INTRODUCTION
Improved glucose control improves clinical outcomes in all patients with diabetes, including those affected by type 2 diabetes. The surrogate endpoint for glucose control is hemoglobin A1c (A1c), a measure of average glycemia over the preceding few months. The 2008 guidance by the United States (US) Food and Drug Administration (FDA) requiring the assessment of cardiovascular safety of new drugs for diabetes mellitus was issued because of safety concerns surrounding certain glucose-lowering drugs. Subsequent large-scale cardiovascular outcome trials (CVOTs) demonstrated an absence of excess cardiovascular risk with few exceptions. These trials unexpectedly led to the discovery that two new drug classes for glucose-lowering, the sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1RA), also had significant beneficial effects on cardiovascular disease and kidney disease risk as compared with placebo control, despite minor differences in glycemic control between treatment groups, and in the setting of contemporary background therapy. To understand the regulation of diabetes drugs, this chapter will review the historical context of the 2008 guidance by the US FDA and parallel events in the European Union, the impact of the FDA guidance, the current regulatory environment, and the future.
HISTORY OF REGULATION OF DIABETES DRUGS
Regulatory Standards Prior to 2008
The treatment of diabetes has evolved significantly since the purification of insulin in 1921 leading to awarding of the Nobel Prize in Physiology or Medicine to Frederick G. Banting and John JR MacCleod in 1923. The Diabetes Control and Complications Trial (DCCT), the United Kingdom Prospective Diabetes Study, and subsequent follow-up studies demonstrated conclusively that lowering A1c decreases the risk of diabetes complications in type 1 diabetes (T1D) and type 2 diabetes (T2D), respectively. Therefore the goals for diabetes therapy advanced from survival to alleviating symptoms to prevention of complications.
New antihyperglycemic agents were and are based on demonstrating efficacy for A1c-lowering in different treatment scenarios. Trial populations before 2008 were generally composed of patients with T2D with relatively short duration of diabetes who were not otherwise at high risk for cardiovascular events. Trial durations were short (less than 6 or at most 12 months’ duration). Patients with recent or advanced cardiovascular disease were excluded from trials. The assessment of adverse cardiovascular events was based on adverse event term reporting by investigators. One analysis using a specific custom query of adverse event terms found the numbers of events in these trials to be low, as outlined in Table 11.1 , making evaluation of cardiovascular safety problematic.
Table 11.1
Cardiovascular Outcomes Data for Selected T2D Drugs Before and After the 2008 FDA Requirement That New Antihyperglycemic Drugs Demonstrate Cardiovascular.
| MEDICATION | TRIALS CNDUCTED BEFORE OR AFTER 2008 GUIDANCE | TRIAL PHASE(S) OR TRIAL (YEAR) AND IDENTIFIER | CARDIOVASCULAR SAFETY SIGNALS OR 3-POINT MACE HAZARD RATIO (95%CI) | SUBJECTS, N | MAJOR ADVERSE CARDIOVASCULAR EVENTS, N | OTHER OUTCOMES |
|---|---|---|---|---|---|---|
| DPP4i | ||||||
| Saxagliptin | Before | Phase 3 | Custom MACE SMQ | 4607 | 40 | |
| Saxagliptin | After | SAVOR-TIMI 53 (2013) | 1.00 (0.89–1.12) | 16,492 | 1222 | HHF 1.27 (1.07–1.51) |
| Alogliptin | Before | Phase 3 | Custom MACE SMQ | 4702 | 18 | |
| Alogliptin | After | EXAMINE (2013) | 0.96 (0.80–1.16) | 5380 | 621 | HHF 1.19 (0.90–1.58) |
| Sitagliptin | Before | Phase 3 | Cardiac disorders SAEs | 2342 | 12 | |
| Sitagliptin | After | TECOS (2015) | 0.98 (0.89–1.08) | 14,671 | 1690 | HHF 1.00 (0.83–1.20) |
| GLP1RA | ||||||
| Exenatide | Before | Phase 2 and 3 | Cardiac disorders SAEs | 2371 | 27 | |
| Exenatide | After | EXSCEL (2017) | 0.91 (0.83–1.00) | 14,752 | 1744 | |
| Liraglutide | Before | Phase 3 | Custom MACE SMQ | 6638 | 38 | |
| Liraglutide | After | LEADER (2016) | 0.87 (0.78–0.97) | 9340 | 1302 | |
| SGLT2i | ||||||
| Dapagliflozin | Before | Meta-analysis phase II/III data | 0.73 (0.46–1.16) | 4359 | 48 | |
| Dapagliflozin | After | DECLARE-TIMI 58 (2018) | 0.93 (0.84–1.03) | 17,160 | 1559 | Diabetic ketoacidosis 2.18 (1.10–4.30) |
| Canagliflozin | Before | Meta-analysis phase II/III data | 0.95 (0.71–1.26) | 6769 | 132 | |
| Canagliflozin | After | CANVAS program (2017) | 0.86 (0.75–0.97) | 10,142 | 1011 | Amputation 1.97 (1.41–2.75) |
CI , Confidence interval; CVD , cardiovascular disease; DPP4i , dipeptidyl peptidase-4 inhibitor; GLP1RA , glucagon-like peptide-1 receptor agonist; HHF , hospitalization for heart failure; 3-point MACE , major adverse cardiovascular event: myocardial infarction, stroke, or cardiovascular death; SAE , serious adverse event; SGLT2i , sodium-glucose cotransporter-2 inhibitor; SMQ , standardized medical query (of adverse event terms).
