Insulin Does Not Increase Vascular Events in Type 2 Diabetes

Lara C. Pullen, PhD

March 14, 2012

March 14, 2012 — The addition of insulin to the treatment regimen of patients with type 2 diabetes does not significantly increase the incidence of vascular events, according to a study involving nearly 15,000 participants. Any perceived differences in vascular events between the 2 groups is likely a result of the fact that patients who are prescribed insulin after a baseline of 1 or 2 oral glucose-lowering drugs (OGLDs) are different from those who are prescribed an additional OGLD.

Gillian C. Hall, PhD, from Grimsdyke House in London, United Kingdom, and colleagues report their analysis of data from the Health Information Network UK primary care database in an article published online January 23 in Pharmacoepidemiology and Drug Safety. 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, spoke with Medscape Medical News about the study. She 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."

Patients Did Not Achieve Glycemic Control Goals

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 posttherapy 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.

The study was funded by sanofi-aventis, including funding of some of the authors' time and comment on study design and the manuscript, but the company had no direct involvement in the collection, analysis, and interpretation of data, and no restriction on publication. Dr. Hatipoglu has disclosed no relevant financial relationships.

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

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