There are currently four SGLT-2 inhibitors licensed for the treatment of diabetes. Canagliflozin, dapagliflozin, empagliflozin and ertugliflozin.
At the 2020 virtual conference of the America Diabetes Association the results of the cardiovascular outcomes study for ertugliflozin were released. This was the final drug in the group to release the results of a cardiovascular study although full publication in a peer reviewed medical journal is still pending.
We already know that these drugs are effective in reducing HbA1c, blood pressure and body weight. We also know that this group of medicines reduce hospital admissions for heart failure and renal function decline. However there is variation in the impact on cardiovascular outcomes. Empagliflozin reduced cardiovascular events and cardiovascular deaths; canagliflozin reduced cardiovascular events, but not deaths; while dapagliflozin was not statistically significant in either of these areas. This latter finding may be explained in part by the much higher proportion of patients without overt signs of cardiovascular disease (60% compared to 0% in the empagliflozin study and 35% and 50% in the canagliflozin studies).
So what does this new study add? It was conducted in just over 8,000 patients and exclusively in secondary prevention patients who were followed up for around 3 years. The study failed to demonstrate a reduction in major cardiovascular events compared to placebo. Nor did it show reductions in cardiovascular deaths or renal-related outcomes. It did demonstrate a 30% reduction in the risk of heart failure related hospital admission.
It was hoped that this study would mirror the results of the empagliflozin study and demonstrate reductions on cardiovascular endpoints and death, thus confirming a group of medicines that deliver cardiovascular benefits to patients with diabetes. Although previous and updated meta-analyses indicate there is a statistically significant reduction in cardiovascular events in secondary prevention patients, there is only a trend in primary prevention patients. And these findings are not replicated for all of these drugs in individual studies.
Based on the current evidence it would seem that this group of drugs do reduce hospital admission for heart failure. Furthermore, as a group, they also seem to reduce cardiovascular endpoints, cardiovascular deaths and renal outcomes. But there is only one drug in the group that has shown individually that it does all of these things in a single trial; and that drug is empagliflozin.
Based on the curent evidence then, it would seem prudent, despite ertugliflozin being less expensive, to use empagliflozin as the agent of choice in patients diabetes who need treatment intensification who:
- also have established cardiovascular disease
- are at risk of hospital admission for heart failure
- are at risk of renal function decline
Patients who are not in one of these groups could be offered an SGLT-2 inhibitor of lowest acquisition cost as an option alongside other classes of drugs that are available to treat hyperglycaemia with discussion of the relative advantages and disadvantages before commencing treatment.
Action: Clinicians should be aware of the emerging evidence for this group of drugs and bases treatment decisions on the best available evidence.
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