Update: What information has been yielded from the cardiovascular safety studies on new anti-hyperglycemic agents?
Introduction
In December 2017, the UIC Drug Information Group reviewed the published cardiovascular outcome trials for new antidiabetic therapies, and the full review is available here. Since this previous review, several additional trials have been completed for various diabetes medications. This updated review will provide an overview of cardiovascular outcome trials that have been published since December 2017.
Background
In 2008, the Food and Drug Administration (FDA) issued a guidance document requiring cardiovascular outcome trials for new antidiabetic agents.1 This guidance was published in response to the growing number of reports outlining cardiovascular events from rosiglitazone. The FDA guidance outlines recommendations for phase 2 and 3 trials to establish the safety of all new antidiabetic medications. Endpoints for these trials should include cardiovascular mortality, myocardial infarction, and stroke with or without hospitalization for acute coronary syndrome or urgent revascularization procedures. Additionally, the upper limit of the 95% confidence interval for the estimated risk ratio should not exceed 1.8 in these trials.
Cardiovascular outcome trials have been completed for agents within 3 medication classes including dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, and sodium-glucose co-transporter-2 (SGLT2) inhibitors.2 Prior to December 2017, only 8 cardiovascular outcome trials had been published for diabetes medications.3-10 The conclusions from these trials are summarized in the table below; however, a full review will not be included in this article. Based on these trials, addition of saxagliptin, alogliptin, sitagliptin, or lixisenatide to current treatment does not increase or decrease cardiovascular events compared to placebo in patients with diabetes. Additionally, liraglutide, semaglutide injection, empagliflozin, and canagliflozin were shown to decrease cardiovascular events compared to placebo when added to standard diabetes treatment. Patients with type 2 diabetes mellitus are at increased risk for cardiovascular events.1 Because of the variety of medications utilized to treat type 2 diabetes, there is an opportunity to select agents based on cardiovascular risk profile.
Table 1. Overview of randomized clinical trials examining cardiovascular safety in DPP-4 inhibitors, GLP-1 agonists, and SGLT2 inhibitors published prior to December 2017.3-10 Heading link
| Table 1. Overview of randomized clinical trials examining cardiovascular safety in DPP-4 inhibitors, GLP-1 agonists, and SGLT2 inhibitors published prior to December 2017.3-10 | |||
|---|---|---|---|
| Medication Class | Study | Drug | Conclusion |
| DPP-4 inhibitors | SAVOR-TIMI 53 3 | Saxagliptin | Addition of saxagliptin to diabetes regimen did not increase or decrease MACE compared to placebo |
| EXAMINE 4 | Alogliptin | Addition of alogliptin to diabetes regimen did not increase or decrease MACE compared to placebo | |
| TECOS 5 | Sitagliptin | Addition of sitagliptin to diabetes regimen did not increase or decrease MACE compared to placebo | |
| GLP-1 agonists | ELIXA 6 | Lixisenatide | Addition of lixisenatide to diabetes regimen did not increase or decrease the rate of MACE compared to placebo |
| LEADER 7 | Liraglutide | Occurrence of MACE was lower with the addition of liraglutide to diabetes regimen compared to placebo | |
| SUSTAIN-6 8 | Semaglutide injection | Occurrence of MACE was lower with the addition of injectable semaglutide to diabetes regimen compared to placebo | |
| SGLT2 inhibitors | EMPA-REG OUTCOME 9 | Empagliflozin | Addition of empagliflozin to diabetes regimen resulted in a lower rate of MACE compared to placebo |
| CANVAS 10 | Canagliflozin | Addition of canagliflozin to diabetes regimen resulted in a lower rate of MACE compared to placebo | |
| Abbreviations: DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; MACE=major adverse cardiovascular events; SGLT2=sodium-glucose co-transporter-2. | |||
Evidence summary
Since the previous FAQ article, 6 cardiovascular outcome trials have been published, which are reviewed in Table 2.11-16 These trials examined the addition of linagliptin, exenatide, albiglutide, dulaglutide, semaglutide tablet, or dapagliflozin to current treatment for patients with type 2 diabetes mellitus. Each trial utilized 3-point major adverse cardiovascular event (MACE) as the primary outcome, which is a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Overall, each of these studies showed that addition of the investigational agent did not increase cardiovascular events more than placebo. Additionally, studies for albiglutide and dulaglutide showed a decrease in cardiovascular events compared to placebo.
