Statin Therapy and Risk for Diabetes: Deconstructing a Flawed Study

Michael Mogadam, MD

Disclosures

February 24, 2012

In This Article

Flaws of This Study

What were some of the more glaring flaws of this study?

1. This was a collaborative study that included 40 centers, each with numerous contributors. The justifications and indications for initiating statin therapy in only 7% of the 153,840 postmenopausal women observed, particularly during the early years of the study, were highly variable and far more stringent than they are now. It is quite likely that many of the women who were selected for statin therapy had various coexisting diabetogenic risk factors including family history, metabolic syndrome, sedentary lifestyle, atherogenic and diabetogenic dietary practices, abdominal obesity, or prediabetes, many or most of which continued during statin therapy.

2. Women not selected to receive statin therapy most likely did not have significant major cardiovascular risk factors, including metabolic syndrome, to justify statin therapy. Therefore they were healthier, hence less likely to develop diabetes.

3. The incidence of diabetes varies from state to state; those with the highest age-adjusted incidence are predominately located in the South, specifically Alabama, Florida, Georgia, Kentucky, Louisiana, South Carolina, Tennessee, Texas, and West Virginia. Thus the number of cases included from geographic locations that have a high incidence of diabetes also impacts the overall number of cases with "diabetes."

4. The diagnosis of "diabetes" is also problematic. Patients on niacin, hydrochlorothiazide, or some beta blockers may develop hyperglycemia, which, in the vast majority of cases, may spontaneously resolve even while on the drug or after the drug's discontinuation. Should we erroneously label these hyperglycemic responses as diabetes?

5. Women not selected to receive statin therapy did not need repeated blood tests and therefore would be far less likely to have an A1c or 2-hour glucose tolerance test. Women selected to receive statins invariably had repeated blood tests each year, creating more opportunities to detect hyperglycemia and therefore undergo additional tests, including an A1c or 2-hour glucose tolerance test to detect diabetes, thus contributing to the frequent testing/screening bias. As examples, screening colonoscopy is associated with a much greater likelihood of detecting dysplastic/precancerous polyps and colon cancers. Regular mammography is also associated with much higher detection rates of breast cancers compared with detection in women who do not have regular mammograms. Testing/screening for almost any disease is more likely to detect the disease in question compared with no testing/screening.

6. We know very little about insulin resistance or insulin insufficiency in cases selected for statin therapy or about the vigor or lack thereof among the various study contributors for diagnosing impaired fasting blood glucose, prediabetes, or diabetes before starting their patients on statins. Conversely, it is quite possible that prediabetes or "slightly elevated blood sugar" with or without other, coexisting risk factors may have biased or reinforced the justification for statin therapy. The fact that BMI and the dose, type, and duration of statin therapy were not contributing factors, but older age was, is consistent with such a bias. I frequently see patients for management of their dyslipidemia who have slightly elevated fasting blood glucose and, on further investigation with 2-hour glucose tolerance test, prediabetes or diabetes. Without pretesting, they, too, would be placed in the "statin-induced diabetes" category.

7. Long-term statin adherence outside of prospective, double-blind studies is highly variable and often poor, and patients remain off statins for months or longer, often without informing their healthcare providers. It is impossible to adjust for these noncompliant cases in an observational study. What happened to the glycemic status of those who stopped their statins (with or without the advice or knowledge of their healthcare providers) or took them intermittently? Did they remain "dysglycemic" or revert to normoglycemia?

These major confounders and individual contributors' practice patterns or judgment as to who would be prescribed statins simply cannot be and were not measured or adjusted for. Thus conclusions based on insufficient and lack of crucial data are neither informative nor reliable and are subject to misinterpretation or spinning. No matter how sincere the authors are, no amount of sincerity can be a substitute for flawed and inadequate data. The harm of such misinformation may be immeasurable if it misleads healthcare providers about the so-called "statin-induced diabetes," hence contributes to their reluctance to prescribe these agents and their patients' resistance to take them.

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