Statins and New-Onset Diabetes Mellitus and Diabetic Complications: A Retrospective Cohort Study of US Healthy Adults

INTRODUCTION

Despite their effectiveness in lowering cardiovascular morbidity and mortality, statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase [HMGR] inhibitors) have been shown to be associated with a small risk of incident diabetes mellitus.¹ A recent cross-sectional study noted higher caloric and fat intake and increased body mass index among statin users in contrast to nonusers.² Additionally, achieving a "cholesterol goal” through swallowing a tablet might result in false self assurance, and may encourage poor dietary choices and a sedentary lifestyle.³ Several randomized trials and observational studies have noted that statin users have higher hemoglobin [Hb]A_1C and fasting plasma glucose measurements than nonusers.^4–8 Hence, it can be surmised that statins may increase the risk of diabetic complications.

Most studies reporting an increased risk of new-onset diabetes among statin users included high-risk populations¹; data are limited regarding incident diabetes risk in healthy populations. For example, patients in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA) study had hypertension and three or more cardiovascular risk factors.⁹ The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT),¹⁰ West of Scotland Coronary Prevention Study (WESCOPS),¹¹ and ASCOT-LLA studies actually included patients who had evidence of preexisting cardiovascular disease (8, 14.2, and 18.5 %, respectively). As a result, some investigators have proposed that statin use is associated with incident diabetes only in the highest-risk population.¹²

The objective of this study was to examine the association between statin use and new-onset diabetes, diabetes with complications, and overweight/obesity in a propensity score-matched “healthy” cohort of statin users and nonusers.

RESEARCH DESIGN AND METHODS

RESULTS

Based on our initial inclusion and exclusion criteria, 43,438 patients were identified (13,626 statin users and 29,812 nonusers). To develop the healthy cohort, we excluded 13,311 subjects with any positive elements in their Charlson comorbidity index, 3876 subjects with diagnoses suggestive of cardiovascular disease, and 281 patients with other comorbidities that might limit life expectancy or physical activity at baseline (Fig 1). Hence, our final healthy cohort included 25,970 patients (3982 statin users and 21,988 nonusers). Overall, 77 % of prescriptions of statins were for simvastatin, 19 % for atorvastatin, 3 % for pravastatin, and 1 % for rosuvastatin. Table 3 describes selected characteristics of the population that met the study criteria. Statin users were older, had higher proportions of men and smokers, had a higher prevalence of comorbidities, and utilized other classes of medications more frequently except for non-steroidal anti-inflammatory drugs and testosterone therapy.

DISCUSSION

This study demonstrated that statin use was associated with an increased likelihood of new diagnoses of diabetes mellitus, diabetic complications, and overweight/obesity. Whereas the increased risk of diabetes with statins is well known, the increased risk of diabetic complications has not been previously described.

The overall proportion of patients who developed diabetes during the follow-up period was approximately 14 %, which is similar to recent national trends.⁵⁸ The increased risk of diabetes among statin users is well described in several studies.^1,59 In a meta-analysis of 13 statin clinical trials (mean follow-up duration from 1.9 to 6 years), the OR of incident diabetes was 1.09 (95 % CI 1.02–1.17).¹ However, these trials used different methods for diagnosing diabetes, and some trials were missing diabetes incidence data. Moreover, all statin primary prevention trials used intention-to-treat analysis, despite high rates of dropout or quitting the study medication (12–33 %), which can result in underestimation of side effects.⁶⁰ Both lipophilic and hydrophilic statins were associated with a similar risk of diabetes,¹ although other studies have noted that the risk varied with different types of statins.⁶¹ In a secondary analysis of the Women’s Health Initiative data, statin use was associated with an increased risk of diabetes (adjusted hazard ratio [HR] 1.48; 95 % CI 1.38–1.59).⁶² Other observational studies have noted higher adjusted risk of incident diabetes among statin users versus nonusers. ranging from 2.8 to 4.7.^63,64

