Does Insulin Increase Vascular Events in Type 2 Diabetes?

Gillian C. Hall, PhD, from Grimsdyke House in London, United Kingdom, and colleagues report their analysis of data in a published article.

This study is the first of its kind to compare the rate of cardiovascular disease after the intensification of treatment of type 2 diabetes.

The investigators followed-up patients for an average of 3.5 years. They used an intention-to-treat analysis and included all outcomes after the study therapy escalation (as opposed to excluding follow-up at a later change of treatment).

Although beginning insulin from a treatment regimen of 1 OGLD was uncommon, insulin therapy was more commonly begun as an alternative to adding another OGLD to double or triple oral therapy. The investigators analyzed 14,904 people who intensified treatment from 1 OGLD (9% added insulin), 7231 from 2 OGLDs (41% added insulin), and 978 from 3 OGLDs (90% added insulin).

The study included all-cause mortality as a surrogate for cardiovascular mortality to avoid incomplete and/or inaccurate records of cause of death. An adjusted hazard ratio for macrovascular events was calculated for each patient group (OGLD vs insulin). The adjusted hazard ratios were 0.53 (95% confidence interval [CI], 0.42 - 0.69) from 1 baseline treatment, 0.85 (95% CI, 0.70 - 1.04) from 2 baseline treatments, and 1.07 (95% CI, 0.50 - 2.30) from 3 baseline treatments. Groups were adjusted for age, sex, duration of diabetes, year of escalation, body mass index, baseline HbA1c levels, and oral treatment.

There were no differences in risk for microvascular disease in any comparison.

Betul A. Hatipoglu, MD, from the Endocrinology and Metabolism Institute of Cleveland Clinic in Ohio, explained that there have always been questions about the risks and benefits of OGLDs vs insulin. Endocrinologists are constantly asking the question, "Does it matter, when you get to the goal, how you got there?"

The current study indicates that it does not matter, she said. The good news for the physician is that both types of treatments achieve the same benefits and do not harm the patient. Dr. Hatipoglu added that the research supports the understanding that, when used appropriately, insulin is an extremely important tool. She acknowledged, however, that the research will not change her practice. "For me, it won't be any change because I always believed what they found in this article."

All groups had a mean decrease in HbA1c levels with treatment adjustment. The study was not able to follow long-term glycemic control, nor did the investigators validate the recorded duration of diabetes. The authors did report that despite the average reduction in HbA1c levels throughout the 14-month post-therapy escalation in all treatment groups, the mean HbA1c value never fell below the UK funding target of 7.5% in any group at any stage.

The investigators did not study the frequency of hypoglycemia because hypoglycemic events are not reliably reported to the general practitioner, and therefore their entry into the database would be incomplete.

All groups had a mean increase in body weight with treatment adjustment. The authors noted a significantly greater weight increase (unadjusted mean difference in oral vs insulin was −2.2; 95% CI, −2.8 to −1.6) when commencing insulin from 1 OGLD.

Although patients receiving insulin therapy are traditionally believed to have more incident macrovascular disease, this perception appears to be caused by residual confounding. The investigators identified residual confounders in the form of disparities in baseline characteristics in the group of patients who were given insulin therapy and those who were given an additional OGLD. In particular there were differences between the groups in terms of disease prevalence, cardiovascular risk factors, and recent switching of OGLDs, which appeared to contribute to the incidence of macrovascular events.

Pharmacoepidemiol Drug Saf. Published online January 23, 2012. Abstract