Each study included patients with high cardiovascular risk, which may limit the applicability of results to patients without high cardiovascular risk.11-16 An additional limitation for several of these studies was the use of concomitant DPP-4 inhibitors, GLP-1 agonists, and/or SGLT2 inhibitors during the study. Because several GLP-1 agonists and SGLT2 inhibitors have been shown to decrease cardiovascular events, concomitant use of these agents may have confounded results. The CARMELINA trial, which studied linagliptin, did not allow the concomitant use of DPP-4 inhibitors, GLP-1 agonists, and SGLT2 inhibitors during the study to decrease confounding effect. In contrast, every study for GLP-1 agonists (EXSCEL, HARMONY, REWIND, PIONEER-6) allowed use of all other diabetes medications, including SGLT2 inhibitors. In the EXSCEL trial, SGLT2 inhibitor use was higher in the exenatide group than the placebo group, which could have masked any safety concerns of exenatide. In the HARMONY, REWIND, and PIONEER-6 trials, use of SGLT2 inhibitors was higher in the placebo group; therefore, cardiovascular benefit would potentially be inflated in the placebo group compared to the treatment group. Similarly, the DECLARE-TIMI trial, which examined the SGLT2 inhibitor dapagliflozin, allowed the concomitant use of GLP-1 agonists; however, GLP-1 agonist use was higher in the placebo group.
Table 2. Overview of randomized clinical trials examining cardiovascular safety in DPP-4 inhibitors, GLP-1 agonists, and SGLT2 inhibitors published since December 2017.11-16 Heading link
| Table 2. Overview of randomized clinical trials examining cardiovascular safety in DPP-4 inhibitors, GLP-1 agonists, and SGLT2 inhibitors published since December 2017.11-16 | |||
|---|---|---|---|
| Study design, treatment, and duration | Subjects | Outcome/adjusted HR and 95% CI for treatment vs. placebo* | Conclusions |
| DPP-4 inhibitors | |||
| CARMELINA11 Rosenstock et al 2019 RCT, DB, PC, MC, NI Linagliptin 5 mg orally once daily vs. placebo Median tx duration=1.9 years; median follow-up=2.2 years | N=6979 patients (linagliptin, 66.1 years of age; placebo, 65.6 years of age) with T2DM and A1C between 6.5% to 10.0% with high CV risk (CAD, stroke, PVD) and renal risk Permitted medications: Use of DPP-4 inhibitors, GLP-1 RA, and SGLT2 inhibitors not allowed. All other diabetes medications permitted. | Primary: MACE occurred in 434 (12.4%) linagliptin patients versus 420 (12.1%) placebo patients (HR, 1.02; 95% CI, 0.89 to 1.17; p<0.001 for NI; p=0.74 for superiority) Secondary: Composite renal outcomes occurred in 327 (9.4%) linagliptin patients and 306 (8.8%) placebo patients (HR, 0.22; 95% CI, -0.52 to 0.97) | The use of linagliptin in the treatment of T2DM did not increase CV events more than placebo |
| GLP-1 agonist | |||
| EXSCEL12 Holman et al 2017 RCT, MC, DB, PC, NI, pragmatic Exenatide XR 2 mg injection weekly vs. placebo Median tx duration=2.4 years; median follow-up=3.2 years | N=14,752 patients (age 62 years) with T2DM, A1C 6.5% to 10.0% and either a previous CV event (70% of patients) or no previous event (30% of patients), receiving up to 3 oral antihyperglycemic agents or insulin Permitted medications: Patients were allowed to continue on all diabetes medications (except for GLP-1 RA) | Primary: MACE occurred in 839 (11.4%) patients in the exenatide group and 905 (12.2%) in the placebo group (HR, 0.91; 95% CI, 0.83 to 1.00; p-value<0.001 for NI; p=0.06 for superiority) Secondary: Death from any cause occurred in 6.9% of exenatide vs. 7.9% of placebo (HR, 0.86; 95% CI, 0.77 to 0.97) There were no statistical differences found among the components of MACE, hospitalization for HF or ACS | Addition of exenatide XR once weekly to standard treatment for T2DM did not increase MACE more than placebo Note: Lipid lowering agents and SGLT2 inhibitors were used more in the exenatide group than placebo |
