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Original Investigation |

Statin Use and Risk of Diabetes Mellitus in Postmenopausal Women in the Women's Health Initiative FREE

Annie L. Culver, BPharm; Ira S. Ockene, MD; Raji Balasubramanian, ScD; Barbara C. Olendzki, RD, MPH; Deidre M. Sepavich, MBA; Jean Wactawski-Wende, PhD; JoAnn E. Manson, MD, DrPH; Yongxia Qiao, MD; Simin Liu, MD, ScD; Philip A. Merriam, MSPH; Catherine Rahilly-Tierny, MD, MPH; Fridtjof Thomas, PhD; Jeffrey S. Berger, MD, MS; Judith K. Ockene, PhD, MEd, MA; J. David Curb, MD; Yunsheng Ma, MD, PhD
[+] Author Affiliations

Author Affiliations: Rochester Methodist Hospital, Mayo Clinic, Rochester, Minnesota (Ms Culver); Divisions of Cardiovascular Medicine (Dr I. S. Ockene) and Preventive and Behavioral Medicine (Mss Olendzki and Sepavich, Drs Qiao, J. K. Ockene, and Ma, and Mr Merriam), Department of Medicine, University of Massachusetts Medical School, Worcester; Division of Biostatistics and Epidemiology, University of Massachusetts Amherst, Amherst (Dr Balasubramanian); Department of Social and Preventive Medicine, University of Buffalo, Buffalo, New York (Dr Wactawski-Wende); Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts (Dr Manson); Department of Preventive Medicine, Tongji University School of Medicine, Shanghai, China (Dr Qiao); Departments of Medicine and Epidemiology, University of California, Los Angeles, School of Public Health and David Geffen School of Medicine, Los Angeles (Dr Liu); Massachusetts Veterans Epidemiology and Research Information Center (MAVERIC), VA Boston Healthcare System, Boston (Dr Rahilly-Tierny); Division of Aging, Department of Medicine, Brigham and Women's Hospital, Chestnut Hill, Massachusetts (Dr Rahilly-Tierny); Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis (Dr Thomas); Division of Cardiology, Department of Medicine, New York University Medical Center, New York (Dr Berger); and Department of Geriatric Medicine, University of Hawaii, John A. Burns School of Medicine, Honolulu (Dr Curb).


Arch Intern Med. 2012;172(2):144-152. doi:10.1001/archinternmed.2011.625.
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Background This study investigates whether the incidence of new-onset diabetes mellitus (DM) is associated with statin use among postmenopausal women participating in the Women's Health Initiative (WHI).

Methods The WHI recruited 161 808 postmenopausal women aged 50 to 79 years at 40 clinical centers across the United States from 1993 to 1998 with ongoing follow-up. The current analysis includes data through 2005. Statin use was captured at enrollment and year 3. Incident DM status was determined annually from enrollment. Cox proportional hazards models were used to estimate the risk of DM by statin use, with adjustments for propensity score and other potential confounding factors. Subgroup analyses by race/ethnicity, obesity status, and age group were conducted to uncover effect modification.

Results This investigation included 153 840 women without DM and no missing data at baseline. At baseline, 7.04% reported taking statin medication. There were 10 242 incident cases of self-reported DM over 1 004 466 person-years of follow-up. Statin use at baseline was associated with an increased risk of DM (hazard ratio [HR], 1.71; 95% CI, 1.61-1.83). This association remained after adjusting for other potential confounders (multivariate-adjusted HR, 1.48; 95% CI, 1.38-1.59) and was observed for all types of statin medications. Subset analyses evaluating the association of self-reported DM with longitudinal measures of statin use in 125 575 women confirmed these findings.

Conclusions Statin medication use in postmenopausal women is associated with an increased risk for DM. This may be a medication class effect. Further study by statin type and dose may reveal varying risk levels for new-onset DM in this population.

Figures in this Article

Given the success of statins in both primary and secondary prevention of cardiovascular morbidity and mortality,16 their use is progressively increasing, especially among older Americans.7 With such widespread use, even small risks are apparent alongside benefits. One emerging risk is an increased incidence of diabetes mellitus (DM). There is evidence that incident DM associated with statin use may be more common in the elderly, in women, and in Asians.812 A recent analysis suggests that preexisting metabolic risk factors control incident DM rate with statin medication.13 It is unclear if this risk varies with individual statins or if this is a dose-driven class effect.9,14 Although experimental and clinical studies find that individual statins act differently on glucose homeostasis as a function of relative lipophilicity and/or potency of action,15 other findings differ. A recent meta-analysis of 17 randomized controlled trials by Mills et al16 found a class effect increase of new-onset DM with statins (odds ratio [OR], 1.09; 95% CI, 1.02-1.16) similar to that reported by Sattar et al.9 Possibly, the grouping of statins masks the effect variation of individual statins. Still, at some given dose threshold, differences may be overcome, as implied by a meta-analysis of 5 trials comparing intensive to moderate dosing regimens using mainly atorvastatin and simvastatin.13,17 Notably, meta-analysis results display intertrial and intratrial variability in diagnostic and statistical methods and do not consistently consider confounding factors. Moreover, contributing sample sizes do not permit balanced comparison by statin type, sex, race/ethnicity, and age. Similarly, single studies may uncover only part of a greater topography.

As a large part of the aging population, postmenopausal women have not been fully represented in past clinical trials.16 Sex differences in DM pathogenesis are well recognized.18,19 Using the Women's Health Initiative (WHI) data, we evaluated the overall effect of statin medication use on incident DM risk and examined these associations by specific statin agent. We stratified analyses by race/ethnicity, body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) category, and age group to determine if any associations were modified by these factors. In addition, we conducted subgroup analysis in women with and without self-reported cardiovascular disease (CVD) at baseline to address potential confounding and selection bias.

PARTICIPANTS

The WHI recruited 161 808 postmenopausal women aged 50 to 79 years at 40 clinical centers across the United States from 1993 to 1998 and followed consenting participants. Of these women, 68 132 were enrolled in 1, 2, or all 3 of the clinical trial (CT) arms: the Dietary Modification Trial, the Hormone Trial, and the Calcium and Vitamin D Trial. Another 93 676 women were enrolled into a prospective observational study (OS).2023 The WHI eligibility criteria included the ability to complete study visits with expected survival and local residency for at least 3 years. Original exclusion criteria addressed conditions that would limit full participation in the study. This analysis used WHI data through 2005. After exclusion for prevalent DM, missing data, and use of cerivastatin (this medication was withdrawn from the market in 2001 for safety reasons), a total of 153 840 women were included (Figure).

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Figure. Flowchart for statin users and diabetes mellitus (DM) analyses using data sets from the Women's Health Initiative.

MEASUREMENT AND CLASSIFICATION OF STATIN MEDICATIONS

The current medication regimens of all CT participants were inventoried at baseline and at years 1, 3, 6, and 9. In the OS, medication data were inventoried at baseline and year 3. At each inventory, the brand or generic name on the medication label was matched to the corresponding item in the Master Drug Data Base (Medi-Span, Indianapolis, