Type 2 Diabetes, Metformin, and Cardioprotection: Are the Data There?

As" tried and true" oral agents to treat type 2 diabetes mellitus (T2DM), the sulfonylureas and metformin have been around a long time. Metformin, for one, boasts some data on protection against the inevitable risks of microvascular and macrovascular complications that come with the disease. But how do these traditional "work horse" agents compare with newer agents, such as the incretin class, especially against cardiovascular (CV) disease risk in pateints with T2DM?

The question takes us back to 1998 and a landmark study. Results of the UK Prospective Diabetes Study (UKPDS)¹ led to a “good news”/“bad news” scenario.

First, the good news. Intensive blood glucose control with insulin or a sulfonylurea reduced microvascular complications. How about the bad news? Neither agent decreased the risks from macrovascular complications such as coronary artery disease. The UKPDS investigators (among others) went back to the drawing board. Would metformin affect cardio-(macro)-vascular risk?
 
UKPDS recruited 4075 patients from 15 centers.² From this group, a cohort was selected whose members (1704) were greater than 120% of ideal weight and had T2DM but no symptoms of hyperglycemia. Next, 753 of these were randomized (for a median of 10.7 years) to a diet alone group (n=411) or to an intensive glucose control group with metformin (n=342). The metformin-treated group was compared in a secondary analysis with the remaining 951 overweight patients who underwent intensive glucose control with chlorpropamide (n=265), glibenclamide (n=277), or insulin (n=409). Outcome measures included any diabetes-related clinical endpoint, diabetes-related death, and all-cause mortality. In the intensive blood glucose control limb, metformin had a greater effect on all the endpoints than the other glucose-lowering agents, including insulin.

So, that was in 1998. Fast forward to 2012.

Hong and colleagues³ studied patients with T2DM and known CV disease-a known high-risk group. Two randomized limbs compared glipizide 30 mg/d with metformin 1.5 g/d with 3-year follow-up.³ Endpoints were times to the composite of recurrent CV events, including death from any cause, death from cardiovascular cause, nonfatal myocardial infarction, nonfatal stroke, and need for arterial revascularization. Both limbs achieved similar A_1C values (7.1% for glipizide group versus 7.0% for metformin group).³ The hazard ratio for the composite of CV events in the metformin-treated T2DM group compared with the glipizide-treated group was 0.54! The authors concluded that there was “a potential benefit from metformin therapy on cardiovascular outcomes in high-risk (known cardiovascular disease) patients.”
 
The data motivated me to review more of the recent literature and similar findings have been discovered. Also in 2012, the sulfonylureas glipizide, glyburide, and glimepiride were compared with metformin.⁴ Overall mortality was greater with the sulfonylureas compared with metformin. In patients with underlying coronary artery disease in this study, there was a significantly increased risk of death in those randomized to glipizide.
 
This story is far from finished, however. More data are needed. On the basis of my own review, the newer agents from the class of dipeptidyl peptidase-4 inhibitors (the DPP-4s) may provide even better cardioprotection than metformin.⁵ Much of the aforementioned data compared metformin with sulfonylureas. Important head-to-head comparisons of metformin and insulin did not demonstrate cardiovascular protection.⁶

We are in a pitched battle against T2DM-associated CV risks and are in need of reinforcements. Metformin may carry the day over the sulfonylureas. We can hope the incretins may add another chapter to the story-and soon.     


1. UKPDS Group. Intensive blood-glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2-diabetes (UKPDS 33). Lancet. 1998;352:837-853.
2. UKPDS Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2-diabetes (UKPDS 34). Lancet. 1998;352:854-865.
3. Hong J, Zhang Y, Lai S, et al. Metformin reduced CV events compared with glipizide in patients with type 2 diabetes and CAD. Diabetes Care. 2012 Dec 10; [Epub ahead of print].
4. Pantalone KM, Kattan MW, Yu C, et al. Incresae in overall mortality risk in patients with type 2 diabetes receiving glipizide, glyburide or glimepiride monotherapy versus metformin: a retrospective analysis. Diabetes Obes Metab. 2012 Apr 29; [Epub ahead of print].
5. Leibovitz E, Gottlieb S, Goldenberg I, et al. Sitagliptin pretreatment in diabetes patients presenting with acute coronary syndrome: results from the Acute Coronary Syndrome Israeli Survey (ACSIS). Cardiovasc Diabetol. 2013 Mar 28; [Epub ahead of print]. 
6. Hemmingsen B, Christensen LL, Wetterslev J, et. al. Comparison of metformin versus insulin alone for type 2 diabetes: systematic review of randomized clinical trials with meta-analyses and trial sequential analyses. BMJ. 2012 Apr 19; [Epub ahead of print].