Cardiovascular disease is the most common cause of death in people living with type 2 diabetes (T2D). It is true that patient prognoses have improved with the use of metformin and by addressing cardiovascular risk factors. But the new oral antidiabetic drugs, SGLT2 (sodium glucose cotransporter-2) inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1Ra), offer fresh therapeutic approaches. Several recent controlled studies and meta-analyses have demonstrated the possibility of a cardioprotective and nephroprotective effect, even in patients without diabetes, especially with regard to SGLT2 inhibitors.
A Cohort of More Than 2 Million Patients With T2D
What about in the real word, far away from the ideal conditions of randomized trials? Could combining SGLT2 inhibitors with GLP-1R agonists be even more effective?
These are the questions answered by a large retrospective cohort study in which 2.2 million patients with T2D receiving insulin were initially enrolled and monitored at 85 specialist centers spread throughout three countries (Denmark, the United Kingdom, and the United States).
Three groups were formed from this cohort according to whether they received monotherapy or combination treatments: SGLT2i (n = 143,600), GLP-1Ra (n = 186,841), and SGLT2i + GLP-1Ra (n = 108,5040). A control group received none of these treatments.
Propensity score matching took into account the following relevant variables: age, sex, ischemic heart disease, hypertension, chronic kidney disease, heart failure, and glycated hemoglobin. The data was analyzed using the Cox’s proportional hazards model, with follow-up at 5 years.
Real-World Benefits — Even Better When Combined
The inter-group comparison suggests that oral antidiabetic agents are effective when taking into account three major events:
All-cause mortality: SGLT2i (hazard ratio HR 0.49; CI 95% 0.48-0.50); GLP-1Ra (HR 0.47, CI 95% 0.46-0.48); SGLT2i + GLP-1Ra (HR 0.25, CI 95% 0.24-0.26).
Admissions rate: respectively HR: 0.73 (0.72-0.74); 0.69 (0.68-0.69); 0.60 (0.59-0.61).
Myocardial infarction rate: respectively HR: 0.75 (0.72-0.78); 0.70 (0.68-0.73); 0.63 (0.60-0.66).
A complementary sub-analysis also revealed a more significant reduction in all-cause mortality in the event of exposure to the combination of two antidiabetic drugs vs SGLT2i alone (HR 0.53 [0.50-0.55]) and GLP-1Ra as monotherapy (HR 0.56 [0.54-0.59]).
This real-world retrospective cohort study involves a large sample size: more than 400,000 patients with T2D treated with new oral antidiabetic drugs and as many control patients. It suggests that SGLT2 inhibitors and GLP-1R agonists have a significant effect on overall mortality, as well as on the risk of myocardial infarction and the admissions rate. Yes, it is retrospective, but its findings are in line with those from the most recent and conclusive randomized trials that suggest a cardio- and nephroprotective effect, at least with regard to SGLT2 inhibitors.
This article was translated from JIM.
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