Which statin (HMG-CoA reductase inhibitor) drugs are most commonly associated with early onset diabetes mellitus?

Statin Drugs and Early Onset Diabetes Risk

High-intensity statins, particularly rosuvastatin and atorvastatin, are most commonly associated with early onset diabetes mellitus, with rosuvastatin showing the highest risk in women and atorvastatin 80mg showing the highest overall risk across populations. 1

Risk Hierarchy by Statin Type

• High-intensity statins (atorvastatin 80mg, rosuvastatin 20-40mg) have approximately 3 excess cases of incident diabetes per 1,000 individuals treated for 1 year compared to placebo (NNH=332 per year) 1

• Atorvastatin 80mg shows the highest risk of diabetes development with an odds ratio of 1.34 (95% CI 1.14-1.57) compared to other statins 2

• Rosuvastatin follows closely with an odds ratio of 1.17 (95% CI 1.02-1.35), with particularly higher risk observed in women (HR 1.49; 95% CI: 1.11-2.01) compared to men (HR 1.14; 95% CI: 0.91-1.43) 1, 2

• Simvastatin shows a moderate risk (OR 1.13; 95% CI: 0.99-1.29) 2

• Pravastatin demonstrates the lowest risk among commonly used statins (OR 1.04; 95% CI: 0.93-1.16) 2, 3

• Pitavastatin appears to have a neutral or potentially beneficial effect on glucose metabolism compared to other statins 4

Dose-Dependent Effects

• High-intensity statin therapy is associated with 2 excess cases of incident diabetes per 1,000 individuals treated for 1 year compared with moderate-intensity statins (NNH=498 per year) 1

• The risk appears to be dose-dependent, with higher doses of atorvastatin and rosuvastatin showing greater diabetogenic effects 1, 2, 5

• According to the 2024 meta-analysis, high-intensity statins showed a 24% increased risk of worsening glycemia (RR 1.24; 95% CI 1.06-1.44) compared to 10% with low-to-moderate intensity statins (RR 1.10; 95% CI 1.06-1.14) 1

Mechanisms and Risk Factors

• Statin-induced diabetes appears to be related to multiple mechanisms including:

  • Increased insulin resistance
  • Impaired insulin secretion from pancreatic β-cells
  • Decreased adipocyte differentiation 6

• The risk is highest in individuals who already have risk factors for diabetes:

  • Older persons have higher risk (NNH=1,002 per year) 1
  • Patients with metabolic syndrome components 1
  • Those with pre-existing impaired fasting glucose (80% of incident diabetes in the JUPITER trial occurred in those with impaired fasting glucose at study entry) 1

Clinical Implications

• Despite the increased diabetes risk, the cardiovascular benefit of statins outweighs the diabetes risk in most patients 1

• High-intensity statin therapy results in 6.5 fewer major cardiovascular events per 1,000 individuals treated for 1 year compared with moderate-intensity statin therapy (NNT=155 per year) 1

• Screening for new-onset diabetes should be performed in patients on statin therapy, particularly those on high-intensity regimens 1

• For patients at high risk of diabetes who require lipid-lowering therapy, pitavastatin may be considered as it appears to have a more neutral effect on glucose metabolism 4

• Pravastatin may be the preferred option among traditional statins for patients at high diabetes risk, as it shows the lowest diabetogenic potential 2, 3

Monitoring Recommendations

• Baseline assessment of glycemic parameters before starting statin therapy 1

• Regular monitoring of fasting plasma glucose and HbA1c in patients on high-intensity statins, particularly those with pre-existing risk factors for diabetes 1

• The absolute risk increase is approximately one case of incident diabetes for every 1,000 women taking statins per year in the Women's Health Initiative study 1

• High-intensity statins are associated with an incidence of diabetes of 0.3 per 100 persons treated, compared to 0.1 per 100 in those without statin treatment 1