Importantly, our study demonstrated that high-intensity statin therapy was associated with the highest risk of diabetes, diabetic complications, and overweight/obesity (adjusted OR 2.55, 3.68, and 1.58, respectively), thereby demonstrating a dose–response relationship. A recent observational study⁵⁹ and a meta-analysis of five clinical trials (32,752 patients) noted that higher-potency statins were also associated with a higher risk of diabetes compared to lower-potency statins.⁶⁵

In this study, our intent was to examine the risk of outcomes in a healthy population, excluding patients who had ischemic heart diseases or their equivalents, patients with any Charlson comorbidity (which include renal failure, mild liver disease, HIV, and any malignancy other than skin cancers), and patients with any chronic disease that might limit life expectancy or physical activity (including rheumatologic diseases, psychosis, and prior suicide attempts). In contrast, a meta-analysis of statin use and the risk of incident diabetes included patients with several comorbidities, including prior cardiovascular diseases, peripheral vascular diseases, heart failure, and elevated C-reactive protein (CRP).¹ Therefore, our study adds a new perspective to the association between statins and risk of incident diabetes.

The association between the use of statins and diabetic complications has not been reported thus far, and deserves further study. In a recent nested matched study of a Danish population, 15,679 statin users were matched to 47,037 nonusers on the basis of sex, age at diabetes diagnosis, year of diabetes diagnosis, and history of cardiovascular disease⁶⁶; the median follow-up was 2.7 years (range 0–13). The study noted that statin users had lower cumulative incidence of diabetic retinopathy (HR 0.60; 95 % CI 0.54–0.66) and diabetic neuropathy (HR 0.66; 95 % CI 0.57–0.75), but not diabetic nephropathy (HR 0.97; 95 % CI 0.85–1.10). In contrast, our study had a much longer follow-up period (6.5 years), included only healthy adults without prior cardiovascular diseases, and matched patients on 42 variables including 20 different classes of medications.

Two small trials reported that statins were associated with an improvement in diabetic retinopathy in diabetic patients.^67,68 For example, in one of the studies, which was a randomized controlled trial (50 patients with diabetic retinopathy), simvastatin was associated with improved ophthalmologic fundus examination.⁶⁸ On the other hand, several observational and experimental studies have noted that statin use was associated with high blood glucose levels.^4–8

The overall proportion of overweight/obesity in our cohort was high (exceeding 40 %), but is commensurate with recent estimates of overweight/obesity.⁶⁹ Evidence from in vitro studies indicates that statins can increase body and liver fat accumulation.⁷⁰ A recent prospective study noted that, compared to nonusers, statin users expended less metabolic equivalents, engaged in less moderate physical activity and for shorter durations, and exhibited more sedentary behavior for more minutes per day.⁷¹ In the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, an increase in body weight was observed among patients in the rosuvastatin group as compared with the placebo group (0.44 kg vs 0.15 kg, respectively).⁷² A cross-sectional study (27,886 adults) from the National Health and Nutrition Examination Survey (NHANES) noted that caloric intake, fat intake, and body mass index were higher in statin users compared to nonusers.² Lastly, a Mendelian randomization study noted that common variants in the HMGR gene were associated with an LDL-lowering effect and an increase in body mass index, insulin resistance, and type 2 diabetes,⁷³ which further supports the link between statins and a higher risk of diabetes and obesity, and demonstrates that this is an “on-target” effect.⁷⁴ Our study offers additional evidence for the association between statins and overweight/obesity, utilizing retrospective cohort observational data.

Our findings will need to be confirmed by other studies, as they may have significant implications. Our results indicate that extrapolating information from carefully selected patients in short-term randomized controlled studies to decades of statin use for primary prevention might not be appropriate. Additionally, statin effects on overall comorbidity, not only cardiovascular morbidity, need to become part of the risk/benefit assessment.

