithm for type 2 diabetes: a position statement of the Australian Diabetes Society. Med J Aust 201:650–653PubMedCrossRefGoogle Scholar
  28. Guo X (2016) The value of short- and long-acting glucagon-like peptide-1 agonists in the management of type 2 diabetes mellitus: experience with exenatide. Curr Med Res Opin 32:61–76PubMedCrossRefGoogle Scholar
  29. Halimi S, Vergès B (2014) Adverse effects and safety of SGLT-2 inhibitors. Diabetes Metab 40(6 Suppl 1):S28–S34PubMedCrossRefGoogle Scholar
  30. Hedrington MS, Davis SN (2015) The role of empagliflozin in the management of type 2 diabetes by patient profile. Ther Clin Risk Manag 11:739–49PubMedPubMedCentralGoogle Scholar
  31. Heller S, Darpö B, Mitchell MI et al (2015) Considerations for assessing the potential effects of antidiabetes drugs on cardiac ventricular repolarization: a report from the Cardiac Safety Research Consortium. Am Heart J 170:23–35PubMedCrossRefGoogle Scholar
  32. Hiatt WR, Kaul S, Smith RJ (2013) The cardiovascular safety of diabetes drugs: insights from the rosiglitazone experience. N Engl J Med 369:1285–1287PubMedCrossRefGoogle Scholar
  33. Hirshberg B, Katz A (2013) Cardiovascular outcome studies with novel antidiabetes agents: scientific and operational considerations. Diabetes Care 36(Suppl 2):S253–S258PubMedPubMedCentralCrossRefGoogle Scholar
  34. Iijima H, Kifuji T, Maruyama N, Inagaki N (2015) Pharmacokinetics, pharmacodynamics, and safety of canagliflozin in Japanese patients with type 2 diabetes mellitus. Adv Ther 32:768–782PubMedPubMedCentralCrossRefGoogle Scholar
  35. Johansen OE (2015) Interpretation of cardiovascular outcome trials in type 2 diabetes needs a multiaxial approach. World J Diab 6:1092–1096CrossRefGoogle Scholar
  36. Kannan S, Pantalone KM, Matsuda S et al (2016) Risk of overall mortality and cardiovascular events in patients with type 2 diabetes on dual drug therapy including metformin: a large database study from the Cleveland Clinic. J Diabetes 8:279–285PubMedCrossRefGoogle Scholar
  37. Kappel BA, Marx N, Federici M (2015) Oral hypoglycemic agents and the heart failure conundrum: lessons from and for outcome trials. Nutr Metab Cardiovasc Dis 25:697–705PubMedCrossRefGoogle Scholar
  38. Li L, Li S, Deng K, Liu J et al (2016) Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: systematic review and meta-analysis of randomised and observational studies. BMJ 352:i610PubMedPubMedCentralCrossRefGoogle Scholar
  39. Lindamood CA, Taylor JR (2015) Emerging new therapies for the treatment of type 2 diabetes mellitus: glucagon-like peptide-1 receptor agonists. Clin Ther 37:483–493PubMedCrossRefGoogle Scholar
  40. Lueza B, Mauguen A, Pignon JP, Rivero-Arias O, Bonastre J, MAR-LC Collaborative Group (2016) Difference in restricted mean survival time for cost-effectiveness analysis using individual patient data meta-analysis: evidence from a case study. PLoS One 11:e0150032PubMedPubMedCentralCrossRefGoogle Scholar
  41. MacConell L, Gurney K, Malloy J, Zhou M, Kolterman O (2015) Safety and tolerability of exenatide once weekly in patients with type 2 diabetes: an integrated analysis of 4,328 patients. Diabetes Metab Syndr Obes 8:241–253PubMedPubMedCentralGoogle Scholar
  42. Marx N, Rosenstock J, Kahn SE et al (2015) Design and baseline characteristics of the CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes (CAROLINA®). Diab Vasc Dis Res 12:164–174PubMedPubMedCentralCrossRefGoogle Scholar
