Another Study Ties Statins to T2D: Should Practice Change?

Studies have shown links between statin use and type 2 diabetes (T2D) for more than a decade. A US Food and Drug Administration label change for the drugs warned in 2012 about reports of increased risks of high blood glucose and glycosylated hemoglobin (A1c) levels. However, in the same warning, the FDA said it "continues to believe that the cardiovascular benefits of statins outweigh these small increased risks."

Indeed, although the warning triggered much discussion at the time and a number of meta-analyses and other observational studies in more recent years, that conclusion seems to hold among clinicians and society guidelines.

For example, in a recent practice pointer on the risk of diabetes with statins published in the BMJ, Ishak Mansi, MD, of the Orlando VA Health Care System, Orlando, Florida and colleagues, write, "This potential adverse effect of diabetes with statin use should not be a barrier to starting statin treatment when indicated."

They also called for further research to answer such questions as, "Is statin-associated diabetes reversible upon statin discontinuation? Would intermittent use minimize this risk while maintaining cardiovascular benefits?"

An earlier study among individuals at high risk for diabetes found significantly higher rates of incident diabetes at 10 years among patients on placebo, metformin, or lifestyle intervention who also initiated statin therapy. Jill Crandall, MD, Albert Einstein College of Medicine, New York City, and colleagues conclude, "For individual patients, a potential modest increase in diabetes risk clearly needs to be balanced against the consistent and highly significant reductions in myocardial infarction, stroke and cardiovascular death associated with statin treatment."

In the same vein, a recent review by Byron Hoogwerf, Emeritus, Department of Endocrinology, Diabetes, and Metabolism, Cleveland Clinic, Cleveland, Ohio, is titled, "Statins may increase diabetes, but benefit still outweighs risk."

Rosuvastatin vs Atorvastatin

The latest study in this arena is an analysis of the LODESTAR randomized controlled  trial of 4400 patients with coronary artery disease in 12 hospitals in Korea and compares the risks associated with individual statins.

Dr Myeong-Ki Hong

Senior author Myeong-Ki Hong, MD, PhD, Yonsei University College of Medicine, Severance Cardiovascular Hospital, Seoul, South Korea, told theheart.org | Medscape Cardiology that the study was prompted by the "limited" studies evaluating clinical outcomes, including diabetes risk, according to statin type.

Hong and colleagues compared the risk of developing diabetes among those taking rosuvastatin (mean daily dose, 17.1 mg) or atorvastatin (mean daily dose 36 mg) for 3 years. While both statins effectively prevented myocardial infarction, stroke, and death, those taking rosuvastatin had a higher incidence of new-onset T2D requiring initiation of antidiabetic drugs (7.2% v 5.3%; hazard ratio [HR], 1.39) and cataract surgery (2.5% v 1.5%; HR, 1.66).

Overall, the HR of new-onset T2D was 1.29 (95% CI, 1.01 - 1.63; P = .04).

"The percentages of new-onset diabetes and cataract are in line with previous studies regarding statin therapy in patients with atherosclerotic cardiovascular disease," Hong said. "Additional research specifically focusing on these outcomes is required, with more frequent measurement of glucose and A1c levels to detect new-onset diabetes and regular ophthalmologic examinations to detect cataracts."

"However,” he added, "when using rosuvastatin over atorvastatin, we…emphasize the importance of meticulous monitoring and appropriate lifestyle interventions to mitigate the risk of new-onset diabetes or cataracts."

Steven Nissen, MD, chief academic officer of Cleveland Clinic's Heart and Vascular Institute, was not convinced, and said the study "does not provide useful insights into the use of these drugs."

Dr Steven Nissen

The investigators used whatever dose they wanted, "and the authors report only the median dose after 3 years," he told theheart.org | Medscape Cardiology. "Because there was a slightly greater reduction in low-density lipoprotein (LDL) cholesterol with rosuvastatin, the relative dose was actually higher."

"We know that new-onset diabetes with statins is dose-dependent," he said. "The P-values for diabetes incidence were marginal (very close to P = .05). Accordingly, the diabetes data are unconvincing...The similar efficacy is not surprising given the open-label dosing with relatively similar effects on lipids."

Dr Seth Shay Martin

Seth Shay Martin, MD, MHS, director of the Advanced Lipid Disorders Program and Digital Health Lab, Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins Medicine, Baltimore, also commented on the results. The findings are "in line with existing knowledge and current guidelines," he said. "Therefore, the study should not influence prescribing."

"Although the study suggests that rosuvastatin was associated with a higher risk of new-onset diabetes mellitus requiring antidiabetics and cataract surgery compared with atorvastatin, these findings should be interpreted with caution given the open-label nature of the study, and require further investigation," he said.

"The mean daily doses of statins were somewhat below target for secondary prevention," he noted. "Ideally, patients with coronary artery disease (CAD) take 20 to 40 mg daily of rosuvastatin or 40 to 80 mg daily of atorvastatin."

“Furthermore, the LDL cholesterol levels were not optimized in the patients," he said. "The mean LDL-C was 1.8 to 1.9 mmol/L, which is equivalent to 70 to 73 mg/dL. In the current treatment era, we generally treat to LDL-C levels <70 mg/dL and often <55 mg/dL in CAD patients."

"The cataracts finding is particularly odd," he added. "There was historic concern for cataracts with statin therapy, initially because of studies in beagle dogs. However, high-quality evidence from statin trials has not shown a risk for cataracts." 

So which statin has the lowest risk of triggering new-onset diabetes? As Hong noted, the literature is sparse when it comes to comparing the risk among specific statins. Some studies suggest that the risk may depend on the individual and their specific risk factors, as well as the dose and intensity of the prescribed statin.

One recent study suggests that while the overall chance of developing diabetes is small, when looking at risk by years of exposure, atorvastatin, rosuvastatin, and lovastatin carried the largest risk, whereas the risk was lower with pravastatin and simvastatin.

Risks also seemed lower with fluvastatin and pitavastatin, but there were too few study patients taking those drugs long-term to include in the subanalysis.

With input from the latest guidelines from the American Heart Association (AHA) and the American Diabetes Association, as well as findings from a clinical guide on statin-associated diabetes, Hoogwerf suggests in his review that shared decision-making before starting statin therapy of any type include the following considerations/discussion points:

• For all patients: Screening to determine baseline glycemic status; nonstatin therapies to lower cholesterol; and variables associated with an increased risk of diabetes, including antihypertensive drugs.

• For patients without T2D: The possibility of developing T2D; types and doses of statins; the fact that statin benefits "generally far outweigh" risks of developing diabetes.

• For patients with T2D: Possible small adverse effects on glycemic control; statin benefits in reducing risk for atherosclerotic cardiovascular disease, which "significantly outweigh" the small increase in A1c; and mitigation of adverse glycemic effects of statins with glucose-lowering therapies.

It's worth noting that the AHA and ADA guidelines, among others, also emphasize that such discussions should include the importance of weight loss, regular exercise, and adhering to a healthy lifestyle to mitigate risks of both diabetes and heart disease, with or without statins.

Hong, Nissen, and Martin report no relevant financial relationships. Hoogwerf has disclosed ownership interest in Eli Lilly and consulting for MannKind and Zealand Pharmaceuticals.

BMJ. Published online October 18, 2023. Full text

https://www.medscape.com/viewarticle/997884