Insulin may increase the risk of death compared to sulfonylureas
When we refer to diabetes, we think of its complications. It may lead to microvascular maladies that affect vision (retinopathy), the kidneys (nephropathy) and the limbs (peripheral neuropathy), as well as macrovascular diseases such as heart disease and heart attacks. These are important reasons to prevent and treat it.
However, diabetes, in and of itself, is complicated. For example, in the ACCORD trial, we treated diabetes patients aggressively with medication trying to get their HbA1C (three-month sugars) to below 6.0 percent rather than the standard 7.0 percent, because we thought lower would mean fewer complications. According to the results, the patients who were treated more aggressively had a higher risk of mortality (1).
We know that in type 2 diabetes, the first line of therapy beyond lifestyle modifications is metformin. But when that is not enough, we also know that insulin is the most powerful treatment for decreasing glucose, or sugar, levels. But are insulin therapies the best drugs to use? Well, it turns out that they may have more risk of death compared to another drug class, sulfonylureas (e.g., Glucotrol, Amaryl). However, sulfonylureas, along with another drug class, thiazolidinediones (e.g., Avandia, Actos), may increase the risk of fractures. Sulfonylureas and insulin each have also been associated with increased risk of hypoglycemia (low sugar).
Diabetes is also associated with depression. The prevailing thought has been that having diabetes may contribute to depression. However, the association may be related to another common factor, inflammation.
If that were not enough to make your head spin, the Centers for Disease Control reports that one-quarter of patients don’t even know they have diabetes (2). And for people over the age of 20, 33 percent have prediabetes, defined as sugar levels between normal and diabetes, with fasting sugar of 100-125 mg/dl or HbA1C of 5.7-6.4 percent. However, there is good news as it relates to lifestyle modification. Let’s look at the evidence.
Medications: insulin versus
Two of the most common medications for the treatment of diabetes, referred to as second-line therapies since they would be used after metformin, are insulin and sulfonylureas. In a recent observational comparative effectiveness trial with patients already on metformin, results showed that when insulin was added compared to when sulfonylureas were added, there was a 44 percent increased risk of all-cause mortality and a 30 percent increased risk of cardiovascular outcomes including heart attack, stroke or all-cause death (3).
Does this mean we should not use insulin? No. There were limitations to this study. Though it was more sophisticated with its comparative effectiveness design, it was still retrospective, which is not as strong as some other study types and may involve bias. The only conclusion that can be made is that insulin when used with metformin had an association with, but not a link to, significantly negative side effects versus sulfonylureas. These patients were followed for a median of 14 months. We need prospective studies, especially randomized controlled studies. However, the results are intriguing. It makes you think twice before reaching for insulin as a second-line therapy.
Medications: sulfonylureas and thiazolidinediones
Does this mean that we know what to use for second-line therapy? Not necessarily. In a recent study, both sulfonylureas and thiazolidinediones showed a significantly increased risk of fractures. There was a 9 percent increase in fracture risk with sulfonylureas and a 40 percent increased risk with thiazolidinediones when each was compared to metformin (4). The good news is that other drug classes were tested and did not show statistically significant elevated risk occurrences. This was also a retrospective observational study so the same study limitations apply, most importantly, bias and confounding factors.
To complicate matters further, diabetes and depressive symptoms are associated with each other, but not in the way you might think. According to a recent study, these two maladies may not be a classic chicken-and-egg argument, but rather a common denominator; inflammation may be the culprit that is at least partially responsible for both diseases processes (5).
The researchers found that six biomarkers of inflammation were increased in patients with both diabetes and depressive symptoms. These inflammatory markers include C-reactive protein, tumor necrosis factor alpha, triglycerides, white blood cells, interleukin 1 (IL-1B and IL-1RA) and monocyte chemotactic protein-1. Ultimately, if they are both caused by inflammation to varying degrees, then theoretically if we reduced inflammation it may give us beneficial results for both diseases. This is important, since those with both diseases may have a two times greater likelihood of death, according to the authors. They also note that lifestyle modifications, including diet and exercise, are the best way to reduce inflammation. The study involved 1227 newly diagnosed diabetes patients.
Both men and women with diabetes are at increased risk of heart attacks. However, in a recent meta-analysis (group of 64 studies) involving over 800,000 patients, the results surprisingly show that women with diabetes are at a significantly greater risk of having a heart attack than men (6). In fact, these women were at a 44 percent increased risk of having fatal and nonfatal cardiovascular events compared to their male counterparts. The reason for this, according to the authors, was that women may already be in poorer health before the onset of diabetes. What to do?
We tell patients to exercise, but many of us know just how difficult it can be to motivate ourselves to do this. Video games may provide the needed spark. In a randomized controlled trial, the gold standard of studies, those who used Wii Fit Plus saw improvements in their diabetes parameters compared to those who were given usual care (7). Results included significant decreases in their HbA1C, fasting blood sugars and weight. These results were seen in just three months. There were also improvements in daily physical activity, quality of life and depressive symptoms that are so commonly associated with diabetes. Family members were also likely to get involved in the Wii with the patient, creating a natural support network. Interestingly, after 12 weeks, those in the control group were then given the Wii Fit Plus and followed for an additional 12 weeks. They saw similar benefits. The authors called this “exergaming.”
Ultimately, we should do a really good job with lifestyle modifications and if that is not enough add metformin, because we know that both have much greater upsides and very few downsides compared to many other diabetes treatments. Exercise can even be fun, as shown by the exergaming study. However, if insulin or other medications are needed, while there are treatment guidelines, it really comes down to a case-by-case decision to be made by the patient and doctor.
(1) N Engl J Med. 2008;358:2545-2559. (2) cdc.gov/diabetes. (3) JAMA. 2014;311:2288-2296. (4) ADA 2014 Scientific Sessions;165-OR. (5) Diabetes Care Online. 2014 May 19. (6) Diabetologia Online. 2014 May. (7) BMC Endocr Disord. 2013;13:57.
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Dr. Dunaief is a speaker, author and local lifestyle medicine physician focusing on the integration of medicine, nutrition, fitness and stress management. For further information, go to the website medicalcompassmd.com or consult your personal physician.