The following are 10 points to remember about the effects of antihyperglycemic drug therapy in patients with diabetes who have heart failure:

1. Individuals with diabetes are not only at high risk of developing heart failure, but are also at increased risk of dying from it.
2. Reports of hospital admission for heart failure in thiazolidinedione recipients followed soon after their launch, leading to updated advisories of the increased heart failure risk, both from regulatory authorities and pharmaceutical companies.
3. The need for new glucose-lowering drugs to show cardiovascular safety has led to the unexpected finding of an increase in the risk of hospital admission for heart failure in patients treated with the dipeptidylpeptidase-4 (DPP4) inhibitor, saxagliptin, compared with placebo.
4. The association between insulin treatment and heart failure is complex not only because of the drug’s effects on renal sodium handling, but also as a result of the tendency to use it late in the course of type 2 diabetes, where patients older than 60 years with increased duration of disease will be more prone than younger people to developing heart failure.
5. Despite adjustment for known covariates, the need for insulin might simply identify a group of patients who are both at increased risk of developing heart failure and dying from it.
6. In view of the ability of both insulin and thiazolidinediones to stimulate sodium retention that includes their common activation of ENaC and NHE3, to note an increased risk of edema when the two drug classes are used in combination is not surprising.
7. Although sulfonylureas increase circulating insulin concentrations, they have not been associated with sodium retention or edema.
8. A systematic review of observational studies including 34,000 patients concluded that metformin should be considered the treatment of choice in patients with diabetes and heart failure, given potential signs of reduced mortality in the heart failure setting.
9. By contrast with the thiazolidinediones that lead to a roughly 3% decrease in hematocrit, inhibitors of the sodium-glucose linked cotransporter-2 (SGLT2) result in a roughly 3% increase in hematocrit, suggestive of volume contraction. Since fluid overload is a key precipitant for heart failure deterioration, a drug that provides volume reduction, such as an SGLT2 inhibitor, might be beneficial.
10. It is time to design and execute appropriately powered clinical trials that specifically address the safety and possible benefit of antihyperglycemic drugs on the development and progression of heart failure in diabetic individuals.

Keywords: Adamantane, Diabetes Mellitus, Diabetes Mellitus, Type 2, Dipeptides, Edema, Glucose, Heart Failure, Hematocrit, Hyperglycemia, Hypoglycemic Agents, Insulin, Metabolic Syndrome, Metformin, Sulfonylurea Compounds, Sodium, Thiazolidinediones

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