Graduation Year

2026

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Public Health

Major Professor

Amy C. Alman, Ph.D.

Co-Major Professor

Janice Zgibor, Ph.D., RPh, CPH, FACE

Committee Member

Henian Chen, M.D., Ph.D.

Committee Member

Henry Rodriguez, M.D.

Keywords

Epidemiology, Pharmacoepidemiology, Statins, Target Trial Emulation, Type 1 Diabetes

Abstract

Introduction: Hydroxymethylglutaryl-CoA enzyme inhibitors (statins) are frequently used to prevent cardiovascular events in individuals at high risk for cardiovascular diseases, including individuals with diabetes. Prior research has indicated that statins may increase the risk of developing type 2 diabetes (T2D) and may increase hyperglycemia among those previously diagnosed with T2D. To date, little research has investigated the impact of statins on glycemic control and diabetic complications associated with poor glycemic control in those with type 1 diabetes (T1D). The objective of this dissertation is to investigate the association between statin use and measures of glycemic control including hemoglobin A1c (HbA1c), daily insulin dose, severe hypoglycemic events, and diabetic ketoacidosis (DKA) events. Secondary aims include investigating the effects of statins on the risk of developing microvascular diseases commonly associated with poor glycemic control in T1D, including retinopathy, neuropathy and nephropathy, and biomarkers associated with nephropathy such as albumin to creatinine ratio (ACR) and the estimated glomerular filtration rate (eGFR).

Methods: For each aim, data collected from the Type 1 Diabetes Exchange Clinic Registry (T1DX) was used for the analysis. This was a U.S. based registry that followed a cohort of individuals with T1D from 2010 through 2018. Participants were followed up annually and information on demographics, diabetes management, labs, prescriptions, and medical history were collected at each visit. For each aim a target trial emulation framework was used to compare those who initiated a statin to a group of controls. Controls were matched to statin initiators using propensity score matching. For aims one and three, outcomes were measured at a baseline (pre-statin initiation) and follow-up (up to one-year post-statin initiation). The difference in the change from baseline to follow-up between statin initiators and controls were compared using mixed effects linear regression models for continuous outcomes, and the odds of a severe hypoglycemic or DKA event at year 1 were compared using mixed effects logistic regression models. For aim two, time to first diagnosis of a microvascular event was compared between groups using proportional hazards models. Results were reported overall and stratified by intensity of statin therapy.

Results: The adjusted difference between the statin initiators and matched controls in the change in HbA1c from baseline to year 1 was 0.09% (95% CI: -0.07% to 0.25%; p=0.27). Among the high intensity statin initiators, the mean difference in the change from baseline between high intensity statin initiators and controls was 0.28% (95% CI: 0.01% to 0.54%; p=0.04). No significant differences in total daily insulin dose, severe hypoglycemic events, or DKA events were observed. Those who initiated a statin were 1.58 times as likely to be diagnosed with a microvascular event relative to controls (95% CI: 1.04 to 2.41; p=0.03). The 5-year Kaplan-Meier probability of remaining event free was 83.5% among statin initiators and 88.2% among controls. There were 39.2 events per 1000 person-years among low intensity statin users and 30.7 events among high intensity users. For aim three, there were no significant differences in the change in eGFR or ACR from baseline to year 1 between statin initiators and controls.

Conclusions: High intensity statin users saw a modest increase in HbA1c from baseline to 1 year follow-up relative to controls, and a higher risk of microvascular complications during registry follow-up in all statin initiators compared to controls. No meaningful changes in markers for renal function were observed. While the cardiovascular benefits of statins likely outweigh a moderate impact on glycemic control, clinicians and patients with T1D should be aware of potential glycemic related side effects and the possibility of a dose response relationship. Further research is needed to confirm findings that statins increase the risk of microvascular events in those with T1D, given the short duration of follow-up in the present study. These studies emphasize the importance of examining the glycemic impact of drugs in those with T1D, a cohort which is often overlooked given the low prevalence of T1D relative to T2D. More robust investigations into the glycemic side effects of statins are needed.

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