Adapted in part from Wang L, et al. with copyright permission from the American Heart Association.
In addition to the low numbers of cardiovascular adverse events in drug development trials was a growing concern regarding potential cardiovascular risk with certain antihyperglycemic agents. For example, tolbutamide, a first-generation sulfonylurea, was found to result in significantly higher cardiovascular mortality in the University Group Diabetes Program. Muraglitazar, a dual-peroxisome proliferator-activated receptor (PPAR) agonist, was associated with excess incidence of a composite of death, major adverse cardiovascular events (myocardial infarction, stroke, transient ischemic attack) and congestive heart failure. Finally, a meta-analysis of trials of rosiglitazone, a thiazolidinedione, revealed an increased risk of myocardial infarction and an increased odds ratio for cardiovascular death that just missed statistical significance. Although this was later not confirmed by a comprehensive readjudication of the Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemic in Diabetes randomized controlled trial resulting in removal of prescribing restrictions by the FDA, the meta-analysis raised significant concern regarding potential unacceptable cardiovascular risk of a therapy for T2D.
The Action to Control Cardiovascular Risk in Diabetes trial was designed to determine whether normalization of A1c in individuals with T2D would reduce cardiovascular events as compared with standard therapy targeting an A1c of 7% to 7.9%, but the intensive treatment regimen was terminated in 2008, before the scheduled end of the study, because of a finding of increased cardiovascular and all-cause mortality in the intensive therapy arm.
This series of events called into question the adequacy of the regulatory pathway for determining overall clinical benefit of diabetes drugs since it was focused on A1c lowering, and whether development programs were able to detect an unacceptable level of cardiovascular risk in this intended patient population already at higher cardiovascular risk than those without diabetes. The FDA Endocrinologic and Metabolic Drugs Advisory Committee met on July 1 and 2, 2008, to discuss the role of cardiovascular risk assessment during diabetes drug development, and whether a long-term cardiovascular trial should be required of all drugs or biologics for diabetes regardless of the presence or absence of a safety signal during development. The majority of the committee was in favor of recommending more extensive, standardized assessment of cardiovascular risk in the pre- and postmarketing phases, with the goal of ruling out cardiovascular risk, but not necessarily to demonstrate cardiovascular benefit.
In the European Union, new diabetes medications were required to undergo European Medicines Agency (EMA) review starting in 2005, and a guideline for diabetes drug development outlined the criterion for efficacy, which was A1c lowering. Just as the rosiglitazone meta-analysis led to concerns about the cardiovascular safety of antihyperglycemic medications in the United States, similar concerns were identified in Europe.
The 2008 FDA Guidance
In December 2008 the FDA released the Guidance for Industry: Diabetes Mellitus–Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes and focused on “excluding an unacceptable increase in cardiovascular risk for all new therapies to improve glycemic control in patients with T2D regardless of the presence or absence of a signal for cardiovascular risk in the development program.” The safety signals prompting the FDA guidance also led to concerns in Europe, and eventually to new requirements for the assessment of cardiovascular safety of new diabetes medications for the European market. While cardiovascular outcome trials were not required for approval of new antihyperglycemic medications in Europe, they could be mandated prior to approval. Because companies often develop medications for both the American and European markets in tandem, the evidence generated in trials conducted to comply with the 2008 FDA Guidance described below was often used in drug applications to the EMA.
Specific Recommendations From the FDA Guidance Included
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Establishment of an independent cardiovascular endpoints committee for prospective adjudication of cardiovascular mortality, myocardial infarction, and stroke in phase 2 and 3 clinical trials. Other outcomes felt to be acceptable included hospitalization for acute coronary syndrome and urgent revascularization procedures.
