Among adults with type 2 diabetes (T2D), statin initiation was associated with reductions in the risks for all-cause mortality and major cardiovascular disease (CVD) regardless of their predicted short-term cardiovascular risk, according to the results of a large cohort study.

In addition, there was little or no increase in myopathy or liver dysfunction, although myalgia was more frequent with statin initiations than with nonstatin initiators.

“We anticipated benefit in higher-risk patients, but the consistency of benefit across all strata, including low-risk individuals, was striking,” said lead author Eric Yuk Fai Wan, PhD, associate professor in the Department of Family Medicine and Primary Care and Department of Pharmacology and Pharmacy at the University of Hong Kong in Hong Kong, China.

“Even modest absolute risk reductions in low-risk patients are clinically meaningful, especially given the excellent safety profile,” he told Medscape Medical News.

The findings were recently published in the Annals of Internal Medicine. The first author is Vincent Ka Chun Yan, PhD, also of the University of Hong Kong.

“Clinicians should consider statins for most adults with T2D, not only those at high risk, particularly if LDL [low-density lipoprotein] cholesterol is elevated,” Wan advised. “Long-term adherence is essential as benefits emerge after several years. Shared decision-making remains key, but the risk-benefit balance strongly favors statin use.”

Benefit Regardless of Baseline CVD Risk

The cohort study, using the IQVIA Medical Research Data UK database, included more than 4.5 million adults aged 25-84 years with a diagnosis of T2D between 2005 and 2016 and no baseline history of coronary artery disease, myocardial infarction, stroke, heart failure, myopathy, liver disease, rheumatic heart disease, schizophrenia, or cancer.

The adults were stratified into one of four groups based on their baseline QRISK3 score for predicted 10-year CVD risk: low (< 10%), intermediate (10%-19%), high (20%-29%), or very high (≥ 30%). After 1:4 propensity score matching to reduce confounding, 64,589, 117,630, 101,262, and 135,067 individuals in each group, respectively, were included in the study. Approximately 20% of each group initiated statins at baseline.

Over a median follow-up of 81 months for statin initiators and 75 months for nonstatin initiators in the intent-to-treat analysis, there were a total of 6858 and 32,606 deaths from any cause and 5682 and 26,677 major cardiovascular events among statin users and nonusers, respectively.

Statin initiation was associated with 10-year absolute risk reductions for all-cause mortality of 0.53%, 1.88%, 2.74%, and 4.30% for those in the low, intermediate, high, and very high groups, respectively. All were statistically significant.

For major CVD, the 10-year risk reductions were 0.83%, 2.14%, 2.59%, and 4.57%, respectively. Here, all but the reduction in the lowest QRISK3 score group were statistically significant.

There was no detectable difference in the risk for myopathy or liver dysfunction by statin use. Findings were mostly consistent among all age, sex, and baseline LDL cholesterol groups and by baseline statin intensity. However, among the lowest baseline CVD risk group, reductions in all-cause mortality and major CVD with statin use were only significant among those with baseline LDL cholesterol ≥ 2.6 mmol/L.

Findings of the per-protocol analysis taking into account the 30% who discontinued statin therapy and 15% who initiated statins after the trial began without an indication were generally consistent but of greater magnitude. Here, there were also no differences in myopathy or liver function. However, there was a small increased risk for myopathy in patients in the two lowest baseline QRISK3 score groups when the myopathy definition included muscle pain.

‘Broadly Consistent’ With Previous Studies

Asked to comment, Naveed Sattar, MB ChB, PhD, professor of cardiometabolic medicine and honorary consultant at the School of Cardiovascular & Metabolic Health, University of Glasgow, Glasgow, Scotland, told Medscape Medical News that the paper was “well conducted,” but “as it is observational in nature, the possibility of residual confounding remains.”

Sattar also pointed out that “the findings are broadly consistent with evidence from randomized trials. The observation that risk is also reduced in individuals with T2D and a cardiovascular risk below 10% aligns with meta-analyses of statin trials in those at lower cardiovascular risk conducted largely in nondiabetes populations.”

Change in Guidelines?

Guidelines on statin use for people with T2D vary. In 2018, the American Heart Association and the American College of Cardiology recommended statin therapy for all adults aged 40-75 years with diabetes regardless of the 10-year risk for CVD. In 2019, the European Society of Cardiology and the European Atherosclerosis Society recommended reducing LDL cholesterol in those with T2D at high or very high risk.

The National Institute for Health and Care Excellence and US Preventive Services Task Force recommend statins for people with T2D who have a predicted 10-year CVD risk of 10% or higher.

Wan told Medscape Medical News, “Our findings support a more inclusive approach to statin therapy in T2D and may prompt guideline committees to reconsider rigid risk thresholds. While practice change often requires replication in other populations, our results provide strong real-world evidence that could influence future updates.”

Sattar commented, “These results are not unexpected as statins are well established to lower major adverse cardiovascular event (MACE) risk in both diabetes and non-diabetes individuals by similar amounts for a given LDL cholesterol reduction. The present results will therefore not change current guidelines, though as statins are now so cheap, and safe their use could be argued in those at progressively lower risk levels.”

“There is a broader perspective to consider. Efforts to reduce MACE in T2D and related conditions must be accompanied by interventions that address obesity. Without such action, more people will live longer with multiple chronic conditions, resulting in greater suffering and escalating healthcare costs across high-income countries,” he added.

“The same challenges will inevitably affect low- and middle-income countries as obesity prevalence rises globally. Therefore, a far greater focus on holistic care, particularly prioritizing obesity management, must become a central component of cardiometabolic disease prevention and treatment strategies.”

The study was supported by the National Natural Science Foundation of China Excellent Young Scientists Fund. Fan received research grants from the Health Bureau; the Hong Kong Research Grants Council; Narcotics Division, Security Bureau; and the Social Welfare Department, Labour and Welfare Bureau of the Government of the Hong Kong SAR and the National Natural Science Foundation of China. He reported serving as member of Core Team for Expert Group on Drug Registration of Pharmacy and Poisons Board and being the director of Advanced Data Analytics for Medical Science Limited.

Sattar reported receiving consulting, advisory, funding grants, and/or speaking/lecture fees from Boehringer Ingelheim, Roche Diagnostics Corporation, Abbott Laboratories, AbbVie, Amgen, Eli Lilly, Hanmi Pharmaceutical, Janssen, Menarini Ricerche, Novo Nordisk, Pfizer, and Sanofi.

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape Medical News, with other work appearing in the Washington Post, NPR’s Shots blog, and diaTribe. She is on X @MiriamETucker and BlueSky @miriametucker.bsky.social.