  43. Menon V, Lincoff AM (2014) Cardiovascular safety evaluation in the development of new drugs for diabetes mellitus. Circulation 129:2705–2713PubMedCrossRefGoogle Scholar
  44. Nathan DM (2015) Diabetes: advances in diagnosis and treatment. JAMA 314:1052–1062PubMedCrossRefGoogle Scholar
  45. Neeland IJ, Salahuddin U, McGuire DK (2016) A safety evaluation of empagliflozin for the treatment of type 2 diabetes. Expert Opin Drug Saf 15:393–402PubMedPubMedCentralCrossRefGoogle Scholar
  46. Ndefo UA, Anidiobi NO, Basheer E, Eaton AT (2015) Empagliflozin (Jardiance): a novel SGLT2 inhibitor for the treatment of type-2 diabetes. P T 40:364–368PubMedPubMedCentralGoogle Scholar
  47. Ommen ES, Xu L, O’Neill EA et al (2015) Comparison of treatment with sitagliptin or sulfonylurea in patients with type 2 diabetes mellitus and mild renal impairment: a post hoc analysis of clinical trials. Diabetes Ther 6:29–40PubMedPubMedCentralCrossRefGoogle Scholar
  48. Ou HT, Chang KC, Li CY, Wu JS (2016) Risks of cardiovascular diseases associated with dipeptidyl peptidase-4 inhibitors and other antidiabetic drugs in patients with type 2 diabetes: a nation-wide longitudinal study. Cardiovasc Diabetol 15:41PubMedPubMedCentralCrossRefGoogle Scholar
  49. Paneni F (2015) DPP-4 inhibitors, heart failure and type 2 diabetes: all eyes on safety. Cardiovasc Diagn Ther 5:471–478PubMedPubMedCentralGoogle Scholar
  50. Patorno E, Everett BM, Goldfine AB et al (2016) Comparative cardiovascular safety of glucagon-like peptide-1 receptor agonists versus other antidiabetic drugs in routine care: a cohort study. Diabetes Obes Metab. [Epub ahead of print]Google Scholar
  51. Pladevall M, Riera-Guardia N, Margulis AV et al (2016) Cardiovascular risk associated with the use of glitazones, metformin and sufonylureas: meta-analysis of published observational studies. BMC Cardiovasc Disord 16:14PubMedPubMedCentralCrossRefGoogle Scholar
  52. Ponzani P, Scardapane M, Nicolucci A, Rossi MC (2016) Effectiveness and safety of liraglutide after three years of treatment. Minerva Endocrinol 41:35–42PubMedGoogle Scholar
  53. Prasad-Reddy L, Isaacs D (2015) A clinical review of GLP-1 receptor agonists: efficacy and safety in diabetes and beyond. Drugs Context 4:212283PubMedPubMedCentralCrossRefGoogle Scholar
  54. Pryor R, Cabreiro F (2015) Repurposing metformin: an old drug with new tricks in its binding pockets. Biochem J 471:307–322PubMedPubMedCentralCrossRefGoogle Scholar
  55. Quan H, Li M, Zhao PL et al (2013) Considerations for design and data analysis of noninferiority/superiority cardiovascular trials. J Biopharm Stat 23:239–260PubMedCrossRefGoogle Scholar
  56. Rosenstock J, Marx N, Kahn SE et al (2013) Cardiovascular outcome trials in type 2 diabetes and the sulphonylurea controversy: rationale for the active-comparator CAROLINA trial. Diab Vasc Dis Res 10:289–301PubMedCrossRefGoogle Scholar
  57. Rosenstock J, Marx N, Neubacher D et al (2015) Cardiovascular safety of linagliptin in type 2 diabetes: a comprehensive patient-level pooled analysis of prospectively adjudicated cardiovascular events. Cardiovasc Diabetol 14:57PubMedPubMedCentralCrossRefGoogle Scholar
  58. Royston P, Parmar MK (2013) Restricted mean survival time: an alternative to the hazard ratio for the design and analysis of randomized trials with a time-to-event outcome. BMC Med Res Methodol 13:152PubMedPubMedCentralCrossRefGoogle Scholar
