Statin Use and Incident Diabetes Explained by Bias Rather Than Biology

Blackburn, David; Chow, Jonathan Y.; Smith, Amy D.

doi:10.1016/j.cjca.2015.03.025

Cited by 6 publications

(4 citation statements)

References 12 publications

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“…In vitro studies show that statins impair insulin secretion by affecting multiple pathways [13], including cellular cholesterol synthesis, membrane fluidity, and isoprenylation of proteins [14]. Though their cardiovascular benefit exceeds the diabetes hazard [15], the mechanisms whereby statins accelerate the onset of diabetes remain unclear, and whether statins truly exert any action on insulin secretion is debated [16, 17]. This is in part because cellular models used to explore this phenomenon, either cell lines [13, 14] or pooled islets [14], are non-physiologic and lack clinical transferability.…”

Section: Introductionmentioning

confidence: 99%

Simvastatin Rapidly and Reversibly Inhibits Insulin Secretion in Intact Single-Islet Cultures

et al. 2016

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IntroductionEpidemiological studies suggest that statins may promote the development or exacerbation of diabetes, but whether this occurs through inhibition of insulin secretion is unclear. This lack of understanding is partly due to the cellular models used to explore this phenomenon (cell lines or pooled islets), which are non-physiologic and have limited clinical transferability.MethodsHere, we study the effect of simvastatin on insulin secretion using single-islet cultures, an optimal compromise between biological observability and physiologic fidelity. We develop and validate a microfluidic device to study single-islet function ex vivo, which allows for switching between media of different compositions with a resolution of seconds. In parallel, fluorescence imaging provides real-time analysis of the membrane voltage potential, cytosolic Ca2+ dynamics, and insulin release during perfusion under 3 or 11 mM glucose.ResultsWe found that simvastatin reversibly inhibits insulin secretion, even in high-glucose. This phenomenon is very rapid (<60 s), occurs without affecting Ca2+ concentrations, and is likely unrelated to cholesterol biosynthesis and protein isoprenylation, which occur on a time span of hours.ConclusionsOur data provide the first real-time live demonstration that a statin inhibits insulin secretion in intact islets and that single islets respond differently from cell lines on a short time scale.FundingUniversity of Padova, EASD Foundation.Electronic supplementary materialThe online version of this article (doi:10.1007/s13300-016-0210-y) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Simvastatin Rapidly and Reversibly Inhibits Insulin Secretion in Intact Single-Islet Cultures

et al. 2016

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“…A subsequent pooling of five dose-comparison statin trials with 30,000 participants yielded a similar result 4 , adding credence to the statin-diabetes link, though with the same caveats as before. Various plausible suggestions were made to suggest the potential of bias, even in the context of randomized trials 5 . In addition, a plethora of observational studies, all confounded to a greater or lesser extent by virtue of their design, investigated the same topic and produced a wide variety of results 6,7 .…”

Section: Introductionmentioning

confidence: 99%

Genetic insights into statin-associated diabetes risk

Swerdlow

Preiss

2016

Current Opinion in Lipidology

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Genetic studies indicate that the observed effect of statins on diabetes risk in trials is highly likely to be a true on-target effect. Although other recent studies have suggested that genetically determined lower LDL-cholesterol may be linked to diabetes risk, further data from both genetic studies and clinical trials of other LDL-cholesterol lowering agents are needed to confirm or refute this.

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“…11 Their argument is interesting. They propose that when an MCVE occurs in a blinded RCT of a statin, the study physician becomes less diligent in monitoring new onset of diabetes in that patient over the remainder of the trial.…”

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confidence: 97%

“…Using simulated data, Blackburn et al showed that if 10% of patients who experience an MCVE subsequently develop diabetes that was undetected or unreported, the meta-analyses of statin-diabetes association would become completely neutral. 11 However, even if the statin-diabetes association is sometimes an artifact, does any evidence from the world of basic science support a true link?…”

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confidence: 98%