Variables Involved When Adding Medications to Treat Diabetes

Zachary T. Bloomgarden, MD, MACE: When you consider adding medicines for individuals with type 2 diabetes, the most important thing is to try to take into account all of the individual’s other clinical characteristics. You want to know if they have a history of gastrointestinal problems. If they’ve had diarrhea or a lot of problems with heartburn or nausea, they might not be good candidates for the GLP-1 (glucagon-like peptide-1) receptor agonists (as these agents tend to have gastrointestinal side effects).

Do they have a history of urinary infections? In men, prostatism? In women, vaginal yeast infections? In such individuals, the use of an SGLT2 (sodium-glucose cotransporter-2) inhibitor might have the undesirable side effect of worsening these problems.

Do they have a history of congestive heart failure? Do they have peripheral edema? Have they had osteoporotic fractures? Do they have any evidence of macular edema, a form of diabetic retinopathy? Are they individuals for whom we’re worried about weight gain? Those all might be considerations that would lead one to be less likely to use a thiazolidinedione.

Do they have a history of hypoglycemia? If they’ve had hypoglycemia problems, then giving a sulfonylurea or insulin would be undesirable because these agents are intrinsically associated with hypoglycemia. Both the sulfonylureas and insulin tend to be associated with weight gain.

In addition, we want to think about ways in which the drugs might benefit patients. So, we have the recently released results of the IRIS (Insulin Resistance Intervention after Stroke) study with pioglitazone which showed that individuals who don’t have diabetes but have insulin resistance, who are given pioglitazone with a past history of stroke, have a reduction in the possibility of subsequent heart attack and stroke. That, certainly, is a very important consideration, and it supports the findings of the PROactive trial done a number of years ago in which individuals with a history of stroke who did have diabetes had a reduction in subsequent stroke when treated with this agent.

If there are people who have heart failure, then the results of the EMPA-REG trial are of great interest. In the EMPA-REG cardiovascular outcome trial, individuals who were at high risk and were randomized to empagliflozin actually had a reduction in the likelihood of cardiovascular mortality, and as a secondary endpoint, a reduction in the need for hospitalization for heart failure. Thinking of heart failure as a very key part of the diabetes heart disease spectrum, one could say the use of this agent, and perhaps other SGLT2 inhibitors, might be highly beneficial in reducing outcomes.

We have recently learned top-line results of the LEADER trial with liraglutide that showed that again, in a high cardiovascular risk population, the use of liraglutide was associated with a reduction in myocardial infarction, in stroke, and in cardiovascular mortality. This suggests that individuals receiving this agent might really benefit.

To some extent, we don’t know exactly what the mechanisms are. In other ways, we do have ideas. There’s somewhat a diuretic or natriuretic effect of the SGLT2 inhibitors that might be of benefit in heart failure. The insulin sensitization of pioglitazone appears to have benefit in decreasing the atherosclerotic process. Also, the overall potent glucose-lowering without causing hypoglycemia that is seen with liraglutide could be beneficial in individuals at high cardiovascular risk—particularly, one might speculate, if they are able to avoid using sulfonylureas that we think may be associated with intrinsic cardiovascular toxicity.