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Inclusion of patients at higher risk for cardiovascular events in phase 2 and phase 3 trials to obtain sufficient outcomes to allow for a meaningful estimate of risk.
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Trial designs that allow for meta-analysis, lasting more than 3 to 6 months and at a minimum of 2 years to evaluate longer-term cardiovascular risk.
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Exclusion of 1.8 from the upper bound of the two-sided 95% confidence interval for the estimated risk ratio for major adverse cardiovascular events prior to approval.
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Exclusion of 1.3 from the upper bound of the two-sided 95% confidence interval for the estimated risk ratio for major adverse cardiovascular events after approval, to conclude that there is no unacceptable increase in cardiovascular risk.
In terms of trial design, these recommendations for demonstrating absence of increased risk required that for an event rate of 3% per year, 122 events and 4067 patient-years would be needed to achieve 90% power to exclude a risk ratio of 1.8 for major adverse cardiovascular events. To exclude a risk ratio of 1.3 for major adverse cardiovascular events with 90% power, 611 events and 20,367 patient-years would be needed. In the years following the release of the 2008 Guidance, more than 20 large-scale CVOTs of diabetes drugs have been conducted ( Fig. 11.1 ). Most of these trials reported that newly approved antihyperglycemic therapies were not associated with an increased risk of major adverse cardiovascular events, and a few demonstrated evidence of cardiovascular benefit. As anticipated, the larger, longer trials required to meet this regulatory standard meant a substantial increase in the number of randomized patients enrolled, and major adverse cardiovascular events ascertained during the trials, providing far more robust signals of cardiovascular safety (and in some cases, efficacy), and offering insight into other nonatherosclerotic cardiovascular disease (ASCVD) risks and benefits. Table 11.1 provides a contrast of the numbers of patients and cardiovascular events ascertained for select dipeptidyl peptidase-4 inhibitor (DPP4i), GLP1RA, and SGLT2i registration trials with and without major adverse cardiovascular events as the trial outcome.
Timeline of cardiovascular and kidney outcome trials since the 2008 US Food and Drug Administration guidance.
AleCardio , Aleglitazar to Reduce CV Events in Patients with ACS and Diabetes; CANVAS , Canagliflozin Cardiovascular Assessment Study; CARMELINA , Cardiovascular and Renal Microvascular Outcome Study with Linagliptin; CAROLINA , Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients with Type 2 Diabetes; CREDENCE , Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation; DAPA-CKD , Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease; DAPA-HF , Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; DECLARE-TIMI 58 , Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58; DELIVER , Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure; DPP-4 , dipeptidyl peptidase-4; ELIXA , Evaluation of Lixisenatide in Acute Coronary Syndrome; EMPA-REG OUTCOME , BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; EMPEROR-Preserved , Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction; EMPEROR-Reduced , Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Reduced Ejection Fraction; EXAMINE , Examination of Cardiovascular Outcomes with Alogliptin Versus Standard of Care; EXSCEL , Exenatide Study of Cardiovascular Event Lowering; FLOW , Effect of Semaglutide Versus Placebo on the Progression of Renal Impairment in Subjects with Type 2 Diabetes and Chronic Kidney Disease; FREEDOM-CVO , Study to Evaluate Cardiovascular Outcomes with ITCA 650 in Patients Treated with Standard of Care for Type 2 Diabetes; GLP-1RA , glucagon-like peptide 1 receptor agonist; LEADER , Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; OMNEON , Study to Assess Cardiovascular Outcomes Following Treatment with Omarigliptin (MK-3102) in Participants with Type 2 Diabetes Mellitus; PIONEER-6 , A Trial Investigating the Cardiovascular Safety of Oral Semaglutide in Subjects with Type 2 Diabetes; PPAR , peroxisome proliferator-activated receptor agonist; REWIND , Researching Cardiovascular Events with a Weekly Incretin in Diabetes; SAVOR-TIMI 53 , Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes–Thrombolysis in Myocardial Infarction 53; SCORED , Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk; SGLT2 , sodium-glucose cotransporter-2; SOLOIST-WHF , Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure; SOUL , Semaglutide Cardiovascular Outcomes Trial in Patients with Type 2 Diabetes; SUMMIT , Study of Tirzepatide in Participants with Heart Failure with Preserved Ejection Fraction and Obesity; SURPASS-CVOT , The Effect of Tirzepatide Versus Dulaglutide on Major Adverse Cardiovascular Events in Patients with Type 2 Diabetes; SUSTAIN-6 , Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes; TECOS , Trial Evaluating Cardiovascular Outcomes with Sitagliptin; TOSCA-IT , Thiazolidinediones or Sulfonylureas Cardiovascular Accidents Intervention Trial; and VERTIS-CV , Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants with Vascular Disease.
