Cardiovascular outcomes trials: a paradigm shift in the current management of type 2 diabetes

Abstract

Cardiovascular disease (CVD) is the leading cause of mortality and morbidity in patients with type 2 diabetes (T2D). Historical concerns about cardiovascular (CV) risks associated with certain glucose-lowering medications gave rise to the introduction of cardiovascular outcomes trials (CVOTs). Initially implemented to help monitor the CV safety of glucose-lowering drugs in patients with T2D, who either had established CVD or were at high risk of CVD, data that emerged from some of these trials started to show benefits. Alongside the anticipated CV safety of many of these agents, evidence for certain sodium-glucose transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have revealed potential cardioprotective effects in patients with T2D who are at high risk of CVD events. Reductions in 3-point major adverse CV events (3P-MACE) and CV death have been noted in some of these CVOTs, with additional benefits including reduced risks of hospitalisation for heart failure, progression of renal disease, and all-cause mortality. These new data are leading to a paradigm shift in the current management of T2D, with international guidelines now prioritising SGLT2 inhibitors and/or GLP-1 RAs in certain patient populations. However, clinicians are faced with a large volume of CVOT data when seeking to use this evidence base to bring opportunities to improve CV, heart failure and renal outcomes, and even reduce mortality, in their patients with T2D. The aim of this review is to provide an in-depth summary of CVOT data-crystallising the key findings, from safety to efficacy-and to offer a practical perspective for physicians. Finally, we discuss the next steps for the post-CVOT era, with ongoing studies that may further transform clinical practice and improve outcomes for people with T2D, heart failure or renal disease.

Keywords: CVOTs; Cardiovascular disease; Cardiovascular outcomes trials; Cardiovascular safety; Chronic kidney disease; GLP-1 RAs; Glucose-lowering drug; Heart failure; SGLT2 inhibitors; Type 2 diabetes.

Fig. 1

A timeline of published diabetes CVOTs. The comparator in all trials was placebo, unless otherwise stated. Primary endpoints for each trial are listed. 3/4P-MACE, 3/4-point major adverse CV event; CV, cardiovascular; DPP-4, dipeptidyl peptidase-4; GLP-1 RA, glucagon-like peptide-1 receptor agonist; HHF, hospitalisation for heart failure; SGLT2, sodium–glucose transporter 2. Source: clinicaltrials.gov. *3P-MACE is a composite of CV death, nonfatal myocardial infarction and nonfatal stroke. 4P-MACE is an expanded composite of 3P-MACE plus either hospitalisation for unstable angina (ELIXA, TECOS and FREEDOM-CVO) or death from undetermined causes (AMPLITUDE-O). ^†TECOS and FREEDOM-CVO included 3P-MACE as a secondary outcome. ^‡CAROLINA was conducted in addition to regulatory requirements, as an active-controlled CVOT complementary to the core placebo-controlled CVOT CARMELINA. ^§Albiglutide is no longer a licensed treatment. ^‖Efpeglenatide is not a currently licensed treatment. ^¶FREEDOM-CVO (exenatide subcutaneous implant; not a currently licensed treatment) was completed in 2016, but the primary outcome (4P-MACE) was reported in 2022

Fig. 2

Exploring possible HF benefits with glucose-lowering drugs (mainly SGLT2 inhibitors). All clinical trials shown are of SLGT2 inhibitors, except for AMPLITUDE-O (efpeglenatide, GLP-1 RA). A consistent pattern of fewer HHF events, with a large effect size, has been seen across the SGLT2 inhibitor class [13, 62, 139]. These reductions were closely mirrored in a dedicated renal outcomes study of canagliflozin in patients with diabetic kidney disease [36], and in dedicated HF outcomes studies of dapagliflozin and empagliflozin in patients with HFrEF with or without diabetes [69, 71] and of empagliflozin in patients with HFpEF with or without diabetes [86] (A). Results from these trials are shown to illustrate the consistency of findings regarding HHF; they should not be directly compared, due to differences in study design, definitions and populations. Note that HHF as a standalone endpoint was not a primary outcome measure in any of the studies shown and has not been reported for the SOLOIST-WHF HF outcomes study, DAPA-CKD renal outcomes or SCORED cardiorenal studies. Diabetes CVOTs were not initially designed to assess any protective effect on HHF (for example, most patients were not diagnosed with HF at baseline (B) [16, 18, 27, 30, 36, 37, 63, 69, 70, 72]). International guidelines for the treatment of patients with T2D now recommend SGLT2 inhibitors to protect patients from HF [38, 40, 42] (C), while real-world studies have confirmed the pattern of fewer HHF events in the more diverse patients seen in routine clinical practice [, , –82, 89, 90] (D). ACC, American College of Cardiology; ADA, American Diabetes Association; CI, confidence interval; CVD, cardiovascular disease; CVOT, cardiovascular outcomes trial; DPP-4, dipeptidyl peptidase-4; EASD, European Association for the Study of Diabetes; ESC, European Society of Cardiology; GLD, glucose lowering drug; GLP-1 RA, glucagon-like peptide-1 receptor agonist; Hb1Ac, haemoglobin A1c; HF, heart failure; HFpEF, HF with preserved ejection fraction; HFrEF, HF with reduced ejection fraction; HHF, hospitalisation for HF; HR, hazard ratio; SGLT2, sodium–glucose transporter 2; T2D, type 2 diabetes; TZD, thiazolidinedione. *p < 0.05. ^†Exploratory analysis. ^‡Efpeglenatide is not a currently licensed treatment

