Case Study: Incident Type 2 Diabetes Mellitus following Statin Initiation in Youth

Introduction

The association of statin use, and incident type 2 diabetes (T2D) is well established in adults.¹ Similar observations have not been reported in youth. Despite this association, the benefits of statins in preventing atherosclerotic cardiovascular disease (ASCVD) appear to outweigh their adverse effects on glycemic control.

Case #1

A 14-year-old White, non-Hispanic male was referred for fasting triglycerides (TG) of 640 mg/dL, non-HDL cholesterol 170 mg/dL and high-density lipoprotein cholesterol (HDL-C) of 21 mg/dL. His initial fasting glucose was 98 mg/dL; hemoglobin A1c (HgA1c) 5.5%. Thyroid and kidney function were normal. He had a history of autism, attention-deficit/hyperactivity disorder, and obesity (BMI 34.2 kg/m²). Blood pressure was 132/70 mmHg. (<95th percentile for age and sex). The mother had a history of hypertriglyceridemia, cholelithiasis and acute pancreatitis; the father’s history is unknown.  
 
Although he received dietary counseling and was encouraged to participate in 30-60 minutes of moderate to vigorous physical activity per day, compliance was limited, and his TG remained >500 mg/dL. Genetic testing of APOA5, APOC2, GPIHBP1, LMF1 and LPL revealed no variants. He was treated with fenofibrate 48 mg/day, later increased to 145 mg/day. After 2 years, his non-HDL-C remained elevated, and atorvastatin 20 mg/day was added to his fenofibrate.

Although he remained asymptomatic, a gradual rise in his fasting blood glucose was noted. One year after initiation of statin therapy, his BMI had increased to 37 kg/m² and his HbAC was 9.1%. His C-peptide was 7.74 ng/mL (expected 0.8-3.85) and no diabetes-related antibodies were found. At diagnosis, microalbuminuria and steatohepatitis were present.

Case #2

A 12-year-old Vietnamese-American boy was referred for mixed dyslipidemia and obesity (BMI 33 kg/m²). His LDL-C was 178 mg/dL, TG 257 mg/dL and ApoB 118 mg/dL with an HDL-C of 39 mg/dL. Fasting glucose was 77 mg/dL; HgA1c 5.1%. Thyroid and kidney function were normal. Despite attempts at lifestyle changes, he was inconsistent and his lipid profile showed little improvement. The biological mother, who had hypercholesterolemia, died of a stroke in her 50s. The maternal grandfather has hypercholesterolemia treated with lipid-lowering medication (LLM). There is a strong family history of diabetes, hypertension, and hypercholesterolemia. 
 
Because of his multiple risk factors and family history, he was treated with atorvastatin 20 mg/day, which was subsequently increased to 40 mg/day. After 6 months, his BMI remained elevated 32 Kg/m², he was noted to have acanthosis nigricans and underwent a 2-hour oral glucose tolerance test. His baseline fasting glucose was 126 mg/dL and 266 mg/dL at 2 hours (expected <100 mg/dL and <200 mg/dL, respectively).

Discussion

Statin use in adults is associated with increased risk of incident diabetes, although the magnitude of the effect has varied across studies, including differences between randomized controlled and observational studies.^2-7 A meta-analyses estimated the risk of incident T2D to be approximately 10-12%; higher (25-30%) in those with risk factors, including obesity.¹ Treatment of 255 (95% CI 150-852) adults with statins for 4 years resulted in 1 case of diabetes.⁴

The putative mechanism by which dysglycemia occurs in this setting is complex. Statins competitively inhibit HMG-CoA reductase, which prevents substrate access thereby blocking the conversion of HMG-CoA to mevalonic acid. In addition to decreasing cholesterol production, this effect impacts gluconeogenesis, insulin signaling, and glucose transport.⁸ 

The occurrence of incident T2D in this setting appears to be:

1. Associated with the type of statin used and duration of treatment. Lipophilic statins, which have higher diffusion rates and more readily penetrate cell membranes, appear to be more diabetogenic than hydrophilic statins, which are better localized to the liver and less likely to interfere with extra-hepatic biosynthetic pathways.⁸ 
2. Dose related. Atorvastatin 80 mg was associated with the highest risk of diabetes (OR 1.34; 95% CI 1.14-1.57) when compared with rosuvastatin, pravastatin, simvastatin and low-dose atorvastatin.⁹ Being lipophilic, atorvastatin is thought to penetrate pancreatic β-cells, inducing reactive oxygen species production and suppressing antioxidant defense systems in the mitochondria, thus preventing insulin release.¹⁰
3. Limited to those with major risk factors.^2,8

The 2 children we describe had multiple risk factors for both T2D and CVD (see Figure). 

Lack of response to lifestyle changes prompted guideline-directed interventions of modifiable risk factors, including LLM.12 While only FDA approved in youth with clinically suspected or genetic confirmed FH, LLM was used “off label” in our 2 cases following a shared clinical decision discussion with the child and parents. 

With its rising prevalence in youth, T2D our 2 cases may be coincidental. The estimated prevalence of T2D in youth 10 to 19 years-of-age has increased significantly from 0.34/1000 in 2001 to 0.67 in 2017, a 95.3% relative increase.¹³ Racial and ethnic minority populations carried the largest burden of the disease, with the greatest absolute increases among non-Hispanic Black and Hispanic youth. In several non-White racial and ethnic groups, the incidence of T2D in adolescents is twice that of T1D.^14,15 There has been a steady rise in the incidence of T2D in youth14, with 9 new cases/100,000/year in 2002-2003; and 13.8 in 2014-2016, corresponding to an age- and sex-adjusted annual percent change in incidence of 4.8% from 2002 to 2015.

CVD risk factors are present in 92% of youth with T2D, often at time of diagnosis and independently associated with age and race/ethnicity.^16-18 Elevated ApoB and dense LDL are more common in youth with T2D, and the prevalence of these risk factors substantially increased with poor glycemic control and minorities.¹⁹ Despite shorter duration of diabetes and lower HBA1c values, comorbidities in youth with T2D appear to be higher and the progression of vascular abnormalities more pronounced than in youth with T1D.¹⁷

Conclusion

Modifiable and non-modifiable risk factors are frequently present in childhood and play a key role in the development of atherosclerosis, the underlying cause of CVD. While incident T2D has been reported with statin use in adults, overweight and obesity are the strongest risk factors for T2D development at any age. Despite the potential risk of incident T2D, experience in adults suggest the benefits of statins in improving outcomes outweigh their adverse effects on glycemic control. Although potentially coincidental, our 2 cases serve as a reminder of the association between statin use and incident T2D in adults and the importance of monitoring and follow-up when treating at-risk children with statins.¹

Ms. Webster has no financial relationships to disclose. Ms. Vinson has no financial relationships to disclose. Mr. Hamilton has no financial relationships to disclose. Dr. Wilson has received honorarium from Alexion, Regeneron, Experion, and NLA. 

References

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