14th September 2020, Dr Chee L Khoo
Over the last decade, there has been a push for a less glucocentric management of diabetes. For some, less glucocentric means accepting poorer glycaemic control in our patients with diabetes. It was meant to direct us to not be fixated on managing glucose control without looking at other aspects of the diabetes complications. Of course, cardiovascular complications are what is killing our patients with diabetes. To me “less gluco-centric” also remind me to look at the other effects of glucose lowering agents. This week we look at the another “landmark” trial published in the NEJM just over the last 7 days.
We reviewed the major cardiovascular outcome trials (CVOTs) over the last couple of years. In particular we looked at CVOTs involving the SGLT2 inhibitors (EMPA-REQ (1), DECLARE-TIMI 58 (2), CANVAS (3)) in the past and we are convinced that SGLT2 inhibitors significantly reduced composite major adverse cardiovascular events (MACE) in different population of patients with T2D. They were originally safety trials but ended up being beneficial (i.e. superior to placebo) in other ways.
Unfortunately, because they were originally designed to prove that these agents were cardiac safe, the primary outcomes were primarily composite outcomes of non-fatal myocardial infarcts, non-fatal strokes and cardiac mortality. Hospitalisation for heart failure (HHF) were secondary outcomes in both EMPA-REQ and CANVAS but was a co-primary in DECLARE-TIMI 58. Remember, these were safety trials and not heart failure trials. In fact, only 10-12% of the subjects in each of those trials had heart failure at baseline.
We finally had a dedicated heart failure trial when DAPA-HF reported in November 2019. We discussed the findings in December 2019. The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial showed a reduction in the risk of cardiovascular death or hospitalisation for heart failure with dapagliflozin in patients with heart failure with reduce ejection fraction (HFrEF) regardless of the presence or absence of diabetes. We foreshadowed at the time that EMPEROR-Reduced was due to complete this year and report shortly after that. Well, those results came out last week.
In the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction (EMPEROR-Reduced), empagliflozin 10mg was evaluated in a population of patients with chronic heart failure and a reduced ejection fraction (with or without diabetes) (5). Adults who had chronic heart failure (functional class II, III, or IV) with a left ventricular ejection fraction of 40% or less were recruited for the trial. All the patients were receiving appropriate treatments for heart failure.
The primary outcome was a composite of cardiovascular death or hospitalization for heart failure, analysed as the time to the first event. The first secondary outcome was the occurrence of all hospitalisations for heart failure, including first and recurrent events. The second secondary outcome was the rate of the decline in the estimated GFR (eGFR) during double-blind treatment.
Of the 3730 patients recruited, only half had a history of diabetes, 73% had a left ventricular ejection fraction of 30% or less, 79% had a NT-proBNP level of at least 1000 pg/ml, 48% had an estimated GFR of less than 60 ml per minute/1.73 m2 and nearly 20% were receiving an angiotensin receptor–neprilysin inhibitor.
The combined risk of cardiovascular death or hospitalization for heart failure was 25% lower among the patients who received empagliflozin than among those who received placebo, a difference that was primarily related to a 31% lower risk of HHF. The effect of empagliflozin on the primary outcome was consistent across prespecified subgroups, including patients with diabetes and those without diabetes at baseline. The rate of the decline in the eGFR over the duration of the double-blind treatment period was slower in the empagliflozin group than in the placebo group. Composite renal outcomes (chronic dialysis or renal transplantation or a profound, sustained reduction in the eGFR) was reduced in the empagliflozin group by 50%.
In the old days (actually, not that long ago but it is the old days indeed), if we have not achieved glycaemic target with lifestyle and metformin, we look to see which agent is the most potent to help us get our patients with type 2 diabetes (T2D) to glycaemic target. When you think about it, apart from insulin injections, pretty much most of the oral agents gives us about 0.8-1.5% reduction in HbA1c. The higher the starting HbA1c , generally, the bigger the reduction irrespective of which agent you choose. The average reduction is about 1%. When we are instructed to be less glucocentric, it is meant to mean that we should not just look at how potent the next agent is but what other benefits it comes with.
If patients with T2D also have multiple cardiac risk factors or established atherosclerotic cardiovascular disease (ASCVD) or diabetic renal disease, then we should consider either an SGLT2 inhibitor or a GLP1 agonist after metformin. Both have proven benefits beyond glucose lowering.
- Zinman B, Lachin JM, Inzucchi SE. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2016;374(11):1094. doi:10.1056/NEJMc1600827
- Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2019;380(4):347-357. doi:10.1056/NEJMoa1812389
- Neal B, Perkovic V, Matthews DR. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017;377(21):2099. doi:10.1056/NEJMc1712572
- McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Bělohlávek J, Böhm M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukát A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CEA, Merkely B, Nicolau JC, O’Meara E, Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O, Sjöstrand M, Langkilde AM. DAPA-HF Trial Committees and Investigators Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381:1995–2008.
- Packer M, Anker SD, Butler J, et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure
[published online ahead of print, 2020 Aug 29]
. N Engl J Med. 2020;10.1056/NEJMoa2022190. doi:10.1056/NEJMoa2022190