Fig. 2

Exploring possible HF benefits with glucose-lowering drugs (mainly SGLT2 inhibitors). All clinical trials shown are of SLGT2 inhibitors, except for AMPLITUDE-O (efpeglenatide, GLP-1 RA). A consistent pattern of fewer HHF events, with a large effect size, has been seen across the SGLT2 inhibitor class [13, 62, 139]. These reductions were closely mirrored in a dedicated renal outcomes study of canagliflozin in patients with diabetic kidney disease [36], and in dedicated HF outcomes studies of dapagliflozin and empagliflozin in patients with HFrEF with or without diabetes [69, 71] and of empagliflozin in patients with HFpEF with or without diabetes [86] (A). Results from these trials are shown to illustrate the consistency of findings regarding HHF; they should not be directly compared, due to differences in study design, definitions and populations. Note that HHF as a standalone endpoint was not a primary outcome measure in any of the studies shown and has not been reported for the SOLOIST-WHF HF outcomes study, DAPA-CKD renal outcomes or SCORED cardiorenal studies. Diabetes CVOTs were not initially designed to assess any protective effect on HHF (for example, most patients were not diagnosed with HF at baseline (B) [16, 18, 27, 30, 36, 37, 63, 69, 70, 72]). International guidelines for the treatment of patients with T2D now recommend SGLT2 inhibitors to protect patients from HF [38, 40, 42] (C), while real-world studies have confirmed the pattern of fewer HHF events in the more diverse patients seen in routine clinical practice [, , –82, 89, 90] (D). ACC, American College of Cardiology; ADA, American Diabetes Association; CI, confidence interval; CVD, cardiovascular disease; CVOT, cardiovascular outcomes trial; DPP-4, dipeptidyl peptidase-4; EASD, European Association for the Study of Diabetes; ESC, European Society of Cardiology; GLD, glucose lowering drug; GLP-1 RA, glucagon-like peptide-1 receptor agonist; Hb1Ac, haemoglobin A1c; HF, heart failure; HFpEF, HF with preserved ejection fraction; HFrEF, HF with reduced ejection fraction; HHF, hospitalisation for HF; HR, hazard ratio; SGLT2, sodium–glucose transporter 2; T2D, type 2 diabetes; TZD, thiazolidinedione. *p < 0.05. ^†Exploratory analysis. ^‡Efpeglenatide is not a currently licensed treatment

Fig. 3

Exploring possible renal benefits with glucose-lowering drugs. CVOTs typically included renal endpoints among secondary outcomes. Effects on renal outcomes have been generally consistent between studies—showing a reduced risk for progression of renal impairment with SGLT2 inhibitors [28, 36, 37, 92, 95, 140], and a slowed progression of albuminuria with both SGLT2 inhibitors [28, 30, 36, 95] and GLP-1 RAs [31, 96, 97]. In addition to CVOTs, renal benefits of SGLT2 inhibitors have been shown in dedicated renal outcomes trials (CREDENCE and DAPA-CKD) [20, 36, 68, 72] (A). Dulaglutide showed a benefit for some renal impairment outcomes in an exploratory analysis of the REWIND CVOT [97]. Renal outcomes with DPP-4 inhibitors in CVOTs have typically been neutral, although linagliptin showed a modest benefit regarding reduced progression of albuminuria in CARMELINA, a CVOT notable for the prevalence of CKD among the population [14], and SAVOR-TIMI 53 showed a slower progression of albuminuria with saxagliptin compared with placebo [100]. Note that trials differed significantly in the measures used to assess renal function and albuminuria progression, and there was also a large variation in renal risk at baseline (for example, degree of renal impairment [, , , , , , , , , , –142]), and therefore should not be directly compared [14] (B). While we await further results from dedicated renal studies, the consistency of effect size in slowing renal function decline has been sufficiently persuasive to lead to updated guidelines recommending SGLT2 inhibitors for patients with T2D in a CKD setting [–42, 44, 102] (C). ADA, American Diabetes Association; CKD, chronic kidney disease; Cr, creatinine; CVD, cardiovascular disease; CVOT, cardiovascular outcomes trial; EASD, European Association for the Study of Diabetes; EDTA–ERA, European Dialysis and Transplant Association–European Renal Association; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; GLD, glucose lowering drug; GLP-1 RA, glucagon-like peptide-1 receptor agonist; Hb1Ac, haemoglobin A1c; KDIGO, Kidney Disease Improving Global Outcomes; RRT, renal-replacement therapy; RRR, relative risk reduction; SGLT2, sodium–glucose transporter 2; UACR, urinary albumin-to-creatinine ratio. *p < 0.05. ^†Exploratory analysis. ^‡Efpeglenatide is not a currently licensed treatment. ^§In AMPLITUDE-O, the composite renal outcome was incident macroalbuminuria (UACR > 300 mg/g or > 33.9 mg/mmol), ≥ 30% increase in UACR from baseline, sustained ≥ 40% decrease in eGFR for ≥ 30 days, renal-replacement therapy for ≥ 90 days, and sustained eGFR of < 15 mL/min/1.73 m² for ≥ 30 days). ^‖In AMPLITUDE-O, 31.6% of patients had eGFR < 60 mL/min/1.73 m², and proportions of patients with other eGFR levels were not reported; eGFR < 25 mL/min/1.73 m² was an exclusion criterion

