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New antidiabetic drugs and cardiovascular outcomes

Until very recently antidiabetic drugs were prescribed just in order to regulate glucose levels and delay diabetes complications but with no direct benefit and with possible harms. The new antidiabetic drug generations provide also direct cardiovascular benefits with short-term reduction of CV mortality. Clinical cardiologists should know which drug class suits which patient.



Rosiglitazone in a metanalysis in 2007, years after its launch was related to adverse cardiac events in diabetic patients. The drug was taken off the market due to safety issues from FDA and EMA and reintroduced years later in the US after further studies and metanalysis did not confirm increased risk. After this episode, FDA asked all new antidiabetic drugs that plan to go on the market to perform a safety trial confirming their cardiovascular neutrality.

Metformin has potentially a good CV profile although there is a lack of safety and efficacy data for this drug after UKPDS and no new studies are performed. DPP4s (with the exemption of saxagliptin) have confirmed their neutral profile and were introduced as a safe CV category. Four of their trials confirmed statistical non-inferiority vs. placebo (which included alternative glucose-lowering medication to achieve glycaemic equipoise) for the primary composite CV outcome examined. However, none of the DPP4 inhibitors were associated with significant CV benefits in their trial populations

The big positive surprise came with the introduction of SGLT2 inhibitors and GLP-1 agonists. This new era of antidiabetic drugs showed for the first time not only CV safety but also superiority on cardiovascular efficacy versus placebo.

Several  CVOTs have examined the effects of GLP1-RAs and SGLT2 inhibitors on CV events in patients with DM and high CV. 

In the EXSCEL study of a DM population in whom 73% had experienced a previous CV event, exenatide 2 mg once weekly showed non-inferiority vs. placebo and a numerical, but non-significant, 14% reduction of the primary three-point MACE.

In the LEADER trial, diabetic patients at high CV risk (81% with previous CVD) were randomized to liraglutide vs. placebo as add-on to other glucose-lowering drugs. All patients had a long history of DM and CVRFs that were well controlled. After a follow-up of 3.1 years, liraglutide significantly reduced the composite three-point primary endpoint by 13%. In addition, liraglutide significantly reduced CV death and total death by 22 and 15%, respectively, and produced a non-significant numerical reduction in non-fatal MI and non-fatal stroke.

SUSTAIN-6 showed in diabetic patients with high CV risk that after 2.1 years, semaglutide significantly reduced the three-point MACE by 26%, an effect driven mainly by a 39% significant reduction of non-fatal stroke. 

The REWIND trial assessed the effect of once-weekly subcutaneous dulaglutide vs. placebo on three-point MACE in diabetics who had either a previous CV event or CVRFs. During a median follow-up of 5.4 years, the primary composite outcome occurred in  12.0% vs 13.4% in the placebo group (P=0.026).

In EMPA-REG OUTCOME,  patients with DM of long duration and CVD were randomized to empagliflozin or placebo for a mean of 3.1 years.  Empagliflozin significantly reduced the risk of the three-point MACE by 14% compared with placebo. This reduction was driven mainly by a highly significant 38% reduction in CV death (P < 0.0001), with separation of the empagliflozin and placebo arms evident as early as 2 months into the trial. Empagliflozin was associated with a 35% reduction in hospitalization for HF (P < 0.002), with separation of the empagliflozin and placebo groups evident almost immediately after treatment initiation, suggesting a very early effect on HF risk. Empagliflozin also reduced overall mortality by 32% (P < 0.0001), translating into a NNt of 39 over 3 years to prevent one death. The CV benefit was gained by those with and without HF at baseline.

In the CANVAS Program patients with DM at high CV risk were randomized to canagliflozin vs. placebo. After 3.1 years, canagliflozin significantly reduced a composite three-point MACE by 14% but did not significantly alter CV death or overall death.309 Similar to the findings in EMPA-REG OUTCOME, canaglifozin significantly reduced HF hospitalization.

DECLARE–TIMI 58 examined the effect of dapagliflozin vs. placebo in patients with DM and CVD, or multiple CVRFs. After a median follow-up of 4.2 years, dapagliflozin met the pre-specified criterion for non-inferiority for the composite three-point MACE compared with placebo. In the two primary efficacy analyses, dapaglifozin did not significantly reduce MACE, but resulted in a lower rate of the combined endpoint of CV death or HF hospitalization (4.9 vs. 5.8%; P=0.005). This was driven by a lower rate of HF hospitalizations, but no between-group difference in CV death. The benefit of dapagliflozin with respect to CV death or HF hospitalization was similar in the subgroup with CVD, as well as those with multiple risk factors only.

The DAPA-HF trial presented at the latest ESC congress showed for the first time that dapagliflozin is effective in reducing a composite of worsening heart failure or cardiovascular death ( 16,3% vs 21, 2%) in patients with heart failure with findings similar in diabetics and non-diabetics.

Although we don't know yet the exact mechanism of action of the two later categories we do know that we have new successful drugs for the treatment of DM with CV benefit and as dapagliflozin showed new drugs for the treatment of Heart Failure even in non-diabetics.

About the Author

Dimitrios Richter, MD, FESC

Head of Cardiac Department
Euroclinic Hospital, Athens, Greece
Chairperson of the ESC Council for Cardiology Practice 2018-2020