Statins Work for Primary Prevention Even in Low-risk Patients With Type 2 Diabetes

Using statins for primary prevention is safe and beneficial in adults with type 2 diabetes irrespective of their estimated 10-year risk of cardiovascular disease at baseline, a target trial emulation study suggests.

Though the estimated benefits increased along with baseline QRISK3 predicted risk, there were significant long-term reductions in all-cause mortality and major CVD events even among the lowest-risk patients who started statins versus those who did not, researchers led by Vincent Ka Chun Yan, PhD, and Joseph Edgar Blais, PhD (both from the University of Hong Kong), report.

Statin use was not associated with substantial differences in myopathy or liver dysfunction, according to findings published online recently in Annals of Internal Medicine. The study did not explore potential impacts on glucose control.

The balance of risks and benefits “strongly favors statin use,” senior author Eric Yuk Fai Wan, PhD (University of Hong Kong), told TCTMD via email.

“We expected statins to help higher-risk patients but were surprised by the consistent benefit even in low-risk groups—especially those with elevated LDL cholesterol,” he said. “The safety profile was also reassuring, with no significant liver harm and only a very small increase in muscle-related issues.”

Uncertainty at Lower Risk Levels

International guidelines on primary prevention in patients with type 2 diabetes are not consistent when it comes to thresholds of predicted 10-year CVD risk that would justify starting statins. There is uncertainty about whether the lipid-lowering medications should be used when baseline risk is low, Wan noted, as previous trials have mostly excluded younger or low-risk patients and have had only short follow-up.

The investigators aimed to fill that gap by examining outcomes associated with statin use in patients across the risk spectrum. They performed a target trial emulation study based on primary care data from the United Kingdom that were included in the IQVIA Medical Research Data resource. The analysis included patients ages 25 to 84 years who were diagnosed with type 2 diabetes between 2005 and 2016 and had no history of statin use, coronary artery disease, MI, stroke, heart failure, myopathy, liver disease, rheumatic heart disease, schizophrenia, or cancer.

Patients were divided into four groups depending on their predicted 10-year risk of CVD based on the QRISK3 tool: low (< 10%), intermediate (10% to 19%), high (20% to 29%), and very high (≥ 30%). After propensity-score matching, the analysis included 64,589 eligible person-trials for the low-risk group, 117,630 for the intermediate-risk group, 101,262 for the high-risk group, and 135,067 for the very-high-risk group. Based on 1:4 matching, 20% of patients initiated statins and the rest did not.

Mean age was 44 years in the low-risk stratum, as compared to 68 years among those with very high risk at baseline. The proportion of men was lower in the low-risk stratum (41%) than in the intermediate- (52%), high- (61%), and very-high-risk (66%) groups.

Through a median follow-up of 81 months for statin initiators and 75 months for those who didn’t take statins, use of the lipid-lowering drugs was associated with reduced risks of all-cause mortality and major CVD events (MI, stroke, or heart failure) across risk strata in an intention-to-treat (ITT) analysis.

Outcomes Across QRISK3 Strata: Statin Initiators vs Noninitiators

There were no significant differences in risks of myopathy or liver dysfunction based on statin use.

The findings of a per-protocol (PP) analysis were largely consistent with the ITT results, with larger effect sizes. There was a small increased risk for myopathy (0.08% absolute difference) associated with statin use in the patients who had an intermediate predicted risk of CVD at baseline.

In both the ITT and PP analyses, the reductions in mortality and major CVD events observed in the low-risk stratum appeared to be confined to patients with a baseline LDL-cholesterol level ≥ 2.6 mmol/L (about 101 mg/dL) or a baseline non-HDL cholesterol level ≥ 3.4 mmol/L (about 131 mg/dL).

“Clinicians should consider statins for most adults with type 2 diabetes mellitus, not just those at high risk—especially if LDL cholesterol is elevated,” Wan said. “Long-term adherence is key, as benefits become clear after several years.”

The results, he continued, “support a more inclusive approach to statin therapy in diabetes mellitus and may help harmonize international guidelines. They provide strong evidence for lowering or removing rigid risk thresholds in favor of individualized decisions.”