LESSONS LEARNED IN THE 2008 FDA GUIDANCE FOR INDUSTRY ERA
Since the advent of the 2008 FDA guidance for the pharmaceutical industry on assessing cardiovascular safety for antihyperglycemic agents, more than 20 CVOTs conducted in patients with T2D have been completed, with many more underway as of 2024 ( Fig. 11.1 ). These trials have expanded our understanding of the cardiovascular, kidney, and metabolic effects of various classes of antihyperglycemic agents, many of which might never have come to light without the 2008 FDA guidance. Importantly, however, the evolution of these trials has added greatly to our understanding of how to conduct conclusive, efficient, and impactful trials that assess both cardiovascular safety and other important clinical outcomes. Below, we outline some of the learnings gained in trial design and conduct since the 2008 FDA guidance.
CLASSES OF DRUGS ASSESSED
First, we will briefly review the various drug classes that have been evaluated for cardiovascular safety under the 2008 FDA guidance. A table summarizing key aspects of the study design is presented in Table 11.2 . The initial CVOTs assessed the cardiovascular effects of DPP4i, with each of the tested drugs showing noninferiority with respect to major adverse cardiovascular events (MACE) compared with a placebo or active comparator. Of note, the SAVOR-TIMI 53 trial did show an increased rate of heart failure hospitalization with saxagliptin compared with a placebo, but this effect was not seen with the other DPP4i agents. Seven CVOTs have evaluated the cardiovascular impact of SGLT2i solely among patients with T2D; all of these have not only confirmed cardiovascular safety but have also mostly shown significant benefit in various outcomes, including heart failure hospitalization and progression of kidney disease. Subsequent studies in populations both with and without T2D have shown the benefits of empagliflozin and dapagliflozin in heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, and chronic kidney disease. Sotagliflozin, a combined sodium-glucose cotransporter 1 (SGLT1) and sodium-glucose cotransporter 2 (SGLT2) inhibitor, has demonstrated efficacy in preventing recurrent heart failure and kidney disease progression in patients with T2D. Eight published CVOTs with GLP1RA in patients with T2D have shown cardiovascular safety and a few (liraglutide, semaglutide, dulaglutide) have also demonstrated reduction in risk of MACE and kidney outcomes. CVOTs were terminated due to safety or business concerns for the following agents: thiazolidinediones, aleglitazar, fasiglifam, omarigliptin, and taspoglutide. Ongoing CVOTs are assessing additional drug classes including dual GLP1 receptor/glucose-dependent insulinotropic polypeptide (GIP) agonists (NCT04255433).
Table 11.2
Study Design Aspects of CVOTs in patients with T2D since 2008 FDA Guidance. All trials are placebo-controlled except CAROLINA, which used glimepiride as an active comparator; SURPASS, which uses dulaglutide as an active comparator; and PRECIDENTD, which is a comparative effectiveness study of active GLP-1RA versus active SGLT2i.
| TRIAL | DRUG | N | STUDY POPULATION | PRIMARY OUTCOME | MEDIAN FOLLOW-UP (Y) | HR (95% CI) FOR THE PRIMARY ENDPOINT | UNIQUE ASPECTS |
|---|---|---|---|---|---|---|---|
| EXAMINE | Alogliptin | 5380 | T2D, ACS 15-90 days before randomization | 3p MACE | 1.5 | 0.96 (≤1.16) | Post-ACS population |
| SAVOR-TIMI 53 | Saxagliptin | 16,492 | T2D, HRPP (21%) or ASCVD (79%) | 3p MACE | 2.1 | 1.00 (0.89–1.12) | Only CVOT to show increased HF hospitalization |
| ELIXA | Lixisenatide | 6068 | T2D, ACS 0-180 d before screening | 4p MACE | 2.1 | 1.02 (0.89–1.17) | Post-ACS population |
