A guideline committee established by the American College of Physicians recently reviewed oral medications for treatment of type 2 diabetes. Assuming blood sugars were still too high after diet and lifestyle modification, the firmest drug recommendations were:
- Use metformin first.
- If blood sugars are still too high, add a second agent to metformin.
This was not nearly as helpful as I’d hoped it would be!
The Problem: Too Many Options
We now have 11 classes of drugs for treatment of 26 million diabetics in the United States. Clinicians are often at a loss as to which drug(s) to recommend for a particular patient. For most of these drugs, we know very little about the long-term implications, such as effects on overall death rates, diabetes complications, heart attacks, cancer, and strokes.
I can think of three diabetes drugs once approved by the U.S. Food and Drug Administration, but are now off the market or severely restricted due to serious adverse side effects: phenformin, troglitazone (Rezulin), and rosiglitazone (Avandia). I fully expect one or more of our current drugs will have a similar fate; only time will tell which ones.
France took pioglitazone off the shelves in 2011 because of a link with bladder cancer. It’s still available and popular in the U.S.
When you get into multi-drug therapy with two or three different oral drugs, the situation becomes even cloudier.
Some Needles in the Haystack
I reviewed the report from the guideline committee and found just a few clinical pearls to share with you.
- They didn’t mention at all the FDA’s recent restrictions on rosiglitazone, so I assume they don’t believe it’s more toxic to the heart than is pioglitazone.
- Most oral drugs reduce hemoglobin A1c by an average of 1% (absolute decrease).
- All double-drug regimens were more effective at controlling blood sugars than monotherapy (using only one drug): adding a second drug drops hemoglobin A1c another 1%.
- “It was difficult to draw conclusions about the comparative effectiveness of type 2 diabetes medications on all-cause mortality, cardiovascular morbidity and mortality, and microvascular outcomes because of low quality or insufficient evidence.” It was so difficult that they didn’t draw any firm conclusions. In other words, in terms of overall deaths , heart attacks, heart failure, and strokes, it’s hard to favor some of these drugs over others. However…
- Compared to sulfonylureas, metformin was linked to a lower overall death rate and cardiovascular illness (e.g., heart attacks, heart failure, angina).
- Sulfonylureas and meglitinides tend to cause more hypoglycemia.
- Thiazolidinediones are linked to a higher risk of heart failure; they shouldn’t be used in patients who already have serious heart failure.
- Thiazolidinediones may increase the risk of bone fractures.
- Metformin helps with loss of excess weight, reduces LDL (bad) cholesterol, and lowers triglycerides.
- Metformin is cheaper than most other diabetes drugs.
- For double-drug therapy: “No good evidence supports one combination therapy over another, even though some evidence shows that the combination of metformin with another agent generally tends to have better efficacy [better blood sugar control] than any other monotherapy or combination therapy.”
In contrast to these guidelines, the American Association of Clinical Endocrinology guidelines of 2009 recommend that the following should be used earlier and more frequently: GLP-1 agonists (exenatide) and DPP-4 inhibitors (sitagliptin, saxagliptin, linagliptin). Furthermore, sulfonylureas should have a lower priority than in the past. From my limited perspective here in the Sonoran desert, I have no way of knowing how much influence, if any, Big Pharma had over the AACE guidlelines.
My concern about long-term safety of some these drugs compels me to favor carbohydrate restriction, which reduces the overall need for drugs. Sure, that’s not true for everybody and it may not last forever. The more carbs you eat, the more drugs you’re likely to need to keep blood sugars in control in an effort to avoid diabetes complications.
Don’t get me wrong; I’m not anti-drug. As an internist, I prescribe plenty of drugs every day. They are a major weapon in my armamentarium. Regardless of the condition I’m treating, I always try to avoid drugs with unknown and potentially serious long-term consequences.
Reference: Qaseem, Amir, et al. Oral pharmacologic treatment of type 2 diabetes mellitus: A clinical practice guideline from the American College of Physicians. Annals of Internal Medicine, 156 (2012): 218-231.