| HARMONY13 Hernandez et al 2018 RCT, MC, DB, PC, NI Albiglutide 30 or 50 mg injection weekly vs. placebo Median follow-up=1.6 years | N=9463 patients (mean age, 64.1 years) greater than 40 years of age with T2DM, A1C > 7.0%, with significant CV history involving the coronary, cerebrovascular, or peripheral arterial circulation Permitted medications: Patients were allowed to continue on all diabetes medications (except for GLP-1 RA) | Primary: MACE occurred in 338 (7%) albiglutide patients and 428 (9%) placebo patients (HR, 0.78; 95% CI, 0.68 to 0.90; p<0.0001 for NI; p=0.0006 for superiority) Secondary: Fatal and non-fatal MI was lower in the albiglutide group (181 patients, 4%) compared to the placebo group (240 patients, 5%); (HR, 0.75; 95% CI, 0.61 to 0.90; p=0.003) No difference was seen between CV death, fatal or non-fatal stroke (p=0.578 and p=0.113) | Addition of albiglutide once weekly to standard treatment for T2DM significantly reduced the incidence of MACE compared to placebo Note: SGLT2 inhibitor use was more common in the placebo group |
| REWIND14 Gerstein et al 2019 RCT, MC, DB, PC, superiority Dulaglutide 1.5 mg injection weekly vs. placebo Median follow-up=5.4 years | N=9901 patients (mean age, 66.2 years) with T2DM, A1C < 9.5%, BMI < 23 kg/m2, and vascular disease Patients > 55 years had to have MI, artery stenosis, LV hypertrophy, GFR 15 to 60 mL/min/1.73m2, or albuminuria Patients >60 years had to have 2 of 4 risks: tobacco use, dyslipidemia, hypertension, or obesity. Permitted medications: Patients were allowed to continue on all diabetes medications (except for GLP-1 RA and pramlinitide) | Primary: MACE occurred in 594 (12.0%) patients in the dulaglutide group and 663 (13.4%) patients in the placebo group (HR, 0.88; 95% CI, 0.79 to 0.99; p=0.026) Secondary: Fatal and non-fatal stroke occurred in 158 (3.2%) dulaglutide patients vs 208 (4.1%) placebo patients (HR, 0.76; 95% CI, 0.62 to 0.94; p=0.01) Composite microvascular outcome (diabetic retinopathy or renal disease) occurred in 18.4% of dulaglutide vs 20.6% of placebo (HR, 0.87; 95% CI, 0.79 to 0.95; p=0.002) No statistically significant difference in hospitalization for unstable angina, hospitalization for HF, death, or any other component of MACE | Addition of dulaglutide once weekly to standard of care significantly reduced MACE in patients with T2DM compared to placebo Note: Use of SGLT2 inhibitor, metformin, SU, and insulin were more common in the placebo group, and several patients in the placebo group received a GLP-1 RA |
| PIONEER-615 Husain et al 2019 RCT, MC, DB, PC, NI Semaglutide orally once daily (target dose 14 mg) vs. placebo Median follow-up=15.9 months | N=3183 patients (mean age, 66 years) with T2DM aged 50 years or older with CVD or CKD (or CV risk factors if > 60 years of age) Permitted medications: Patients were allowed to continue on all diabetes medications; however, patients receiving GLP-1 RA, DPP-4 inhibitor, or pramlinitide within previous 90 days were excluded | Primary: MACE occurred in 61 (3.8%) semaglutide patients and 76 (4.8%) placebo patients (HR, 0.79; 95% CI, 0.57 to 1.11; p<0.001 for NI; p=0.17 for superiority) Secondary: Death from CV cause occurred in 15 (0.9%) semaglutide patients and 30 (1.9%) placebo patients (HR, 0.49; 95% CI, 0.27 to 0.92) No significant difference seen in other components of MACE | Oral semaglutide added to standard of care does not increase CV events compared to placebo in patients with T2DM Note: SGLT2 inhibitor use was more common in the placebo group |
| SGLT2 Inhibitors | |||
