Statin therapy initiation is associated with diabetes progression

1. A group of patients who newly initiated statins, compared to one that newly initiated another type of type 2 diabetes medication, had an increased odds of their diabetes progressing.

2. Participants with the greatest LDL cholesterol reduction had the worst diabetes progression.

Evidence Rating Level: 2 (Good)

Study Rundown: Statins are recommended for patients with diabetes type 2 with a high low-density lipoprotein (LDL) cholesterol level to prevent cardiovascular disease, but they may worsen insulin resistance and may increase blood glucose levels, including fasting and hemoglobin A_1C (HbA_1C). Understanding the impact of statins on insulin resistance is important to identify if they progress diabetes. This retrospective cohort study compared patients who used statins (statin users) to a matched active comparator group (patients who initiated an H2-blocker or proton pump inhibitor and not a statin) on their diabetes therapy severity (insulin amount and the number of glucose-lowering medication classes taken) and glycemic control (number of episodes of hyperglycemia, number of times of extremely high blood glucose levels, or a new diagnosis of ketoacidosis or uncontrolled diabetes). The matched groups (n = 83,022) had comparable baseline characteristics. The chance of progression of diabetes was higher in the statin user group than the non-statin user group overall. Similarly, the chance of progression for each component of diabetes was higher in the statin group, including an increased number of glucose-lowering medication classes, more required insulin, more hyperglycemia, and more diagnosis of ketoacidosis or uncontrolled diabetes. This finding remained when excluding all participants with highly uncontrolled diabetes or all those with any comorbidities. Participants with the greatest LDL cholesterol reduction had the worst diabetes progression. This study had high power due to its large sample size and effective matching. Participants were balanced on the number of follow-up visits to reduce the chance of ascertainment bias. Another strength of this study was the longitudinal follow-up. However, this study is limited by its nature as a retrospective observational cohort. Additionally, some of the secondary measures of diabetes progression, like the number of glucose-lowering agents, make assumptions, like that all medications have equal potency. Given the data is predominantly from men, this study may not be generalizable to women with diabetes.

Click to read the study in JAMA Internal Medicine

Relevant Reading: Statin-associated incident diabetes: a literature review

In-Depth [retrospective cohort]: Data from the Veteran’s Affairs database on new (not in prior 12 months) statin users were compared to a propensity-matched new active comparator group to assess if statins increase insulin resistance. Baseline characteristics were averaged from the year before the respective prescription initiation. The change in insulin resistance, glycemic control, and the individual components that comprised these measures from baseline to follow-up 60 days post-prescription initiation were compared between the statin and non-statin groups. The Charlson comorbidity index score and cardiovascular risk were extracted from the database to perform a subgroup analysis of healthy diabetes patients on statins and non-statins. 83,022 pairs were matched from the total of 595,579 statin users and 110,195 non-users in the database (age = 60.1±11.6 years; 94.9% men; 2.1% American Indian/Pacific Islander/Alaska Native, 0.8% Asian, 21.5% Black, and 68.2% White individuals). The matched groups had similar rates of diabetes, complications, high blood glucose (≥200 mg/dL) episodes, number of glucose-lowering agents, mean blood glucose levels and follow-up duration. The odds of diabetes progression of statin users were increased compared to the non-user group (OR = 1.37, 95% CI = 1.35-1.40), including aspects like taking an increased number of glucose-lowering medication classes (OR = 1.41, 95% CI = 1.38-1.43), more required insulin (OR = 1.16, 95%CI = 1.12-1.19), more hyperglycemia (OR = 1.13, 95% CI = 1.10-1.16), and more diagnosis of ketoacidosis or uncontrolled diabetes (OR = 1.24, 95% CI = 1.19-1.30). These results were the same in a sensitivity analysis that excluded patients with diabetic complications, ketoacidosis, uncontrolled diabetes, or CVD, suggesting these results are not just due to worse diabetes in the statin group. The odds of diabetes progression in the subgroup of patients with no comorbidities was similarly higher in the statin group than the non-statin group (OR = 1.56 vs 1.40). The subgroup of statin users who experienced High-intensity cholesterol-lowering (decrease of ≥50% in mean LDL cholesterol from follow-up vs baseline) had the highest odds of diabetes progression compared to non-users.

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