Diabetes Medication Associated with Heart Disease in Women

Last month, Diabetes Care, a journal of the American Diabetes Association, published an article linking sulfonylurea use to increased risk of cardiovascular disease in women. Sulfonylureas stimulate the pancreas to produce insulin and include glipizide (Glucotrol), glyburide (Micronase), and glimepiride (Amaryl) in the US, as well as gliclazide (Diamicron), available in Great Britain and Australia. Although many newer medications are receiving a lot of attention in the media, sulfonylureas remain among the most widely prescribed diabetes medications on the market. Dr. Steve Parker wrote a nice overview of sulfonylureas  a few years back.

A few pertinent facts about the study referenced above:

• It was a long-term study following 4900 women for more than 10 years as part of the Nurses' Health Study
• Researchers took into consideration confounding variables such as family history of CVD, smoking, duration of diabetes, etc.
• The association with coronary heart disease (CHD) increased with duration of sulfonylurea use

I find this quite concerning, but I've only read the abstract and would like to read the entire study before commenting further. (If anyone is willing to share the full text with me, it would be much appreciated.) However, the well-known side effects of sulfonylureas are precisely what I saw in many patients in my former position as an outpatient dietitian in a large hospital:

• Hypoglycemia due to incorrect timing with food intake and/or absorption of food. Some (such as glipizide) are designed to work within 30 minutes, but patients often forget and take the medication afterward, which can lead to low blood sugar. In rare cases, people taking sulfonylureas have died from severe hypoglycemia.
• Increased hunger at and between meals
• Weight gain secondary to increased caloric intake and hyperinsulinemia 

Contrast these undesirable effects with those of metformin, a diabetes medication which is relatively safe, improves insulin sensitivity, decreases hepatic glucose output, and doesn't result in hypoglycemia or weight gain. 

A very important point is that sulfonylureas are only used to cover postprandial blood glucose in response to a carbohydrate-containing meal. If minimal carbohydrate is consumed, sulfonylureas aren't necessary and can definitely cause hypoglycemia. So someone following a very-low-carbohydrate diet would need to discontinue sulfonylurea treatment but might continue taking metformin indefinitely, depending on fasting and postprandial blood glucose levels.

I realize most dietitians and diabetes educators advise people with type 2 diabetes that they should consume the same foods as everyone else and take insulin or insulin-stimulating medications to control the inevitable postmeal rise in blood glucose. But with all of the side effects listed above -- and now a potential increase in CHD risk -- I think that's a very misguided approach. It also places a large burden on the beta cells of the pancreas and may increase the rate of disease progression. Let's compare the risks of these medications to carbohydrate restriction for diabetes control. As long as the diet contains ample protein, healthy fat, plenty of vegetables, and smaller amounts of slow-digesting carbs from foods like nuts and berries, there are essentially no adverse effects than perhaps constipation, which is easily treated. And the benefits of low-carbing for someone with diabetes? No risk of hypoglycemia, increased satiety, and easier weight loss -- exactly the opposite of eating a "normal" amount of carbohydrates and taking sulfonylureas or insulin for coverage.

At the Low Carb Down Under conference in Melbourne at the end of September, I said that being respectful and courteous is the best way to convince dietitians and diabetes educators to recognize the benefits of carbohydrate restriction, and I stand by that statement. Remember, up until a few years ago I was one of those dietitians who promoted a low-fat diet with plenty of whole grains. But as we continue to find out about the drawbacks of various diabetes medications -- including several of the newer ones --  I understand people's frustration at being told they're a necessary part of diabetes management instead of being presented with an alternative solution. Since you're reading this, I hope you're someone who has benefitted from a low-carbohydrate lifestyle or would like to. The best that we can do is to continue speaking out and sharing our experiences, knowing that the evidence is on our side and at some point most health professionals will understand that carbohydrate restriction is the best and safest option.

References
1. Li Y, et al. Sulfonylurea Use and Incident Cardiovascular Disease Among Patients With Type 2 Diabetes: Prospective Cohort Study Among Women. Diabetes Care 2014 Aug 22 
2.  Braatvedt GD, et al. The clinical course of patients with type 2 diabetes presenting to the hospital with sulfonyl-induced hypoglycemia.Diabetes Technol Ther 2014 Jul 10 
3. Fonseca V, et al. Determinants of weight gain in the action to control cardiovascular risk in diabetes trial. Diabetes Care 2013 Aug;36(8):2162-8
4. Madiraju AK. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 2014 Jun 26;510(7506):542-6
5. Feinman, et al. Dietary Carbohydrate restriction as the first approach in diabetes management. Critical review and evidence base. Nutrition 2014 July 16