Statins associated with new-onset diabetes in dose-dependent manner: Lancet

The study findings, The Lancet Diabetes & Endocrinology, reaffirm a dose-dependent association between statin therapy, which may be relevant for guidelines and shared decision-making. However, these glycaemic effects do not outweigh the statin therapy benefit among individuals for whom they are recommended.

"Statins cause a moderate dose-dependent increase in new diabetes diagnoses that are consistent with a small upward shift in glycemic, with the majority of new diagnoses of diabetes occurring in people with baseline glycaemic markers that are close to the diagnostic threshold for diabetes," the researchers wrote.

"Importantly, however, any theoretical adverse effects of statins on the cardiovascular (CV) risk that might arise from these small increases in glycemia are already accounted for in the overall reduction in CV risk seen with statin therapy in these trials."

Previous meta-analyses of summary data from randomized controlled trials (RCTs) have revealed that stating therapy raises the risk of diabetes, however, not much is known about the timing or size of this effect, or who is at greatest risk. To fill this knowledge gap, Christina Reith and colleagues from Cholesterol Treatment Trialists’ (CTT) Collaboration, analyzed individual participant data from large, long-term, randomized, double-blind trials of statin therapy.

For this purpose, the researchers conducted a meta-analysis of individual participant data from RCTs of statin therapy that participated in the CTT Collaboration. The meta-analysis included double-blind RCTs of statin therapy of at least 2 years' scheduled duration and with at least 1000 participants. All recorded diabetes-related adverse events, measures of glycemia, and treatments were sought from eligible trials.

Meta-analyses assessed the effects of allocation to statins on new-onset diabetes and on worsening glycemia in people with diabetes. New-onset diabetes was defined as the use of new glucose-lowering medications, diabetes-related adverse events, glucose concentrations, or HbA1c values.

Of the trials participating in the CTT Collaboration, 19 trials compared statin versus placebo (123 940 participants, 21% with diabetes; median follow-up of 4·3 years), and four trials compared more versus less intensive statin therapy (30 724 participants, 17% with diabetes, median follow-up of 4·9 years).

The study led to the following findings:

• Compared with placebo, allocation to low-intensity or moderate-intensity statin therapy resulted in a 10% proportional increase in new-onset diabetes, and allocation to high-intensity statin therapy resulted in a 36% proportional increase.
• For each trial, the rate of new-onset diabetes among participants allocated to receive a placebo depended mostly on the proportion of participants who had at least one follow-up HbA1c measurement; this proportion was much higher in the high-intensity than in the low-intensity or moderate-intensity trials.
• The main determinant of the magnitude of the absolute excesses in the two types of trials was the extent of HbA1c measurement rather than the proportional increase in risk associated with statin therapy.
• In participants without baseline diabetes, mean glucose increased by 0·04 mmol/L with both low-intensity or moderate-intensity and high-intensity statins, and mean HbA1c increased by 0·06% with low-intensity or moderate-intensity statins and 0·08% with high-intensity statins.
• Among those with a baseline measure of glycemia, approximately 62% of new-onset diabetes cases were among participants who were already in the top quarter of the baseline distribution.
• The relative effects of statin therapy on new-onset diabetes were similar among different types of participants and over time.
• Among participants with baseline diabetes, the RRs for worsening glycemia were 1·10 for low-intensity or moderate-intensity statin therapy and 1·24 for high-intensity statin therapy compared with placebo.

In conclusion, among individuals without diabetes, statin therapy produces a dose-dependent rise in the rate of diabetes diagnosis by inducing a small increase in glycemia. People are most at risk of exceeding the diagnostic threshold for diabetes due to statins if their glycaemic control is close to the threshold before treatment.

"The diabetes-related risks arising from the small changes in glycemia resulting from statin therapy greatly outweighed the benefits of statins on major vascular events when the direct clinical consequences of these outcomes are taken into consideration," the researchers wrote.

Reference:

Cholesterol Treatment Trialists’ (CTT) Collaboration. Electronic address: ctt@ndph.ox.ac.uk; Cholesterol Treatment Trialists’ (CTT) Collaboration. Effects of statin therapy on diagnoses of new-onset diabetes and worsening glycaemia in large-scale randomised blinded statin trials: an individual participant data meta-analysis. Lancet Diabetes Endocrinol. 2024 Mar 26:S2213-8587(24)00040-8. doi: 10.1016/S2213-8587(24)00040-8. Epub ahead of print. PMID: 38554713.