The cardiovascular safety of sulphonylureas are mired in controversy. Some suggestion from studies of Tolbutamide, that there may be a problem, but in most studies of sulphonylureas, there are methodological issues.

The cardiovascular benefit of GLP-1 [ eg Semaglutide] and SGLT2 Inhibitors[ especially in Heart failure] and even DPP4 inhibitors, like Sitagliptin are clearer and have better study designs.

This would justify large trials of combinations, to look for additive effect

It makes sense to move on from Sulphonylurea therapy to more modern therapy

Regardless of all controversy, Overall, there does not appear to be an increased risk of cardiovascular events with second-generation sulfonylureas and any increase in relative risk for CVD events compared with metformin is thought to be secondary to the benefits of metformin.

in another specifically designed cardiovascular outcomes trial comparing linagliptin with glimepiride in 6042 patients with type 2 diabetes and elevated cardiovascular risk (median follow-up of 6.3 years), the occurrence of the composite outcome (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) was similar in the two groups (11.8 versus 12 percent with glimepiride, hazard ratio [HR] 0.98, 95% CI 0.84-1.14), with slight increase risk of hypoglycemia in patient on sulfonylurea.

Of note, the newer sulfonylureas, such as gliclazide and glipizide, are highly selective for the pancreatic sulfonylurea receptors over the cardiac receptors and do not appear to be associated with increased cardiovascular mortality compared with metformin or other diabetes medications.

source. www.uptodate.com

They can reduce the risk of complications of diabetes, such as heart disease, stroke, neurological damage, kidney problems, or retinopathy along with some less understood issues such as inhibition of telomerase activity. While it is unclear whether DDP4 inhibitors or SGLT2 inhibitors lead to better outcomes with respect to cardiovascular events and overall mortality.

Suphnylureas use in type 2 diabetes in the era of newer oral or injectable antidiabetic agents in patients at risk of or established cardiovascular disease

In primary prevention of diabetic complications newer generations of sulphonylureas (Glipizide, Gliclazide, and Glimepride) when added to Metformin have the same glycemic benefits compared to GLP-1 inhibitors, DPP-4 inhibitors, and SGLT-2 inhibitors have similar efficacy but such patients are more likely to require insulin. This might be related to weight-increasing effects and hypoglycemic episodes related to sulphonylureas. On the other hand, metformin and other newer oral antidiabetics mentioned above are weight neutral or reduce weight. Rosiglitazone is rarely used due to its adverse effects on the liver, heart, and bone (1-3).

However, CVD risk increases in patients with diabetes with the use of sulphonylureas, particularly with glibenclamide. (4-7). SGLT-2 inhibitors reduce cardiovascular events in patients with diabetes, established coronary artery disease, or heart failure (8-9).

Therefore, the recent trend is to use a combination of Metformin, GLP-1, DPP-4, SGLT-2 inhibitors in preference to Sulphonylureas. The use of Sulphonylureas is decreasing particularly in patients with established heart disease. The use of SGLT-2 inhibitors is particularly encouraged in patients with risk of or established IHD or heart failure.

1. Article Comparison of metformin, gliclazide MR and rosiglitazone in ...

2. Article Effectiveness of sitagliptin compared to sulfonylureas for t...

3. Article Comparative efficacy of once-weekly semaglutide versus SGLT-...

4. Article Sulphonylureas and risk of cardiovascular disease: Systemati...

5. Article Do sulfonylurea drugs increase the risk of cardiac events?

6 Article Sulfonylureas and prognosis after myocardial infarction in p...

7. Article Impact of Type of Preadmission Sulfonylureas on Mortality an...

8. Article Cardiovascular protection with SGLT2 inhibitors in type 2 di...

9. Research Role of SGLT2 Inhibitors in Heart Failure