Fig. 4

Diabetes CVOTs in the broader context of cardiology trials. PIONEER-6 was a small study (N = 3183) of short duration, designed to rule out excess risk of 3P-MACE, and not powered to demonstrate superiority. Certain diabetes CVOTs have shown cardiorenal protective effects that may arguably be comparable to outcomes with cardiorenal therapies [116], such as the relative risk reduction of CV events compared with statins [, –32, 34, 143, 144] (A), or NNT to prevent CV events compared with statins, aspirin or antihypertensive therapy [27, 116, 145, 146] (B). For example, patients with diabetes and CVD in the LIPID trial had a 19% reduced risk of CHD death or nonfatal MI over 6 years with the statin pravastatin compared with placebo [143]; meta-analyses of secondary prevention in patients with diabetes in multiple statin trials have produced similar results [143, 144, 147]. 3P-MACE, 3-point major adverse CV event; CHD, coronary heart disease; CV, cardiovascular; CVOT, CV outcomes trial; GLD, glucose-lowering drug; GLP-1 RA, glucagon-like peptide-1 receptor agonist; MI, myocardial infarction; NNT, number needed to treat; NR, not reported; RCT, randomised control trial; SGLT2, sodium–glucose transporter 2. *Four RCTs (4S, CARE, Post-CABG and VA-HIT) for CHD death and nonfatal MI, and 3 RCTs (4S, CARE, Post-CABG) for CHD death. ^†Five RCTs (4S, CARE, LIPID, Post-CABG and VA-HIT). ^‡Includes 1 RCT that investigated a non-statin cholesterol-lowering drug. ^‖Three RCTs (4S, CARE, LIPID)

Fig. 5

Completed and ongoing studies of SGLT2 inhibitors (and linagliptin) in renal risk or HF populations. Secondary HF and renal outcome measures in diabetes CVOTs of SGLT2 inhibitors were hypothesis generating, suggesting possible protective events on HF and renal disease. Only one diabetes CVOT (CARMELINA) included a majority of patients with CKD [101] (A); however, this was a study not on an SGLT2 but on a DPP-4 inhibitor, linagliptin, and was designed to demonstrate CV safety in a renal risk population, and not renal protection [101]. Subsequently, several dedicated HF [18, 69, 71, 148, 149] and renal [36, 68, 72, 150] outcome studies have been completed, or are underway, including studies that include patients with HF (B) or CKD (C) without diabetes [63, 68, 69, 71, 86, 148, 149, 151]. Among HF studies, both HFrEF [18, 69, 71] and HFpEF [18, 86, 148, 149] have recently or are being investigated (B), while renal studies include populations with albuminuria and/or with impaired renal function [36, 68, 72, 150] (C). −, without; +, with; +/−, with or without; CKD, chronic kidney disease; CV, cardiovascular; eGFR, estimated glomerular filtration rate; HF, heart failure; HFp/rEF, HF with preserved/reduced ejection fraction; HHF, hospitalisation for HF; LVEF, left ventricular ejection fraction; T1/2D, type 1/2 diabetes; UACR, urinary albumin–creatinine ratio. Source for study completion dates, prespecified endpoints, enrolment numbers and inclusion criteria: clinicaltrials.gov. *SOLOIST-WHF was terminated early

Fig. 6

Summary of benefits elucidated in diabetes CVOTs and evolution of international guidelines in light of emerging results. Diabetes CVOTs have enabled professional societies to identify agents that may provide benefits across the cardiorenal–metabolic axis of diabetes; as such, international guidelines have now been updated to reflect the new evidence base represented by these studies. Note that some outcomes suggested a benefit but were not statistically significant due to the ranking of the statistical hierarchy. Not all outcomes have been reported for all agents. 3P-MACE, 3-point major adverse CV event; ACC, American College of Cardiologists; ADA, American Diabetes Association; CKD, chronic kidney disease; CV, cardiovascular; CVD, CV disease; CVOT, CV outcomes trial; EASD, European Association for the Study of Diabetes; ERA-EDTA, European Renal Association-Dialysis and Transplant Association; ESC, European Society of Cardiology; GLP-1, glucagon like peptide-1; HHF, hospitalisation for heart failure; SGLT2i, sodium–glucose transporter 2 inhibitor; T2D, type 2 diabetes. *Albiglutide, sotagliflozin and efpeglenatide are not approved for T2D