Year : 2018 | Volume
: 9 | Issue : 1 | Page : 1--2
Cardiovascular safety studies for diabetic medications: Do the benefits outweigh the costs?
Brian K Irons
Department of Pharmacy Practice, Division Head-Ambulatory Care, School of Pharmacy, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
Dr. Brian K Irons
Department of Pharmacy Practice, Division Head-Ambulatory Care, School of Pharmacy, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX. 79430
|How to cite this article:|
Irons BK. Cardiovascular safety studies for diabetic medications: Do the benefits outweigh the costs?.J Diabetol 2018;9:1-2
|How to cite this URL:|
Irons BK. Cardiovascular safety studies for diabetic medications: Do the benefits outweigh the costs?. J Diabetol [serial online] 2018 [cited 2021 Apr 19 ];9:1-2
Available from: https://www.journalofdiabetology.org/text.asp?2018/9/1/1/229013
Since 2005, the Food and Drug Administration (FDA) has approved dozens of new options (including combination products) in the treatment of diabetes, providing clinicians with a plethora of treatment choices to combat hyperglycaemia. However, the use of generic, less costly treatment options is less than optimal and the use of newer diabetes mellitus (DM) agents is increasing and contributing to increased costs of treatment., In 2018, it will have been 10 years since the U.S. FDA required increased study data on cardiovascular (CV) safety of all new antidiabetic treatment options for type 2 diabetes as a requisite for approval. This mandate originally stemmed from a concern that an already approved diabetes agent, rosiglitazone, increased the risk for myocardial infarction and possibly CV death. The questions are, have these studies provided any additional information on the CV safety of newer DM agents and are the costs associated with conducting these studies worth it or do they contribute to the rising costs of diabetic medications?
Of the CV safety studies to date evaluating the current FDA-approved glucagon-like peptide 1 agonists, none have shown a negative CV risk profile in their primary outcome of major atherosclerotic CV events, mainly CV death and non-fatal myocardial infarction or stroke. Lixisenatide and once-weekly exenatide proved to be as safe as placebo in high-CV risk patients whereas liraglutide and semaglutide have shown no increased risk but rather some potential CV benefits.,,, CV safety trials evaluating albiglutide and dulaglutide are still pending completion. Two of the four FDA-approved sodium-glucose cotransporter 2 inhibitors, empagliflozin and canagliflozin, have also completed CV safety studies and in a similar fashion to the GLP1 agonists have shown no increased CV risk and in the case of empagliflozin may have some CV benefits in patients similar to those enrolled in the clinical studies, i.e., patients with a history of established CVD., Data on the other FDA-approved agents in the class, dapagliflozin and ertugliflozin, are also pending. The newest long-acting insulin, insulin degludec, has also shown no increased CV risk when compared to insulin glargine. It should also be noted that some of these trials found an improvement in microvascular complications as well, so despite providing no evidence of an increased CV safety profile, some agents provide an additional benefit that would likely not have been detected in a typical Phase 3 efficacy and safety study.
The data regarding CV safety of newer diabetic agents only get a bit murky when the dipeptidyl peptidase-4 (DPP-4) inhibitor data are evaluated. Three of the four FDA-approved agents, sitagliptin, saxagliptin and alogliptin, have been studied with regard to CV safety, and in each case, the primary outcome required of the FDA (death from CV disease, non-fatal myocardial infarction and non-fatal stroke) was shown to be non-inferior to placebo.,, Sitagliptin has also showed no significant effect on any secondary CV outcome evaluated including hospitalisation for heart failure. Saxagliptin, conversely, showed a 27% relative increase in the secondary outcome of hospitalisation for heart failure (3.5% vs. 2.8% in 2 years for saxagliptin and placebo, respectively, number needed to harm: 143). CV safety data for alogliptin were subsequently re-evaluated for heart failure risk in a post hoc analysis and were found not to show a significant increase in heart failure admission risk in the studied population (not reported in the original study)., However, the post hoc analysis did show a 76% relative increase in admission for heart failure in the subset of patients with no previous history of heart failure (2.2% vs. 1.3% for alogliptin and placebo, respectively, number needed to harm: 333) but no increased risk in those with a history of heart failure upon enrolment. Although not as robust as randomised prospective clinical trials, subsequent observational studies assessing overall heart failure risk have shown no association with saxagliptin.,
Since the original fear of increased CV risk with rosiglitazone, the re-evaluated data suggest no increased risk for myocardial infarction or CV death though an increased risk for heart failure remains. The FDA has since lifted its risk evaluation mitigation strategy that severely limited the use of rosiglitazone. Coupling this with the above CV safety data with all new type 2 diabetic agents entering the market since 2008, it appears that these agents pose no increased CV risk. The increased risk of heart failure with two of the DPP-4 inhibitors was small and was only found in a secondary outcome or as a result of post hoc analysis and there are observational data to refute this risk. However, the FDA CV safety study mandate for all new diabetic agents remains.
