Comparative Effectiveness of Statins on Non-HDL Cholesterol by Type and Intensity in People with Diabetes and at Risk of Cardiovascular Disease: Systematic Review and Network Meta-Analysis

Objective: To compare the efficacy of different statin treatments by intensity on levels of non-high density lipoprotein cholesterol (non-HDL-C) for the prevention of cardiovascular disease in people with diabetes. Design: Systematic review and network meta-analysis. Data sources: Medline, Cochrane Central Register of Controlled Trials, and Embase from inception to 1 December 2021. Review methods: Randomised controlled trials comparing different types and intensities of statins, including placebo, in adults with type 1 or type 2 diabetes mellitus were included. The primary outcome was changes in levels of non-HDL-C, calculated from measures of total cholesterol and HDL-C. Secondary outcomes were changes in levels of low density lipoprotein cholesterol (LDL-C) and total cholesterol, three point major cardiovascular events (non-fatal stroke, non-fatal myocardial infarction, and death related to cardiovascular disease), and discontinuations because of adverse events. A bayesian network meta-analysis of statin intensity (low, moderate, or high) with random effects evaluated the treatment effect on non-HDL-C by mean differences and 95% credible intervals. Subgroup analysis of patients at greater risk of major cardiovascular events was compared with patients at low or moderate risk. The confidence in network meta-analysis (CINeMA) framework was applied to determine the certainty of evidence. Results: In 42 randomised controlled trials involving 20 193 adults, 11 698 were included in the meta-analysis. Compared with placebo, the greatest reductions in levels of non-HDL-C were seen with rosuvastatin at high (−2.31 mmol/L, 95% credible interval −3.39 to −1.21) and moderate (−2.27, −3.00 to −1.49) intensities, and simvastatin (−2.26, −2.99 to −1.51) and atorvastatin (−2.20, −2.69 to −1.70) at high intensity. Atorvastatin and simvastatin at any intensity and pravastatin at low intensity were also effective in reducing levels of non-HDL-C. In 4670 patients at greater risk of a major cardiovascular events, atorvastatin at high intensity showed the largest reduction in levels of non-HDL-C (−1.98, −4.16 to 0.26, surface under the cumulative ranking curve 64%). Simvastatin (−1.93, −2.63 to −1.21) and rosuvastatin (−1.76, −2.37 to −1.15) at high intensity were the most effective treatment options for reducing LDL-C. Significant reductions in non-fatal myocardial infarction were found for atorvastatin at moderate intensity compared with placebo (relative risk=0.57, confidence interval 0.43 to 0.76, n=4 studies). No significant differences were found for discontinuations, non-fatal stroke, and cardiovascular deaths. Conclusions: This network meta-analysis indicated that rosuvastatin, at moderate and high intensity doses, and simvastatin and atorvastatin, at high intensity doses, were most effective at moderately reducing levels of non-HDL-C in patients with diabetes. Given the potential improvement in accuracy in predicting cardiovascular disease when reduction in levels of non-HDL-C is used as the primary target, these findings provide guidance on which statin types and intensities are most effective by reducing non-HDL-C in patients with diabetes. Systematic review registration: PROSPERO CRD42021258819