Conference Coverage

Study investigates statin-diabetes link



– On any given day, type “statins” in the subject line of your favorite search engine and many results are likely to focus on risks: some based on science, others not so much.

Dr. Joshua Knowles, Stanford Center for Inherited Cardiac Disease Doug Brunk/MDedge News

Dr. Joshua W. Knowles

“There is all kind of misinformation that are preventing people from taking statins,” Joshua W. Knowles, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “The most important side effects of statins are the increased lifespan and decreased risk of heart attacks, but that’s not what our patients are telling us. One of the things that is true is that statins do seem to increase the risk of diabetes. This only emerged after many years and it’s gotten a lot of press.”

In 2016, Dr. Knowles, a cardiologist at the Stanford (Calif.) Center for Inherited Cardiovascular Disease, coauthored a retrospective analysis of data from subjects without diabetes in the Treating to New Targets (TNT) and the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) randomized controlled trials (Am J Cardiol 2016;118[9]:1275-81). The authors found that statins particularly increase the risk of type 2 diabetes in those with prediabetes and insulin resistance. “That’s a risk group that we are all treating,” he said. “But that still doesn’t answer the question as to why this happens. Is this because statins increase insulin resistance, because they decrease beta cell function, or because they increase insulin clearance rate?”

In an effort to find out, Dr. Knowles and his colleagues have launched a clinical trial entitled “Relationship Between Insulin Resistance and Statin Induced Type 2 Diabetes, and Integrative Personal Omics Profiling” (NCT 02437084). Candidates do not have diabetes, yet qualify for statin therapy because they have a greater than 7.5% risk of cardiovascular disease over 10 years. To date, the researchers have enrolled 74 patients: 42 to the insulin-sensitive group (defined as having an LDL above 130 mg/dL and a triglyceride level below 150 mg/dL) and 11 to the insulin-resistant group (defined as having an LDL of 130 mg/dL or greater and a triglyceride level of 150 mg/dL or greater). Dr. Knowles said that about two-thirds of patients have been recruited and that full results are expected in late 2019.

At baseline, subjects underwent the insulin suppression test, the graded glucose infusion test, metabolic characterization, and integrated personal omics profiling (iPOP), a monitoring method. After 3 months of atorvastatin therapy 40 mg/day, the researchers repeated these measures and compared the results between groups. “Basically we were looking for changes in insulin resistance, secretion, and clearance between those groups over time,” said Dr. Knowles, who is the study’s principal investigator.

Of the 74 subjects, 13 decided that they did not want to participate and 6 are still undergoing baseline tests. In all, 55 started statin therapy, and 2 have dropped out. This left 42 in the low-triglyceride group and 11 in the high-triglyceride group.

The average age of the 52 individuals who have completed the study so far is 61 years, 30 are male, 35 are non-Hispanic white, their mean body mass index was 27.9 kg/m2, and their mean blood pressure was 127/79 mm Hg. By the end of statin therapy, body mass index did not change, but total cholesterol fell from a median of 234 mg/dL to a median of 150 mg/dL, triglycerides fell from a median of 109 mg/dL to a median of 78 mg/dL, LDL cholesterol fell from a median of 153 mg/dL to a median of 71 mg/dL, and mean high-sensitivity C-reactive protein dropped from a median of 1.2 mg/L to a median of 0.8 mg/L. All differences were statistically significant.

Fasting glucose levels have been completed on only 35 patients. “Two-hour glucose is going up, but it’s not yet significant, and on the oral glucose tolerance test, the curves are separating slightly but are not yet significant,” Dr. Knowles said.

On average, insulin resistance among the 35 patients worsened slightly, from 156 mg/dL before statin therapy to 170 mg/dL after initiation. “This is nominally significant (P = 0.03), and we’ll have to see if this holds up over time,” he said. The researchers also observed that statin use was associated with slight decreases in insulin secretion and clearance. Dr. Knowles emphasized that these are preliminary results and need to be further validated.

The study is funded by the Doris Duke Charitable Foundation. Dr. Knowles reported having no disclosures.

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