  59. Royston P, Parmar MK (2016) Augmenting the logrank test in the design of clinical trials in which non-proportional hazards of the treatment effect may be anticipated. BMC Med Res Methodol 16:16PubMedPubMedCentralCrossRefGoogle Scholar
  60. Sanford M (2014) Dulaglutide: first global approval. Drugs 74:2097–2103PubMedCrossRefGoogle Scholar
  61. Scheen AJ (2013) Cardiovascular effects of dipeptidyl peptidase-4 inhibitors: from risk factors to clinical outcomes. Postgrad Med 125:7–20PubMedCrossRefGoogle Scholar
  62. Scheen AJ (2015) Pharmacodynamics, efficacy and safety of sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs 75:33–59PubMedCrossRefGoogle Scholar
  63. Scheen AJ (2015) SGLT2 inhibition: efficacy and safety in type 2 diabetes treatment. Expert Opin Drug Saf 14:1879–1904PubMedCrossRefGoogle Scholar
  64. Schwartz SS, Ahmed I (2016) Sodium-glucose cotransporter-2 inhibitors: an evidence-based practice approach to their use in the natural history of type 2 diabetes. Curr Med Res Opin 32:907–919PubMedCrossRefGoogle Scholar
  65. Seshasai SR, Bennett RL, Petrie JR et al (2015) Cardiovascular safety of the glucagon-like peptide-1 receptor agonist taspoglutide in people with type 2 diabetes: an individual participant data meta-analysis of randomized controlled trials. Diabetes Obes Metab 17:505–510PubMedCrossRefGoogle Scholar
  66. Shah S, Sharma SK, Singh P, Muruganathan A, Das AK, Diabetes Consensus Group (2014) Consensus evidence-based guidelines for insulin initiation, optimization and continuation in type 2 diabetes mellitus. J Assoc Physicians India 62(7 Suppl):49–54PubMedGoogle Scholar
  67. Singh S (2014) Type 2 diabetes pharmacoepidemiology update 2014: safety versus efficacy. Curr Diab Rep 14:563PubMedCrossRefGoogle Scholar
  68. Sportiello L, Rafaniello C, Scavone C et al (2016) The importance of pharmacovigilance for the drug safety: focus on cardiovascular profile of incretin-based therapy. Int J Cardiol 202:731–735PubMedCrossRefGoogle Scholar
  69. Steinberg HO (2016) Sodium-glucose cotransporter 2 inhibitors and cardiovascular outcomes. Postgrad Med 128:398–408PubMedCrossRefGoogle Scholar
  70. Tella SH, Rendell MS (2015) DPP-4 inhibitors: focus on safety. Expert Opin Drug Saf 14:127–140PubMedCrossRefGoogle Scholar
  71. Thompson AM, Trujillo JM (2015) Dulaglutide: the newest GLP-1 receptor agonist for the management of type 2 diabetes. Ann Pharmacother 49:351–359PubMedCrossRefGoogle Scholar
  72. Tian L, Zhao L, Wei LJ (2014) Predicting the restricted mean event time with the subject’s baseline covariates in survival analysis. Biostatistics 15:222–233PubMedCrossRefGoogle Scholar
  73. Tiwari P (2015) Recent trends in therapeutic approaches for diabetes management: a comprehensive update. J Diabetes Res 2015:340838PubMedPubMedCentralCrossRefGoogle Scholar
  74. Trinquart L, Jacot J, Conner SC, Porcher R (2016) Comparison of treatment effects measured by the hazard ratio and by the ratio of restricted mean survival times in oncology randomized controlled trials. J Clin Oncol. 34:1813–1819 [Epub ahead of print]Google Scholar
  75. Trujillo JM, Nuffer W (2014) GLP-1 receptor agonists for type 2 diabetes mellitus: recent developments and emerging agents. Pharmacotherapy 34:1174–1186PubMedCrossRefGoogle Scholar
  76. Uccellatore A, Genovese S, Dicembrini I, Mannucci E, Ceriello A (2015) Comparison review of short-acting and long-acting glucagon-like peptide-1 receptor agonists. Diabetes Ther 6:239–256PubMedPubMedCentralCrossRefGoogle Scholar
