Reduction of major CV events by SGLT2 inhibitors – who will benefit from what?

13th April 2019, Dr Chee L Khoo

SGLT2 inhibitors, as a class of anti-diabetic drugs, have been shown in multiple cardiovascular outcomes trials (EMPA-REQ, DECLARE-TIMI 58, CANVAS) to “reduce cardiovascular events in patients with type 2 diabetes (T2D)”. These are big headlines but as obsessive clinicians, we need to be more specific in the benefits of SGLT2 inhibitors in patients with T2D. We need to know whom will benefit from what. In other words, should we prescribe a SGLT2i for all our patients with T2D? If not, who among them will derive the most benefit from a SGLT2 inhibitors?

The EMPA-REQ trial demonstrated that, in patients with T2D and established cardiovascular disease empagliflozin reduce death from cardiovascular death by 38%, hospitalisation for heart failure by 35% and death from any cause by 32% over a median duration of 2.6 years. There was no benefit with myocardial infarct or strokes. What about patients with T2D that do not have established cardiovascular disease but just have multiple risk cardiovascular risk factors? Oh, they were not included in the EMPA-REQ trial.

We reported on DECLARE-TIMI 58 trial back in November 2018. While the EMPA-REQ trial had 7028 participants, DECLARE-TIMI 58 was a much bigger trial with 17,160 subjects. More importantly, 40% of the subjects had established CV disease (like EMPA-REQ) and 60% only had multiple risk factors (MRF) for atherosclerotic cardiovascular disease (ASCVD). These are similar to the patients we see at our practice in primary care. Patients 40 years or older with T2D whose HbA1c >6.5% but < 12% were randomised to receive either 10mg dapagliflozin or placebo. Subjects were followed up, on average, for 4.2 years.

In DECLARE-TIMI 58, dapagliflozin did not reduce major adverse cardiovascular events (MACE) which is a composite of CV deaths, myocardial infarction and ischaemic stroke compared with placebo. Dapagliflozin reduced composite of CV death and hospitalisation for heart failure rates by 17% although most of the reduction was from hospitalisation for heart failure. Dapagliflozin also reduced the rate of renal events by 24%.

Even when we separate the group with established ASCVD from the group with MRF, dapagliflozin was still not superior to placebo in MACE outcomes irrespective of whether there was established ASCVD or not. Dapagliflozin reduce hospitalisation for heart failure in both groups regardless of presence of established ASCVD. These include primary care patients who only have MRF.

Established ASCVD in these trials is defined as clinically evident ischaemic heart disease, ischaemic cerebrovascular disease, or peripheral artery disease. In the overall DECLARE trial population, 21% of the patients had a prior MI but 50% of the group with established ASCVD had history of MI at baseline. Patients with prior MI tended to be younger, white, male, have dyslipidaemia, shorter duration of diabetes and more likely to be on insulin therapy at baseline. They were also more likely to have a history of heart failure.

Not unexpectedly, patients in the placebo group who had prior MI had higher event rates for both MACE, CV deaths and hospitalisation for heart failure compared with those who did not have prior MI.

Establish ASCVD is such a heterogenous group of CV disease. What if we only look at patients with prior MI. For patients who are on dapagliflozin, those with prior MI had a 16% reduction in MACE compared with the placebo arm. For patients without prior MI, there were no difference in MACE between the dapagliflozin and placebo groups. Even if you compare patients with established ASCVD and patients with MRF, dapagliflozin did not benefit MACE if there were no prior MI.

The reduction in MACE in patients with prior MI were mainly driven by recurrent MI. The rate of MACE tended to be higher the closer patients were to their qualifying MI. The more recent the recent MI was, the greater the benefit is from dapagliflozin.

What does all these mean to our T2D patients in primary care?

Patients with T2D with established ASCVD will benefit from an SGLT2 inhibitor (EMPA-REQ and DECLARE-TIMI 58). The question is not whether we should commenced an SGLT2 inhibitor in patients with established ASCVD but why wouldn’t you.

The DECLARE-TIMI 58 demonstrated that in patients with MRF which are like our patients in primary care, dapagliflozin reduces cardiovascular death and hospitalisation for heart failure rates. As we all know, patients with prior MI are more likely to have more MI. DECLARE-TIMI 58 have shown that this subgroup of patients with established ASCVD benefit the most from dapagliflozin. Further, the earlier to start them on dapagliflozin, the better it is as the more recent the MI is, the greater the benefit is from initiation of dapagliflozin.

Access the abstract here.


Bernard Zinman, M.D., Christoph Wanner, M.D., John M. Lachin et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med 2015; 373:2117-2128 DOI: 10.1056/NEJMoa1504720

S.D. Wiviott, I. Raz, M.P. Bonaca, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2019; 380:347-357
DOI: 10.1056/NEJMoa1812389

Remo H. M. Furtado, Marc P. Bonaca, Itamar Raz, et al. Dapagliflozin and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Prior Myocardial Infarction: A Sub-analysis From DECLARE TIMI-58 Trial.