| DECLARE-TIMI 5816 Wiviott et al 2019 RCT, MC, DB, PC, NI Dapagliflozin 10 mg orally daily vs. placebo Median follow-up=4.2 years | N=17,160 patients (mean age, dapagliflozin 63.9 years, placebo 64.0 years) with T2DM with or at risk for CVD, A1C 6.5% to 12.0%, and age > 40 years Permitted medications: Concomitant SGLT2 inhibitors and TZDs not allowed | Primary: MACE occurred in 756 (8.8%) dapagliflozin patients and 803 (9.4%) placebo patients (HR, 0.93; 95% CI, 0.84 to 1.03; p<0.001 for NI; p=0.17 for superiority) Secondary: The composite of CV death or HF hospitalization occurred in 417 (4.9%) dapagliflozin patients and 496 (5.8%) placebo patients (HR, 0.83; 95% CI, 0.73 to 0.95; p=0.005) Hospitalization due to HF was lower in the dapagliflozin group (2.5%) compared to placebo group (3.3%) (HR, 0.73; 95% CI, 0.61 to 0.88) No statistical difference observed in CV death (HR, 0.98; 95% CI, 0.82 to 1.17) | Dapagliflozin daily added to standard of care does not increase CV outcomes compared to placebo in patients with T2DM Note: Patients in both the dapagliflozin group and placebo group received GLP-1 RA (9.5% and 11.4%, respectively), as well as other SGLT2 inhibitors (3.4% and 6.1%, respectively) |
| *MACE= composite of cardiovascular mortality, myocardial infarction, and stroke; all analyses performed in intention to treat population. Abbreviations: ACS=acute coronary syndrome; BMI=body mass index; CAD=coronary artery disease; CI=confidence interval; CKD=chronic kidney disease; CV=cardiovascular; CVD=cardiovascular disease; DB=double-blind; DPP-4=dipeptidyl peptidase-4; GFR=glomerular filtration rate; GLP-1 RA=glucagon-like peptide-1 receptor agonist; HF=heart failure; HR=hazard ratio; LV=left ventricular; MACE=major adverse cardiac events; MC=multicenter; MI=myocardial infarction; NI=non-inferiority; PC=placebo controlled; PVD=peripheral vascular disease; RCT=randomized control trial; SGLT2= sodium-glucose co-transporter-2; SU=sulfonylurea; T2DM=type 2 diabetes mellitus; tx=treatment; TZD=thiazolidinedione; XR=extended release. |
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Meta-analysis/Systematic reviews
Several meta-analyses have been performed examining cardiovascular outcome trials for diabetes medications. A recent meta-analysis of 14 randomized controlled trials (RCTs) showed that SGLT2 inhibitors and GLP-1 agonists decreased MACE and hospitalization for heart failure compared to placebo.17 Additionally, SGLT2 inhibitors showed a greater reduction in cardiovascular death compared to placebo and DPP-4 inhibitors. Finally, it showed that GLP-1 agonists significantly reduced nonfatal stroke compared to placebo. Of note, this meta-analysis included all of the cardiovascular outcome trials with the exception of REWIND (dulaglutide) and PIONEER-6 (oral semaglutide).
Several meta-analyses of GLP-1 agonists have been completed since the publications of REWIND and PIONEER-6.18-20 These meta-analyses all show a significant reduction in MACE, cardiovascular mortality, all-cause mortality, and stroke with the use of GLP-1 agonists compared to placebo. Although every meta-analysis showed a reduction in myocardial infarction and hospitalization due to heart failure, statistical significance was not consistently shown.
One additional meta-analysis compared patients with or without pre-existing cardiovascular disease.21 This study found that use of SGLT2 inhibitors or GLP-1 agonists significantly reduced MACE risk in patients with pre-existing cardiovascular disease, but the same effect was not seen in patients without cardiovascular disease. This meta-analysis included all of the cardiovascular outcome trials for antidiabetic agents, with the exception of REWIND (dulaglutide) and PIONEER-6 (oral semaglutide).
Ongoing trials
A randomized clinical trial, VERTIS-CV, is currently being conducted to examine the cardiovascular safety profile for the SGLT2 inhibitor ertugliflozin.22 Similar to the other cardiovascular trials, this trial will aim to show non-inferiority of ertugliflozin compared to placebo with the primary composite outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. While the trials reviewed in Table 2 included patients with or at risk for cardiovascular disease, VERTIS-CV only includes patients with established cardiovascular disease, which could limit generalizability to all patients.
