Diabetes Progression in Statin-Treated Patients: VA Data

Statins are known to be associated with increased insulin resistance and higher blood glucose levels, but now a new observational study demonstrates that these metabolic changes translate into clinically meaningful outcomes in patients with diabetes—namely, an increased risk of disease progression requiring the initiation of insulin and new prescriptions for glucose-lowering medications.

Physicians need to be vigilant in balancing the benefit of statins against metabolic affects that may detrimentally impact patients with diabetes, say researchers. More research, they add, is needed to specifically examine the trade-off.

“We know well about the benefits, but the harms are much less investigated,” lead author Ishak A. Mansi, MD (UT Southwestern Medical Center/VA North Texas Health Care System, Dallas), told TCTMD. “Observational data and registries can be an excellent method to examine this topic. Specifically, what are the population’s characteristics that may benefit less from use of statins for primary prevention or get more harm? This type of study should be prioritized since diabetes is very common in the USA and the world. Answering these questions impacts hundreds of millions of patients and cannot be postponed.”

Nearly 10 years ago, the US Food and Drug Administration mandated changes to the label of all statins, with the exception of pravastatin, stating the drugs can raise blood sugar and HbA1c levels. Red flags were largely raised after the 2008 publication of the JUPITER trial with rosuvastatin, but increased risks have been observed in other studies. In one meta-analysis of 13 studies, it was demonstrated that statin therapy increased the risk of new-onset diabetes by 9%.

In diabetic patients, several randomized trials and observational studies have shown that statin therapy is associated with increased insulin resistance, which in turn may result in less controlled diabetes and/or the escalation of medications to control blood glucose levels, said Mansi. Annual visits to the emergency department (ED) for hyperglycemic crises almost doubled between 2009 and 2015, while hospitalizations increased by nearly 75% and related deaths by 55%, according to data from the Centers for Disease Control and Prevention. While Mansi emphasized that he is not blaming statin use for the increase in ED visits and hospitalizations, “it is prudent to examine everything we do.”

The American Diabetes Association (ADA) and American College of Cardiology/American Heart Association recommend statin therapy for patients aged 40 to 75 years with type 2 diabetes mellitus and LDL-cholesterol levels of 70 mg/dL or greater.

Robert Gabbay, MD, PhD, the chief scientific and medical officer of the ADA, said the new analysis builds on available evidence that statins increase the risk of insulin resistance and “slightly increase” the development of diabetes.

“We need to weigh the risk of diabetes and the advancement of diabetes therapy seen in this study versus the known and well-established impact of statins to decrease cardiovascular disease and death,” he said in an emailed statement. “Statin use has been responsible for saving many lives of people with diabetes, and the authors are not suggesting that people with diabetes stop their statin medications.”

For Gabbay, the study emphasizes the importance of tracking blood-glucose levels closely and adjusting therapy as needed, a conclusion that aligns with the ADA’s efforts to overcome therapeutic inertia when it comes to escalating therapy. Mansi echoed the point, noting that their research should remind clinicians to pay close attention to statin-treated patients with diabetes and expect to adjust medications, which is a common practice in the management of that disease.

Rationale for Research

Published October 4, 2021, in JAMA Internal Medicine, the new study matched 83,022 diabetic patients treated with statins against an equal number of active-comparator patients (taking an H2-blocker or proton pump inhibitor). On average, the statin-treated patients were on the therapy for 5.3 years, with 63.4% filling a prescription for simvastatin, 12.4% for atorvastatin, 10.5% for rosuvastatin, and 9.5% for pravastatin. In the matched cohorts, 68.2% of patients were white, 21.5% were Black, 2.1% were American Indian or from the Pacific Islands/Alaska, and 0.8% were Asian. The vast majority (94.9%) of participants were men.

We need to weigh the risk of diabetes and the advancement of diabetes therapy seen in this study versus the known and well-established impact of statins to decrease cardiovascular disease and death. Robert Gabbay

The progression of diabetes was defined as the need for escalating therapy, such as starting insulin or an increase in the number of glucose-lowering medications during follow-up, and new persistent hyperglycemia or acute glycemic complications. Among statin users, progression was reported in 55.9% of participants compared with 48.0% of participants in the active-comparator group (OR 1.37; 95% CI 1.35-1.40).

In terms of individual components of the primary outcome, 14.4% of statin users started insulin during follow-up compared with 12.7% of those not on statins (P < 0.001). Similarly, 51.3% of statin-treated patients required the use of more glucose-lowering drugs compared with 42.8% in the comparator arm (P < 0.001). Additionally, statin users had a relative 13% higher risk of persistent hyperglycemia and a 24% higher risk of developing ketoacidosis or uncontrolled diabetes, both of which were significantly higher compared with controls. Compared with the active-comparator group, the odds of diabetes progression were 83%, 55%, and 43% higher in patients treated with high-, moderate-, and low-intensity lipid lowering, respectively.

In terms of the risk-benefit equation, Mansi said their study was not designed to address this issue but pointed out that the healthiest patients in their analysis had a greater risk of diabetes progression than the overall cohort. In a secondary analysis that focused only on patients without comorbidities at baseline, statin-treated patients had a 56% higher risk of diabetes progression compared with controls.

“Of course, we have to differentiate between using statins for primary prevention of cardiovascular diseases and those using statins for secondary prevention,” he said. “In the latter group, statins are one of the most important lines of treatment and their benefits are tremendous. Even in the primary prevention arm, the risk may extensively vary between different patients with diabetes based on presence of other risk factors and factors related to their diabetes status itself.”

While no single study should dictate treatment policy, nor lead to any patient stopping their medication, Mansi said that adding up the lines of research suggests more study is needed about unintended side effects of commonly used medications, research that can be difficult to get done. “There is no dedicated funding mechanism for a study like our study,” said Mansi. “I can see many researchers deterred from performing necessary research due to difficulty in obtaining funding.”