People with diabetes have a higher than average risk of developing cardiovascular disease.1,2 The mechanisms underlying the relationship between diabetes and cardiovascular disease are not fully understood, but recent studies have explored this rapidly evolving research field.3 As a result, there is a clear need for cardiologists to improve and increase their involvement in the therapeutic management of diabetes. In this volume of European Cardiology Review, Ahmad et al. provide an update on the most recent pharmacological advances and mechanisms linking diabetes and cardiovascular disease, with a focus on clinical practice.4
A number of therapies in cardiology improve surrogate measures of disease, but do not necessarily translate to better patient outcomes.5 It was previously assumed that strict glucose control, reflected by improved HbA1c, would lead not only to reductions in microvascular outcomes but would also reduce cardiovascular complications.6 After some trials with hypoglycaemic drugs demonstrated an increase in major adverse cardiovascular events (MACE) and, in particular, heart failure-related outcomes, some of the main international regulatory agencies required that all antidiabetic therapies demonstrate cardiovascular safety when compared with placebo.7–9 Since that decision, a long list of compounds have been designed to evaluate not only the antidiabetic/metabolic effects, but also cardiovascular benefits and safety of diabetes drugs. The results of these trials showed surprising and important positive impacts in MACE, particularly in heart failure outcomes. Two groups of drugs are changing the management of diabetes and cardiovascular disease: glucagon-like peptide-1 (GLP-1) receptor agonists, also known as incretin mimetics, and sodium–glucose transporter 2 (SGLT2) inhibitors, also known as gliflozins.9 This editorial is focused on these two groups of drugs.
Glucagon-like Peptide-1 Receptor Agonists
GLP-1 receptor agonists differ in their structure and duration of action and have been studied in trials of varying sizes and with different patient populations; inconsistent effects on cardiovascular outcomes have been reported by Ahmad et al. after they analysed seven cardiovascular outcome studies evaluating GLP-1 receptor agonists, some demonstrating benefits in cardiovascular outcomes.4 These studies include large and well-known trials, such as LEADER (with liraglutide), SUSTAIN-6 (with semaglutide), EXSCEL (with exenatide), ELIXA (with lixisenatide) and HARMONY (with albiglutide).10–14 More than 50,000 diabetic patients were randomised in those trials, and they generally demonstrated consistent results of reduced incidence of MACE.15
In a meta-analysis by Kristensen et al., GLP-1 receptor agonist treatment reduced MACE by 12% (HR 0.88, 95% CI [0.82–0.94], p<0.0001), with no evidence of treatment heterogeneity across the subgroups examined.16 The results also showed an improvement in renal outcomes. They observed a reduction in the composite of new-onset macroalbuminuria, estimated glomerular filtration rate, progression to end-stage kidney disease and death attributable to kidney causes by 17%.
It has been demonstrated that these drugs reduce cardiovascular outcomes in people with diabetes, and there are ongoing trials investigating if the same benefits occur in people without diabetes.
SGLT2 Inhibitors: The New Star
Recent trials with SGLT2 inhibitors, have shown that this group of drugs is emerging as a new and viable option for preventing and treating cardiac and renal dysfunction.17 SGLT-2 inhibitors were the first glucose-lowering drugs to show a reduction in MACE in people with type 2 diabetes and at high cardiovascular risk, according to the results of the EMPA-REG OUTCOME trial.18,19 Another trial, CANVAS, showed similar results for people with diabetes.20 Both trials demonstrated a significant decrease in the rate of heart failure-associated hospitalisation and mortality. Other large studies, such as DECLARE–TIMI 58 (with dapaglifozine), were included in a meta-analysis by Zelniker et al. that demonstrated consistency of the results.21,22 More recently, the VERTIS trial of ertruglifozine demonstrated some similar findings.23 In all cases, the study populations only included subjects with diabetes and there was an observed decrease in MACE in patients receiving SGLT2 inhibitors, albeit with some differences. Registries of people with diabetes patients have also demonstrated that those treated with SGLT2 inhibitors show a lower morbidity and mortality compared with those treated with other antidiabetic drugs, indicating that the results of clinical trials are similar to those observed in real world clinical practice.24,25
SGLT2 inhibitors were initially thought to provide the most benefit to patients with heart failure and then clinical trials then began to test them in the general population. The first of these studies was DAPA-HF, which randomised 4,744 patients with left ventricular ejection fraction ≤40% and symptomatic heart failure to dapagliflozin versus placebo.26 The primary outcome was a composite of worsening heart failure (hospitalisation or an urgent hospital visit resulting in IV therapy for heart failure) or cardiovascular death. This endpoint was significantly less in the dapagliflozin arm (HR: 0.74, 95% CI [0.65–0.85]; p<0.001). Importantly, the benefits were almost identical in patients with and without diabetes. It was the first evidence of a benefit of a SGLT2 inhibitor in heart failure, and Ahmad et al. anticipate that SGLT-2 inhibitors will play a major role in the treatment of heart failure in the near future.4 Another study of DAPA-HF indicated that the beneficial effect of SGLT2 inhibitors was similar in subgroups of all ages, including elderly patients, in whom the incidence of heart failure is higher.27
The EMPEROR-Reduced study showed that patients in the empagliflozin group were found to have a lower risk of cardiovascular death or heart-related hospitalisation compared with the control group, regardless of whether or not they had diabetes.28 The evidence of this trial added to the previous results of DAPA-HF, and was examined in a recent meta-analysis by Zannad et al.29 They found that the effects of both dapagliflozin and empagliflozin were consistent in lowering hospitalisation for heart failure with reduced ejection fraction patients. They suggested that these agents also improve renal outcomes and reduce all-cause and cardiovascular death. This study attracted media and medical attention, with many agreeing that the results of DAPA-HF and EMPEROR-Reduced substantially strengthened the rationale for the use of SGLT2 inhibitors in patients with heart failure with reduced ejection fraction.30
There are currently two ongoing trials with gliflozins for heart failure with preserved ejection fraction: EMPEROR-Preserved and DELIVER. The results of both trials are expected to be presented in late 2021/early 2022.
Ahmad et al.’s review includes an in-depth analysis of the adverse effects of GLP-1 and SGLT2 drugs.4 GLP-1 receptor agonists are relatively safe, and most common side-effects are transient nausea and vomiting, especially when initiating therapy or up-titrating the dose. For SGLT2 inhibitors, an increase in the risk of genital mycotic infections has been reported, and more rarely, haemoconcentration.31
New drugs originally developed for the treatment of diabetes are showing consistent benefits in cardiovascular disease, including MACE and heart failure with reduced ejection fraction. Currently, the main evidence comes from trials using SGLT2 inhibitors in patients with and without diabetes and those investigating GLP-1s in people with diabetes. Ongoing trials will confirm if more GLP-1 and SGLT2 drugs have the same benefits, and if the results are similar for patients with heart failure with preserved ejection fraction. These findings will be important for cardiologists and diabetologists.