Ronan Roussel, MD, PhD


July 08, 2014

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The Risk-Benefit Ratio of Antidiabetic Drugs

Welcome to Medscape. I am Ronan Roussel, Professor of Diabetology at the Bichat Hospital in Paris, France. We will talk today about the safety of antidiabetic drugs.

For the chronic disease that is diabetes, we very often need antidiabetic drugs because modification of lifestyle is not always sufficient by itself. We need the drugs, and we need to consider for each patient the risk-benefit ratio of the different classes of antidiabetic drugs that are available today.

The main safety issues with these kinds of drugs are the risk for hypoglycemia, the effect on weight, and the gastrointestinal problems that patients face with some of the drug classes. Although not often severe, they are 3 very common safety issues.

We also have to consider the effects of the drugs on the complications of diabetes. The aim of all of these treatments is to avoid or limit the progression of diabetes and its complications. However, in addition to glycemic control, we have to consider the potential direct effect of these drugs on the occurrence of complications.

First, with respect to microvascular complications, we should keep in mind that, for example, with the thiazolidinedione (TZD) drugs rosiglitazone and pioglitazone, we have seen some effects on the retina. We have seen some increasing general edema as well as an increase in macular edema in some patients, which is a manifestation of diabetic retinopathy. Although this is quite uncommon, we have to check that for each class of antidiabetic drugs.

Much more severe, and a big concern with some antidiabetic drugs, are the microvascular and cardiovascular complications. With the TZD class, we faced some troubles with rosiglitazone that led finally to this drug being taken off markets around the world. To prove the cardiovascular safety of a drug, the US Food and Drug Administration now requires proof that the drug does not increase the cardiovascular risk by more than 80% when the drug is launched on the market. After that, with the accumulation of evidence, the manufacturer has to prove that the increase in cardiovascular risk (if there is an increase) is less than 40%. The drug will also be evaluated for efficacy on the cardiovascular side.

We may also see in some drug classes some uncommon or drug-specific safety issues; for example, some dermatitis specific to the class of the inhibitors of dipeptidyl peptidase-4 (DPP-4) inhibitors, the risk for lactic acidosis with metformin (which is very uncommon but potentially very severe), and also the risk for mycotic infection with the new class of inhibitors of sodium glucose cotransporter 2 (SGLT2).

The Safety of Our Current Drugs

Now that we have positioned the main issue with respect to the safety of antidiabetic drugs, how safe are the drugs that are available? With such old drugs as sulfonylurea, we have seen an effect on hypoglycemia. The risk for hypoglycemia is increased in parallel with an increased risk for weight gain.

The picture is the same for insulin, and repaglinide and nateglinide are also potential inducers of hypoglycemia. On the other side, we have some drugs that are quite safe with respect to the risk for hypoglycemia and the risk for weight gain, such as metformin and acarbose, an alpha glucosidase inhibitor. However, most of these drugs can induce gastrointestinal problems.

In the new system of incretin-based therapy, the glucagon-like peptide-1 inhibitors (GLP-1), which are injectable drugs, are also potential inducers of gastrointestinal problems. The incretin-based therapies, the DPP-4 inhibitors (gliptins), are less problematic. They are also neutral for weight change and do not promote hypoglycemia.

Finally, the newly available class of inhibitors of SGLT2 is also safe on these 3 points. They don't induce hypoglycemia, they are weight-neutral, and they are well-tolerated in the gastrointestinal tract.

The recommendations are to individualize the treatment of every patient with diabetes, and we can now use our knowledge of the particular profile of safety for the treatment options for each patient. Thank you for your attention.


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