It is unknown how much these CV safety trials cost to perform, but with at least 17 prospective studies either completed or ongoing involving >140,000 participants and given the length and size of the clinical trials are significantly greater than in typical Phase 3 studies historically evaluating diabetic medication efficacy and safety, it must be significant. The increased costs and time of funding and performing these studies contribute to the overall costs of new type 2 diabetic agents.
Newer agents will always be more costly than those that have been on the market for a significant time. Costs of many of these newer agents will remain high as the potential for generic or biosimilar alternatives will not occur in the near future. As a result of being cost prohibitive to some patients who lack sufficient medical insurance, this could also lead to poorer medication compliance and further increase the risk for costly diabetes-related complications estimated to be 18% of the $245 billion spent annually on treating diabetes in the United States  Given the lack of proven CV risk associated with newer diabetic agents, and that the original fear with rosiglitazone, less the risk for heart failure, leading to the requested FDA CV safety study requirements has since been redacted, is it time for the FDA to stop this costly requirement? Decreasing the potential for cost-prohibitive medications to patients and third-party payers could help decrease costs attributed to treating DM complications and the overall treatment of DM in future.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
|1||Edelman SV, Polonsky WH. Type 2 diabetes in the real world: The elusive nature of glycemic control. Diabetes Care 2017;40:1425-32.|
|2||Hua X, Carvalho N, Tew M, Huang ES, Herman WH, Clarke P, et al. Expenditures and prices of antihyperglycemic medications in the United States: 2002-2013. JAMA 2016;315:1400-2.|
|3||Montvida O, Shaw J, Atherton JJ, Stringer F, Paul SK. Long-term trends in antidiabetes drug usage in the U.S.: Real-world evidence in patients newly diagnosed with type 2 diabetes. Diabetes Care 2018;41:69-78.|
|4||Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457-71.|
|5||Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Køber LV, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 2015;373:2247-57.|
|6||Holman RR, Bethel MA, Mentz RJ, Thompson VP, Lokhnygina Y, Buse JB, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2017;377:1228-39.|
|7||Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311-22.|
|8||Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375:1834-44.|
|9||Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28.|
|10||Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644-57.|
|11||Marso SP, McGuire DK, Zinman B, Poulter NR, Emerson SS, Pieber TR, et al. Efficacy and safety of degludec versus glargine in type 2 diabetes. N Engl J Med 2017;377:723-32.|
|12||Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015;373:232-42.|
|13||White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369:1327-35.|
|14||Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317-26.|
|15||Zannad F, Cannon CP, Cushman WC, Bakris GL, Menon V, Perez AT, et al. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: A multicentre, randomised, double-blind trial. Lancet 2015;385:2067-76.|
|16||Fu AZ, Johnston SS, Ghannam A, Tsai K, Cappell K, Fowler R, et al. Association between hospitalization for heart failure and dipeptidyl peptidase 4 inhibitors in patients with type 2 diabetes: An observational study. Diabetes Care 2016;39:726-34.|
|17||Toh S, Hampp C, Reichman ME, Graham DJ, Balakrishnan S, Pucino F, et al. Risk for hospitalized heart failure among new users of saxagliptin, sitagliptin, and other antihyperglycemic drugs: A Retrospective cohort study. Ann Intern Med 2016;164:705-14.|
|18||Mahaffey KW, Hafley G, Dickerson S, Burns S, Tourt-Uhlig S, White J, et al. Results of a reevaluation of cardiovascular outcomes in the RECORD trial. Am Heart J 2013;166:240-90.|
|19||Smith RJ, Goldfine AB, Hiatt WR. Evaluating the cardiovascular safety of new medications for type 2 diabetes: Time to reassess? Diabetes Care 2016;39:738-42.|
|20||American Diabetes Association. Economic costs of diabetes in the U.S. In 2012. Diabetes Care 2013;36:1033-46.|