Hemoglobin A1C Relationship with Statin Induced Diabetes

Baseline hemoglobin A1C may be inversely proportional to the risk of statin-induced new-onset diabetes. 

There are growing concerns with statin safety, along with increasing evidence of the beneficial role of statin use for primary prevention and secondary prevention of atherosclerotic cardiovascular and cerebrovascular diseases. Adverse drug events of statins include elevated liver function tests, myopathy, and myalgia as significant adverse drug reactions. However, the development of new-onset diabetes is one of the relatively new evolving concerns about using statin that has been recently studied. In an earlier systematic review, a strong association between statin therapy for primary prevention and the risk of new-onset diabetes mellitus was found. In addition, there was a dose- and time-dependent association of statin therapy with an increased risk of diabetes mellitus incidents. 

However, this safety issue of statin therapy regarding the incident of new-onset diabetes mellitus remains controversial. Although several trials’ data, including meta-analyses and observational studies, suggest that statin use was associated with increased risk of NODM, the absolute risk of statin-induced new-onset diabetes is small, and it is unclear whether there are specific factors that might increase hyperglycemia risk following statin use. In addition, although previous small prospective studies have shown that hypertension, metabolic syndrome, or low exercise tolerance have been suggested as potential risk factors, those studies were not designed to evaluate statin-induced NODM. Therefore, a retrospective nationwide cohort study of US Veterans was conducted to determine if baseline hemoglobin A1c (HbA1c) is a significant independent risk factor that may increase the risk of statin-induced new-onset diabetes.  

Between January 2011 and December 2018, 152,358 patients who had no previous diagnosis of diabetes were included in this retrospective cohort study. Patients were using either atorvastatin, simvastatin, or pravastatin for dyslipidemia; other inclusion criteria include baseline HbA1c less than 6.5 %, availability of complete demographic and clinical information, no prior use of diabetes medications except metformin for indications other than diabetes, baseline calculated low-density lipoprotein cholesterol (LDL-C) value. In addition, patients show adherence to statins (evaluated based on the proportion of days covered ≥80%).  

Patients had been divided into three groups based on their baseline HbA1c values: patients with HbA1c ≤5.6%, patients with HbA1c 5.7%–5.9%, and finally patients with HbA1c 6.0%–6.4%. However, all characteristics were matched as close as possible between study groups. 

For statistical analysis, Cox proportional hazards model adjusted for case-mix had been used to assess the risk of statin-induced NODM in the whole cohort and according to the mentioned earlier baseline HbA1c groups. Age, gender, ethnicity, baseline LDL-C level, obesity, hypertension, coronary artery disease, cerebrovascular disease, and metformin use had been included as Covariates for risk adjustment for continuous variables. Effect size measures of omega squared had been used. In contrast, for categorical variables, Cramer’s V had been used. Follow-up was 6.89 (SD 2.26) and 3.85 (SD 2.29) for non-statin and statin users, respectively. The rate of statin-induced NODM was similar to prior observations. Results showed that statin-induced NODM risk was inversely related to HbA1c levels for adjusted models. In statin users’ group, HRs were 2.08 (1.85 to 2.35) HbA1c groups of ≤5.6%, 1.57 (1.40 to 1.75) HbA1c groups of 5.7%– 5.9%, and 1.03 (0.93 to 1.15) for HbA1c groups of 6.0%–6.4%, with a P-value of < 0.0001 for this decreasing trend which was persistent with all types of studied statins. This cohort study included the largest to date assessment of statin inducing new-onset diabetes and suggested a reverse association between the rate of statin-induced new-onset diabetes and baseline HbA1c. 

Since high diabetes development is typically associated with HbA1c levels between 6.0% and 6.4%, the additional risks from statin will not be significant. However, in a previous systematic review, the highest risk of developing diabetes was in patients with HbA1c ≥6.0%, consistent only with non-statin users with HbA1c 6.0%–6.4%, where unadjusted HR for new-onset diabetes mellitus was 9.3 (8.9 t0 9.7). The findings of this cohort study are supported by the findings from the previous trials that showed a higher incidence of statin-induced new-onset diabetes in individuals with baseline HbA1c less than 6%. In conclusion, this study’s results suggested that for patients with baseline HbA1c levels between 6.0% and 6.4% and significant baseline CV risk, statin would not put them at higher risk of developing new-onset diabetes. 

Practice Pearls: 

• For patients with baseline HbA1c levels between 6.0% and 6.4% and significant baseline CV risk, statin would not put them at higher risk of developing new-onset diabetes. 
• Clinicians may consider the risk of statin-induced diabetes as a negative factor in the decision to initiate statin therapy. 
• No evidence until now would support avoidance of statin initiation to decrease the risk of diabetes.  

Ko, Min Jung et al. “Time- and Dose-Dependent Association of Statin Use With Risk of Clinically Relevant New-Onset Diabetes Mellitus in Primary Prevention: A Nationwide Observational Cohort Study.” Journal of the American Heart Association vol. 8,8 (2019): e011320. 

Ziganshina, Anna P et al.   BMJ open diabetes research & care  vol. 10,1 (2022): e002554. doi:10.1136/bmjdrc-2021-002554. 

Hebatullah Abdelgawad, PharmD Candidate, Skaggs School of Pharmacy & Pharmaceutical Sciences