The purpose of our study was not to examine whether the increased risk of diabetes and its complications among statin users is outweighed by the reduced risk of atherosclerotic cardiovascular disease. Comparing risks of cardiovascular disease between statin users and nonusers in observational data may be subject to confounding by indication—that is, statin users were prescribed statins because they may have had a family history of premature cardiovascular disease, high CRP, or increasing lipid profiles over time. Some investigators have suggested doubling the observed risks to account for this bias.⁷⁵ Moreover, to appropriately account for the risk of cardiovascular disease in statin users and nonusers, both groups should be matched on lipid profile and blood pressure measurements and on Framingham or other cardiovascular risk score. This information was missing for most of our patients, and therefore our results cannot be used to examine the value of statins in primary prevention among healthy adults. Rather, they only indicate that short-term clinical studies may not fully describe the effects of statins in long-term real life utilization for primary prevention, and hence additional research utilizing prospective observational and pragmatic studies is needed. Our study also indicates that in order to examine the effects of statins in primary prevention, a measure for overall comorbidity must be developed and utilized in reporting the benefits, rather than depending entirely on total cardiovascular mortality and morbidity.

Our study has several limitations, including its retrospective observational design, which may suffer from unrecognized confounding factors despite our best effort to identify confounders. Additionally, our study used ICD-9-CM codes of AHRQ-CCS, which may lack sensitivity toward some variables such as smoking and overweight/obesity. We also lacked data on body mass index, HbA_1c, serum creatinine, and urinalysis, all of which are important in supporting our outcomes. Although the use of ICD-9 codes in extracting diagnoses of diabetes with and without complications has good sensitivity and excellent specificity, we are not aware that using AHRQ-CCS codes was specifically validated in Tricare data. The use of ICD-9 codes to identify obesity as an outcome has low sensitivity but high specificity, which is another limitation to our study. However, the proportions of patients identified as overweight or obese in our outcome were similar to national trends; this may be due to the comprehensive longitudinal database, complete follow-up, easy and equal access to care within the military health care system, and the mandated routine visits for military personnel. It should be also noted that body mass index may not be reliable in identifying overweight/obesity in athletic and military populations.^76,77 Determining baseline characteristics based on ICD-9 codes was another limitation, given the variable sensitivity and specificity of each disease group. However, we are not aware of any reason for differential ascertainment bias between statin users and nonusers (i.e., underestimation or overestimation is likely to affect both treatments equally). First, both statin users and nonusers had extensive continuous follow-up for almost 7 years and a mean number of > 60 visits (despite being a healthy population). Second, the Tricare Prime/Plus health care system has unique features that offer easy and ample access to health care, and specific aspects of health care are mandated; therefore, there was ample chance to capture diseases. Third, controlling for the number of medical encounters during the follow-up period did not significantly change our results. Fourth, as demonstrated in Table 1, nonusers actually had higher proportions of obesity at baseline. Lastly, the prevalence of overweight/obesity and diabetes were similar to recently published national trends,^58,69 suggesting that the magnitude of underestimation was not sizable. Another limitation is that ICD-9-CM codes do not provide information on severity of illness. Therefore, it may be assumed that physicians were more biased to prescribe statins in patients with more severe overweight/obesity at baseline, and consequently, statin users were more to likely to develop diabetes and diabetic complications. However, such bias, if it existed, is unlikely to be responsible for an approximately twofold increase in the odds of diabetes incidence and a threefold increase in the odds of diabetic complications. The use of pharmacy data to account for medication use assumes, but cannot ascertain, that patients are actually taking their medications. However, approximately 73 % of our statin users filled their statin prescriptions for 4 years, which may be considered a surrogate marker for actual use of medications. The pattern of statin use in our study, where 77 % of statin users used simvastatin, may be different from current statin utilization trends. Data from the private sector indicate that the use of atorvastatin in certain markets may be as high as 48 %, and that rosuvastatin use has risen to 65 % in some markets.^78,79 Since using OR rather than relative risk (RR) may exaggerate the perception of risk, we calculated the RR of the outcomes using a previously published formula^,80 as follows: RR of diabetes = 1.60, diabetes with complications = 1.90, and overweight/obesity = 1.07.

In conclusion, statin use was associated with increased likelihood of patients being diagnosed with diabetes and of diabetic complications and overweight/obesity. Further investigations, including randomized controlled studies for prolonged periods and larger-scale prospective studies, are needed in order to obtain a more complete risk/benefit assessment of statin therapy for primary prevention.