Statin Therapy and Risk for Diabetes: Deconstructing a Flawed Study

Michael Mogadam, MD

Disclosures

February 24, 2012

In This Article

Final Comments

As yet, there is no clear or plausible reason(s) or mechanism(s) by which statins might raise blood glucose level: Is it upstream at pancreatic beta cell level or downstream due to insulin resistance at the liver or the muscle cells? Statins have an impact on muscle cell mitochondria and result in reduced coenzyme Q10 in myocytes. Leptin enters the hypothalamic appetite/satiety center thorough leptin-receptors, where it signals mitochondria to produce a host of hormones including melanocortins. Among other functions, melanocortins stimulate muscle cells to burn more glucose at a faster rate. Theoretically, statins may decrease the production or release of melanocortins from the hypothalamic appetite/satiety center, or decrease peripheral myocytes' mitochondrial response to melanocortins. If so, then such changes may result in delayed or slow glucose metabolism downstream from the pancreas, and contribute to dysglycemia, but not to insulin resistance or diabetes. This is only speculation on my part and I know of no study to support or refute this speculation.

Meta-analyses, like observational studies, cannot establish causation, because they cannot change or adjust for data deficiencies, unmeasured confounders, and flaws in the studies they put together. Furthermore, none of the trials included in the meta-analyses nor the current observational study was designed a priori to test the hypothesis of statin-associated diabetes; hence individually or in aggregate they do not establish cause and effect but only association. The key question is whether raising the fasting blood glucose by 15 to 20 mg/dL to reach the threshold for up-classifying patients to diabetes has any clinical significance.

Every study included in the meta-analyses referred to above showed significant adjudicated benefit of statin therapy even among the subgroup with dysglycemia/diabetes, suggesting that statin-induced dysglycemia, even if real, may well be a distraction and "much ado about nothing." Only large-scale, randomized, long-term prospective studies with adequate control for all the variables outlined above may answer whether statin-associated dysglycemia has significant micro- and macrovascular negative consequences.[8] Such studies will be very difficult to organize and carry out over many years and therefore highly unlikely to be done anytime soon. For now, healthcare providers should feel comfortable to assure their patients that the well-established benefits of statin therapy far outweigh the slight risk for dysglycemia. Just as important is the clear need for placing much greater emphasis on dietary and lifestyle modifications than reliance on statin therapy alone.

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