Influence of Empagliflozin on Myocardial Flow Reserve in Patients With Type 2 Diabetes Mellitus

Sodium-glucose cotransporter 2 inhibitors lower the risk of hospitalization in heart failure and cardiovascular death…

 The SIMPLE trial examined the effects of empagliflozin on myocardial flow reserve, showing microvascular perfusion in individuals with type 2 diabetes with high CVD risk. The SIMPLE trial is a single-center, double-blind, randomized clinical trial evaluating the influence of empagliflozin on myocardial flow in high-risk patients with type 2 diabetes. The study involved 91 participants with known CVD or high CVD risk between April 2017 and May 2020. Participants diagnosed with type 2 diabetes at least three months before enrollment on regular glucose-lowering medication were eligible for the study. The study required a hemoglobin A1c between 6.5% and 10% in participants on glucose-lowering treatment and between 6.5% and 9% on treatment naïve participants. Study participation also required confirmed CVD determined as a history of myocardial infarction, coronary stenosis, unstable angina, ischemic stroke, peripheral artery disease, or present CVD risk factor explained as albuminuria or NT proBNP. 

Qualified participants were randomly given either empagliflozin 25 mg once daily or a placebo for the duration of 13 weeks. Central pharmacy performed randomization utilizing block randomization with a block size of ten. Participants of the study were blinded by the treatment group for the entirety of the study. Cardiac RB-PET/CT calculated myocardial perfusion. Siemens Biograph mCT/PET 128 slice scanner carried out all measurements. Cedars Sinai QGS + QPS software completed myocardial blood perfusion quantification. Myocardial flow reserve depends on cardiac work. The change between the overall perfusion deficit at rest and under stress is linked to inducible ischemia in the myocardium. The first endpoint lies the between-group myocardial flow shift reserve from baseline at week 13. The second endpoint includes the difference in resting rate-pressure product adapted myocardial flow reserve, rest flow, stress flow, and amount of reversible ischemia.

While analyzing the per-protocol calculation, the study used a constrained linear mixed model. The analysis of the difference in myocardial reserve flow was done by using Fisher exact test. Ninety patients were given at least one dose of the study drug, forty-five patients were given empagliflozin, and forty-five patients were given a placebo. Treatment with empagliflozin reduced HbA1c BY 0.76% compared with placebo after two months. About half of the participants experienced a history of coronary disease, significant stenosis of a coronary artery, or coronary artery graft bypass. Eight percent of participants had episodes of chest pain. Sixteen percent of participants were prescribed long or short-term nitrates. Ten participants experienced reversible ischemia. Four percent of participants did not receive glucose-lowering medications.

The participants of the study overall tolerated the treatment very well. The main adverse event was polyuria. The study yielded five serious adverse events in total, three in the placebo group and two in the empagliflozin group. Only one participant experienced admission for severe hypotension linked to the treatment. None of the participants had a case of diabetic ketoacidosis. The study medication was an add-on to best practice guidelines and was not in place of glucose-lowering medications. Scheduled phone calls and clinic visits helped examine medication adherence. Supporting endpoints and the small number of participants created limitations in the study.

Furthermore, the study was designed to detect a treatment influence on myocardial flow reserve at 0.8. According to the findings, the increase in myocardial flow reserve is likely less than 0.8, and a greater cohort would be necessary to observe a hypothetical, more modest result. Ultimately, the treatment with empagliflozin for 13 weeks did not ameliorate myocardial flow reserve in patients with type 2 diabetes and high cardiovascular disease risk. The current study did not support that short-term improvement in myocardial flow reserve describes the reduction in cardiovascular events examined in the outcome trials.

Practice pearls

• Sodium-glucose cotransporter 2 inhibitors lower the risk of hospitalization in heart failure and cardiovascular death.
• The SIMPLE trial examined the effects of empagliflozin on myocardial flow reserve, showing microvascular perfusion in individuals with type 2 diabetes with high CVD risk.
• The treatment with empagliflozin did not ameliorate myocardial flow reserve in patients with type 2 diabetes and high cardiovascular disease risk.

References

Jürgens, Mikkel et al. “Effects of Empagliflozin on Myocardial Flow Reserve in Patients with Type 2 Diabetes Mellitus: The SIMPLE Trial.” Journal of the American Heart Association vol. 10,15. 3 Aug 2021. https://pubmed.ncbi.nlm.nih.gov/34278803/

Tripolt, Norbert J et al. “Impact of EMpagliflozin on cardiac function and biomarkers of heart failure in patients with acute MYocardial infarction-The EMMY trial.” American heart journal vol. 221. March 2020. https://pubmed.ncbi.nlm.nih.gov/31901799/

Emmanuella Louissaint, PharmD candidate, LECOM College of Pharmacy