Metabolic Markers to Predict Incident Diabetes Mellitus in Statin-Treated Patients (from the Treating to New Targets and the Stroke Prevention by Aggressive Reduction in Cholesterol Levels Trials)

Kohli P, Knowles JW, Sarraju A, et al.
Am J Cardiol 2016;published online ahead of print

Background

Statin therapy has been associated with the development of type 2 DM, particularly in patients with higher blood pressures, elevated fasting plasma glucose (FPG) and higher triglyceride (TG) concentrations [1]. These parameters are also associated with insulin resistance, an independent predictor of T2DM [2,3].
It is hypothesised that the identification of insulin-resistant individuals before the initiation of statin treatment would decrease the risk of developing statin-related T2DM. Insulin resistance is increased in patients with prediabetes mellitus (PreDM), which is defined by an FPG concentration of ≥5.6 mmol/l (100 mg/dl) and <7.0 mmol/L (126 mg/dl) [4,5].
In this study, the impact of combining a diagnosis of PreDM with a measurement of either fasting TG concentration >1.7 mmol/l (>150 mg/dl) or a BMI of ≥27.0 kg/m² on the identification of individuals on high risk of statin-associated T2DM was evaluated. 939 incident cases (8.2%) of T2DM were identified during a median follow-up of 4.9 years, in a study population pooled from patients without DM in the Treating to New Targets (TNT) and the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trials.

Main results

• The incidence of T2DM increased progressively in statin-treated patients with: normal fasting glucose (NFG) and TG ≤ 1.7 mmol/l: 2.8%, NFG and TG >1.7 mmol/l: 5.2%, PreDM and TG ≤ 1.7 mmol/l: 12.8% and PreDM and a TG >1.7 mmol/l: 22.8%.

• In patients with PreDM, there was a substantially increased baseline risk for incident T2DM even with placebo treatment. Incident T2DM occurred in 7.6% of placebo treated patients with PreDM and TG ≤ 1.7 mmol/l, and 17.9% of placebo treated patients with PreDM and TG >1.7 mmol/l.
• Statin treatment significantly increased the risk of T2DM in patients with PreDM compared to placebo: 22.8% of PreDM patients and TG >1.7 mmol/l developed incident T2DM, a 27% increased risk versus those on placebo.

• HR for developing T2DM on statin treatment was significantly higher (p <0.001) in patients with either a TG concentration of >1.7 mmol/L (1.5; 95% CI: 1.2-2.0), or PreDM 4.0; 95% CI: 3.3-4.9, or both (6.7; 95% CI: 5.4-8.2), compared to those with NFG and TG ≤ 1.7 mmol/l.

• Similar results were seen for the combination of PreDM and BMI, with HR for patients with NFG and BMI ≥ 27 kg/m²: 1.4; 95% CI: 1.1-1.9, HR for patients with PreDM and BMI <27 kg/m²: 3.5; 95% CI: 2.7-4.5, HR for patients with PreDM and BMI ≥27 kg/m²: 7.0; 95% CI: 5.6-8.6.

Conclusion

These data suggest that the statin-related incidence of T2DM is quite modest, but is aggravated if plasma glucose, TG concentrations and BMI increase.  The authors have created a simple 4-tier category system, based on PreDM, TG concentrations and BMI, which may be helpful in identifying individuals at high risk of developing statin-associated T2DM.

Find this article online at Am J Cardiol

References

1. Waters DD, Ho JE, DeMicco DA, et al. Predictors of new-onset diabetes in patients treated with atorvastatin: results from 3 large randomized clinical trials. J Am Coll Cardiol 2011;57:1535e1545.
2. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988;37:1595e1607.
3. Lillioja S, Mott DM, Spraul M, et al. Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus. Prospective studies of Pima Indians. N Engl J Med 1993;329:1988e1992.
4. Novoa FJ, Boronat M, Saavedra P, et al. Differences in cardiovascular risk factors, insulin resistance, and insulin secretion in individuals with normal glucose tolerance and in subjects with impaired glucose regulation: the Telde Study. Diabetes Care 2005;28:2388e2393.
5. Kohli P, Waters DD, Nemr R, et al. Risk of new-onset diabetes and cardiovascular risk reduction from high-dose statin therapy in pre-diabetics and nonpre-diabetics: an analysis from TNT and IDEAL. J Am Coll Cardiol 2015;65:402e404.