  77. Umezawa S, Kubota A, Maeda H et al (2015) Two-year assessment of the efficacy and safety of sitagliptin in elderly patients with type 2 diabetes: post hoc analysis of the ASSET-K study. BMC Endocr Disord 15:34PubMedPubMedCentralCrossRefGoogle Scholar
  78. Uno H, Claggett B, Tian L et al (2014) Moving beyond the hazard ratio in quantifying the between-group difference in survival analysis. J Clin Oncol 32:2380–2385PubMedPubMedCentralCrossRefGoogle Scholar
  79. Van Dieren S, Beulens JSJ, Kengne AP et al (2012) Prediction models for the risk of cardiovascular disease in patients with type 2 diabetes: a systematic review. Heart 98:360–369PubMedCrossRefGoogle Scholar
  80. Varas-Lorenzo C, Margulis AV, Pladevall M et al (2014) The risk of heart failure associated with the use of noninsulin blood glucose-lowering drugs: systematic review and meta-analysis of published observational studies. BMC Cardiovasc Disord 14:129PubMedPubMedCentralCrossRefGoogle Scholar
  81. Waldrop G, Zhong J, Peters M, Rajagopalan S (2016) Incretin-based therapy for diabetes: what a cardiologist needs to know. J Am Coll Cardiol 67:1488–1496PubMedPubMedCentralCrossRefGoogle Scholar
  82. Wei Y, Royston P, Tierney JF, Parmar MK (2015) Meta-analysis of time-to-event outcomes from randomized trials using restricted mean survival time: application to individual participant data. Stat Med 34:2881–2898PubMedPubMedCentralCrossRefGoogle Scholar
  83. White JR Jr (2015) Empagliflozin, an SGLT2 inhibitor for the treatment of type 2 diabetes mellitus: a review of the evidence. Ann Pharmacother 49:582–598PubMedCrossRefGoogle Scholar
  84. White JR Jr (2015) Sodium glucose cotransporter 2 inhibitors. Med Clin North Am 99:131–143PubMedCrossRefGoogle Scholar
  85. White WB, Baker WL (2016) Cardiovascular effects of incretin-based therapies. Annu Rev Med 67:245–260PubMedCrossRefGoogle Scholar
  86. Wu JH, Foote C, Blomster J et al (2016) Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 4:411–419 [Epub ahead of print]Google Scholar
  87. Wu S, Hopper I, Skiba M, Krum H (2014) Dipeptidyl peptidase-4 inhibitors and cardiovascular outcomes: meta-analysis of randomized clinical trials with 55,141 participants. Cardiovasc Ther 32:147–158PubMedCrossRefGoogle Scholar
  88. Yabe D, Seino Y (2016) Alogliptin for the treatment of type 2 diabetes: a drug safety evaluation. Expert Opin Drug Saf 15:249–264PubMedCrossRefGoogle Scholar
  89. Yang F, Stewart M, Ye J, DeMets D (2015) Type 2 diabetes mellitus development programs in the new regulatory environment with cardiovascular safety requirements. Diabetes Metab Syndr Obes 8:315–325PubMedPubMedCentralCrossRefGoogle Scholar
  90. Zhao L, Claggett B, Tian L et al (2015) On the restricted mean survival time curve in survival analysis. Biometrics 72:215–221PubMedPubMedCentralCrossRefGoogle Scholar
  91. Zinman B, Inzucchi SE, Lachin JM et al (2014) Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empagliflozin (EMPA-REG OUTCOME™). Cardiovasc Diabetol 13:102PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  • J. Rick Turner
    • 1
  • Dilip R. Karnad
    • 2
  • Snehal Kothari
    • 3
  1. 1.Cardiac Safety Services QuintilesDurhamUSA
  2. 2.Research TeamCardiac Safety Services QuintilesMumbaiIndia
  3. 3.Cardiac Safety Services Global HeadCardiac Safety Center of Excellence QuintilesMumbaiIndia

Personalised recommendations