| EMPA-REG Outcomes | Empagliflozin | 7020 | T2D, ASCVD (99%) | 3p MACE | 3.1 | 0.86 (0.74–0.99) | |
| TECOS | Sitagliptin | 14,671 | T2D, ASCVD (100%) | 4p MACE | 3.0 | 0.98 (0.88-1.09) | |
| LEADER | Liraglutide | 9340 | T2D, ASCVD (including CKD or HF) (81%) or HRPP (19%) | 3p MACE | 3.8 | 0.87 (0.78–0.97) | |
| SUSTAIN-6 | Injectable Semaglutide | 3297 | T2D, ASCVD (including CKD or HF) (83%) or HRPP (17%) | 3p MACE | 2.1 | 0.74 (0.58–0.95) | |
| EXSCEL | Exenatide | 14,752 | T2D, HRPP (27%) or ASCVD (73%) | 3p MACE | 3.2 | 0.91 (0.83–1.00) | |
| CANVAS Program | Canagliflozin | 10,142 | T2D, HRPP (34%) or ASCVD (66%) | 3p MACE | 3.6 | 0.86 (0.75–0.97) | Integrated data from 2 trials |
| HARMONY Outcomes | Albiglutide | 9463 | T2D, ASCVD (100%) | 3p MACE | 1.6 | 0.78 (0.68–0.90) | |
| PIONEER-6 | Oral Semaglutide | 3183 | T2D, [ASCVD or CKD (85%)] or HRPP (15%) | 3p MACE | 1.3 | 0.79 (0.57–1.11) | |
| REWIND | Dulaglutide | 9901 | T2D, HRPP (69%) or ASCVD (31%) | 3p MACE | 5.4 | 0.88 (0.79–0.99) | Largest HRPP population in a CVOT |
| CARMELINA | Linagliptin | 6979 | T2D, [ASCVD and albuminuria] or CKD | 3p-MACE | 2.2 | 1.02 (0.89–1.17) | |
| CAROLINA | Linagliptin | 6033 | T2D, HRPP (58%) or ASCVD (42%) | 3p MACE | 6.3 | 0.98 (0.84–1.14) | Only CVOT with active comparator |
| DECLARE TIMI-58 | Dapagliflozin | 17,160 | T2D, HRPP (59%) or ASCVD (41%) | Co-primaries: 3pMACE; CV death or HF hospitalization | 4.2 | 0.93 (0.84–1.03) | |
| CREDENCE | Canagliflozin | 4401 | T2D, CKD, and albuminuria | ESKD, doubling of serum Cr, or kidney or CV death | 2.6 | 0.80 (0.67–0.95) | Terminated early due to benefit |
| VERTIS-CV | Ertugliflozin | 8246 | T2D, ASCVD (100%) | 3p MACE | 3.5 | 0.97 (0.85–1.11) | |
| SOLOIST-WHF | Sotagliflozin | 1222 | T2D, hospitalized for worsening HF | Total CV deaths, HF hospitalization, and HF urgent visits | 0.75 | 0.67 (0.52–0.85) | SGLT1 and SGLT2 inhibitor; trial terminated early due to loss of funding |
| SCORED | Sotagliflozin | 10,584 | T2D, CKD, and RFs | Total CV deaths, HF hospitalization, and HF urgent visits | 1.3 | 0.74 (0.63–0.88) | SGLT1 and SGLT2 inhibitor; primary outcome changed during the trial; trial terminated early due to loss of funding |
| AMPLITUDE-O | Efpeglenatide | 4076 | T2D, ASCVD (90%) or CKD (32%) or both (22%) | 3p MACE | 1.8 | 0.73 (0.58–0.92) | Randomization was stratified by use of SGLT2i |
| FLOW | Semaglutide | 3533 | T2D, CKD | Major kidney events, kidney or CV death | 3.4 | 0.76 (0.66–0.88) | First trial of GLP-1RA with kidney disease as primary outcome |
| SURPASS CVOT (NCT04255433) | Tirzepatide | 13,299 | T2D, ASCVD and BMI ≥25 kg/m 2 | 3p MACE | ongoing | ongoing | First trial of a dual GIP/GLP1RA. Estimated completion: 6/2025 |
| PRECIDENTD (NCT05390892) | GLP-1RA vs. SGLT2 inhibitor | Goal 6000 | T2D, ASCVD (70%) or high ASCVD risk | Total CV and kidney events or death | Enrolling now | Enrolling now | Only current comparative effectiveness trial of GLP-1RA vs. SGLT2i |
ACS , Acute coronary syndrome; ASCVD, atherosclerotic cardiovascular disease; CI, confidence interval; CKD, chronic kidney disease; Cr, creatinine; CVOT , cardiovascular outcome trial; ESKD, end stage kidney disease; GIP, glucose-dependent insulinotropic polypeptide; GLP-1RA, glucagon-like peptide 1 receptor agonist; HF, heart failure; HR, hazard ratio; HRPP, high risk primary prevention; SGLT, sodium glucose cotransporter; N, number of subjects; RF, risk factor for ASCVD; T2D, type 2 diabetes mellitus; y, years; 3p MACE , 3 point major adverse cardiovascular event (myocardial infarction, stroke, cardiovascular death); 4p MACE , 4 point major adverse cardiovascular event (myocardial infarction, stroke, hospitalization for unstable angina, cardiovascular death).
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