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Lipoprotein insulin resistance measurement predicts future diabetes risk
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In healthy adults, a lipoprotein insulin resistance measurement can predict future risk for type 2 diabetes, according to a secondary analysis of the JUPITER trial.
“The lipoprotein insulin resistance (LPIR) score is a composite of six lipoprotein parameters measured by nuclear magnetic resonance spectroscopy that reflects the lipoprotein derangements of insulin resistance, which may be apparent months or years before the clinical detection of hyperglycemia,” Samia Mora, MD, MHS, associate professor at Harvard Medical School and cardiologist and director of the Center for Lipid Metabolomics at Brigham and Women’s Hospital, Boston, told Endocrine Today. “In apparently healthy individuals, a simple blood test that measures LPIR, reflecting derangements in cholesterol metabolism, predicted future risk of type 2 diabetes. This was the case even among individuals with ‘normal’ glucose levels and also among individuals treated with a statin. “
Samia Mora
In a secondary analysis, Mora and colleagues analyzed data from 11,918 adults without diabetes at baseline who participated in the JUPITER trial, a worldwide, randomized, placebo-controlled trial conducted in 26 countries (4,334 women; mean age, 66 years) taking place between December 2003 and August 2008. Men aged at least 50 years and women aged at least 60 years had baseline LDL levels less than 130 mg/dL, high-sensitivity C-reactive protein levels at least 2 mg/L and triglyceride levels less than 500 mg/dL. Patients were randomly assigned 20 mg daily Crestor (rosuvastatin, AstraZeneca) or placebo.
Researchers measured size and concentration of lipids, apolipoproteins and lipoproteins at baseline and 12 months after randomization (n = 9,180). The LPIR score was calculated as a weighted combination of size and concentrations of LDL, VLDL and HDL particles.
A prespecified secondary aim of the study was to assess the effect of rosuvastatin on type 2 diabetes; 370 participants (212 from rosuvastatin arm) developed type 2 diabetes during a median 2-year follow-up.
Researchers found that rosuvastatin lowered the levels of LDL particles (–39.6%; 95% CI, –49.4 to –24.6), VLDL particles (–19.6%; 95% CI, –40.6 to 10.3) and VLDL triglycerides (–15.2%; 95% CI, –35.9 to 11.3), and shifted the lipoprotein subclass distribution toward smaller LDL size (–1.5%; 95% CI, –3.7 to 0.5), larger VLDL size (2.8%; 95% CI, –5.8 to 12.7) and lower LPIR score (–3.2%; 95% CI, –20.6 to 16.9). In multivariate analyses, HR for type 2 diabetes per standard deviation of LPIR score in the placebo arm was 1.99 (95% CI, 1.64-2.42) vs. 2.06 in the rosuvastatin arm (95% CI, 1.74-2.43).
After additional adjustment for systolic blood pressure, BMI, high-sensitivity C-reactive protein, HbA1c, HDL, LDL and triglycerides, LPIR score remained associated with type 2 diabetes in the placebo arm (HR = 1.35; 95% CI, 1.03-1.76) and rosuvastatin arm (HR = 1.6; 95% CI, 1.27-2.03). Similar trends were seen at 12 months.
The LPIR score improved the model likelihood ratio (chi-square test = 18.23; P < .001) and categorical net reclassification index (0.039; 95% CI, 0.003-0.072), driven mainly by reclassification of nonevents (0.036) and events (0.002).
“What this translates to for a particular patient is that his or her level of lipoprotein insulin resistance is an important determinant of whether they develop type 2 diabetes in the future, and for these at-risk individuals it is important to start lifestyle changes right away,” Mora said. “For patients who are about to start statin therapy, those who have abnormal levels of lipoprotein insulin resistance are much more likely to develop type 2 diabetes during statin therapy and deserve to be monitored more closely.”
Sagar B. Dugani, MD, PhD, clinical fellow in general internal medicine at St. Michael’s Hospital, Toronto, said the LPIR score has the potential to identify people at risk for developing diabetes independent of traditional markers such as HbA1c.
“As the global burden of diabetes rises, the LPIR score could become part of an overall approach to screen for diabetes and institute lifestyle changes,” Dugani told Endocrine Today. – by Regina Schaffer
For more information:
Samia Mora, MD, MHS, can be reached at the division of preventive medicine at Brigham and Women’s Hospital, 900 Commonwealth Ave. East, 3rd Floor, Boston, MA 02215; email: smora@partners.org.
Disclosure: Dugani reports no relevant financial relationships. Mora reports receiving grants from AstraZeneca and nonfinancial support from LipoScience during the study period, as well as grants from Atherotech Diagnostics and personal fees from Cerenis Therapeutics, Eli Lilly, Genzyme, Pfizer and Quest Diagnostics. Please see the full study for the other authors’ relevant financial disclosures.
Perspective
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Rachel H. Mackey, PhD, MPH, FAHA
The reasons for increased risk of diabetes with statin use is unknown. An analysis from the JUPITER randomized clinical trial of rosuvastatin vs. placebo showed that an LPIR score predicted incident type 2 diabetes over a median 2-year follow-up among both statin- and placebo-treated participants. LPIR added to other known diabetes risk factors in the prediction of diabetes risk in statin-treated and nonstatin-treated individuals, and associations were similar for baseline and 12-month LPIR levels. However, among statin-treated participants, 12-month changes in LPIR, and most of its constituent lipoprotein parameters, as well as triglycerides, HDL, the triglyceride/HDL ratio and apolipoprotein B, were in a favorable direction, suggesting changes in those parameters did not explain the effects of statins on diabetes risk. LPIR and other lipid and lipoproteins identify higher risk among statin-treated and nontreated individuals, but additional work is needed to identify mechanisms of statin-associated increased risk.
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