Conclusion
The 2019 American Diabetes Association (ADA) Standards of Care recommends the use of SGLT2 inhibitors or GLP-1 agonists with proven cardiovascular benefits as part of a treatment regimen for patients with established cardiovascular disease.23 For GLP-1 agonists, the ADA notes that liraglutide has the strongest evidence, followed by semaglutide injection, then exenatide extended release. Empagliflozin is noted in the guidelines as having modestly stronger evidence than canagliflozin, but no other SGLT2 inhibitors are mentioned. The American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) 2019 Diabetes Management algorithm suggests GLP-1 agonists and SGLT2 inhibitors for patients with type 2 diabetes mellitus who are inadequately controlled on metformin, especially in patients with or at risk for cardiovascular disease.24 Furthermore, liraglutide, empagliflozin, and canagliflozin are FDA approved for the indication of reduction in cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease.25
In summary, the cardiovascular outcome trials for DPP-4 inhibitors, GLP-1 agonists, and SGLT2 inhibitors do not show an increase in cardiovascular events compared to placebo when added to standard care in patients with type 2 diabetes mellitus. Several GLP-1 agonists and SGLT2 inhibitors have even shown a statistically significant reduction in cardiovascular events, including dulaglutide, albiglutide, liraglutide, semaglutide injection, canagliflozin, and empagliflozin. Based on these trials and current guideline recommendations, it is reasonable to select an antihyperglycemic agent based on cardiovascular risk of the patient.
References
- Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for industry: diabetes mellitus – evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. 2008. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/diabetes-mellitus-evaluating-cardiovascular-risk-new-antidiabetic-therapies-treat-type-2-diabetes. Accessed October 18, 2019.
- Sinha B, Ghosal S. Meta-analyses of the effects of DPP-4 inhibitors, SGLT2 inhibitors and GLP1 receptor analogues on cardiovascular death, myocardial infarction, stroke and hospitalization for heart failure. Diabetes Res Clin Pract. 2019;150:8-16.
- Scirica S, Bhatt D, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317-1326.
- White W, Cannon C, Heller S, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369(14):1327-1335.
- Green J, Bethel M, Armstrong P, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373(23):2247-2257.
- Pfeffer M, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015; 373(23)2247-2257.
- Marso S, Daniels G, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-322.
- Marso S, Bain S, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834-1844.
- Zinman B, Wanner C, Lachin J, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2017;377(22):2117-2128.
- Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657.
- Rosenstock J, Perkovic V, Johansen OE, et al. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA randomized clinical trial. 2019;321(1):69-79.
- Holman RR, Bethel MA, Mentz RJ, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017;377(13):1228-1239.
- Hernandez AF, Green JB, Janmohamed S, et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (HARMONY Outcomes): a double-blind, randomised placebo-controlled trial. Lancet. 2018;392(10157):1519-1529.
- Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019;394(10193):121-130.
- Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2019;381(9):841-851.
- Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347-357.
- Fei Y, Tsoi MF, Cheung BMY. Cardiovascular outcomes in trials of new antidiabetic drug classes: a network meta-analysis. Cardiovasc Diabetol. 2019;18(1):112.
- Fiugliano D, Maiorino MI, Bellastella G, Longo M, Chiodini P, Esposito K. GLP-1 receptor agonists for prevention of cardiorenal outcomes in type 2 diabetes: An updated meta-analysis including the REWIND and PIONEER-6 trials. Diabetes Obes Metab. 2019;21(11):2576-2580.
- Kristensen SL, Rorth R, Jhund PS, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol. 2019;7(10):776-785.
- Mannucci E, Dicembrini I, Nreu B, Monami M. Glucagon-like peptide-1 receptor agonists and cardiovascular outcomes in patients with and without prior cardiovascular events: an updated meta-analysis and subgroup analysis of randomized controlled trials [published online ahead of print October 8, 2019]. Diabetes Obes Metab. doi: 10.1111/dom.13888.
- Giugliano D, Maiorino MI, Bellastella G, Chiodini P, Esposito K. Glycemic control, preexisting cardiovascular disease, and risk of major cardiovascular events in patients with type 2 diabetes mellitus: systematic review with meta-analysis of cardiovascular outcome trials and intensive glucose control trials. J Am Heart Assoc. 2019;8(12):e012356.
- Cannon CP, McGuire DK, Pratley R, et al. Design and baseline characteristics of the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes trial (VERTIS-CV). Am Heart J. 2018;206:11-23.
- American Diabetes Association. Pharmacologic approaches to glycemic treatment. Diabetes Care. 2019;42(suppl 1):S90-S102.
- Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm. Endocr Pract. 2019; 25(1):69-100.
- Drugs@FDA: FDA Approved Drug Products. U.S. Food and Drug Administration website. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Accessed October 18, 2019.
Prepared by:
Amanda Gerberich, PharmD
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
November 2019
The information presented is current as October 17, 2019. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.