Cardiovascular outcome trials for glucose-lowering drugs
Patients with diabetes have a higher incidence of cardiovascular (CV) diseases, with still striking CV mortality despite continuous advancements targeting multiple risk factors (1). Initial evidence from UKPDS cohort indicated that an early and intensive glycaemic control lowers the incidence of late CV complications (2). However, the successive analysis suggested that “the means” through which glycaemic target is reached is of great importance. Indeed, data from the same cohort showed that metformin was superior to sulphonylureas in terms of long-term CV protection, at least in obese subjects (3). On the other side, subsequently introduced drugs, i.e. thiazolidinediones, have been accompanied by CV safety concerns despite a tangible glucose-lowering effect (4). This and other considerations prompted the introduction (in 2008) of FDA/EMA-requested cardiovascular outcome trials (CVOTs) to demonstrate non-inferiority vs placebo in terms of CV safety for newly introduced glucose-lowering drugs (GLD)s. In CVOTs, the primary outcome is usually a combination of CV endpoints, including CV mortality, non-fatal myocardial infarction (MI), non-fatal stroke, and, in some cases, hospitalisation rate for unstable angina pectoris (3 or 4-point major adverse CV event, 3/4P-MACE). Secondary outcomes often include hospitalisation for heart failure (HF) but also renal endpoints. Since then, a number of trials have been conducted, mainly encompassing four classes of drugs: 1- dipeptidyl-peptidase-4 inhibitors (DPP-4i), 2- glucagon-like peptide-1 receptor agonists (GLP-1 RA), 3- sodium/glucose co-transporter-2 inhibitors (SGLT-2i), and 4- insulins (5).
Evidence emerged from CVOTs
Results have been variable and are subjects of intense research (5). However, it is increasingly evident that: 1-DPP-4i are accompanied by a neutral effect on short-term CV outcomes; 2- selected GLP-1 RA have a proved CV benefit, especially in terms of reduced incidence of cardiovascular events; 3- Empagliflozin and Canagliflozin have shown a protection against MACE, while both plus Dapagliflozin demonstrated a tangible effect also on heart failure and renal endpoints (5-7). Excluding the CANVAS and the DECLARE-TIMI trial, all the patients enrolled in CVOTs had diabetes and prevalent CV diseases or were at a very high CV risk (5). This implies that the results may not be generalizable to the whole population of people with diabetes. On the other side, cardiologists and diabetologists clearly handle new powerful instruments to manage this specific population of patients.
It is unlikely that the reduction in glycated haemoglobin observed in CVOTs account for the beneficial CV and renal effect of GLP-1 RA and SGLT-1i. Similar or indeed more pronounced HbA1c reductions have been observed in trials of glucose-lowering drugs without cardiovascular benefits. The new GLD are accompanied by a plethora of effects, e.g. blood-pressure lowering activity, metabolic and hemodynamic adjustments, hormonal alterations, anti-oxidant and anti-inflammatory effects. Which and how many (if any) of these mechanisms underlie cardioprotection is a matter of basic and clinical investigations (8,9).
ADA/EASD treatment algorithm
New information derived from CVOTs has been integrated into the latest expert consensus document for T2DM management released by ADA and EASD (10). Differently to previous indications, more flexibility and a personalized approach are advised instead of fixed glycaemic goals. Lifestyle interventions and metformin are still the first-line approaches to manage hyperglycaemia. However, when these measures are insufficient, the add-on therapies should be personalized according to patient characteristics and comorbidities. Specifically: 1- In case of a patients with atherosclerotic CVD, a GLP-1 RA or an SGLT-2i (when eGFR is acceptable) with proven CV benefit are recommended; 2- in patients with HF or chronic kidney disease (CKD), SGLT-2i with evidence of reducing HF and/or CKD progression are recommended (with proper adjustments according to eGFR cut-offs) (11); 3- in patients with any of these conditions: risk of hypoglycaemia, body weight, side effects, and cost should be considered to tailor the appropriate therapy (10). Thiazolidinediones increase insulin sensitivity, which may lead to increased sodium and water retention. In clinical trials, they have been associated with an increased risk for HF. These drugs are contraindicated in patients with HF. An increased risk for HF hospitalization was shown for Saxagliptin and a non significant trend for Alogliptin. Such an effect was not found for Sitagliptin and Linagliptin that remains the only dipeptidyl peptidase 4 inhibitor (DPP4-i) drugs to be used in diabetics with HF (12)
What if a cardiac patient develops diabetes?
The beneficial effect of GLP-1 RA and SGLT-2i on CV outcomes is emphasized in the most recent guidelines. However, metformin represents still the first approach for newly diagnosed patients. Usually, T2DM precedes the development of CVDs in unhealthy pathological trajectories (1). However, also the opposite can happen. In the case that a patient with pre-existing CVD develops T2DM, which should be the first-line drug? Metformin is being safely used for decades in almost any kind of patient with diabetes, as suggested by ever-increasing observational data (13). On the other side and differently from GLP-1 RA and SGLT-2i, metformin did not undergo a randomized, placebo-controlled, clinical trial to show non-inferiority in terms of CV outcomes in populations with both T2DM and CVDs (for obvious historical reasons). While the long-term effects of recently-introduced GLDs will emerge after years of observation, a head-to-head comparison of new GLDs vs metformin would help to clarify which drug is more appropriate as first-line approach in newly diagnosed diabetic patients with previous CV events.
The guidelines released in 2019 by the American Heart Association (AHA) and the American College of Cardiology (ACC) suggests as a key take-home message that “for adults with T2DM and additional ASCVD risk factors who require glucose-lowering therapy despite initial lifestyle modifications and metformin, it may be reasonable to initiate a SGLT-2i or a GLP-1RA to reduce CVD risk” (COR IIb, LOE B-R) (14).
Take home message
Recent pharmacological research has provided new medications to manage hyperglycemia in T2DM patients. 10-years of CVOTs have disclosed a plethora of findings suggesting that GLP-1 RA and SGLT-2 inhibitors and, to a certain extent, pioglitazone, are accompanied by beneficial effects against a wide range of CV outcomes. Both diabetologists and cardiologists should take advantage of these new tools to tailor personalized therapies for their patients. Patients with atherosclerotic CVD should be prescribed a GLP-1 RA or an SGLT-2 inhibitor, to intensify glucose-lowering regimen and reduce CV risk, while T2DM patients are very likely going to benefit from the use of an SGLT2i to prevent HHF and CKD (8-9, 15).
The best approach to take care of patients is staying up to date, in order to avoid clinical inertia (16) and to provide always the best option to increase the chances of preventing or delaying the harmful effects of T2DM on CV system (17).
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology
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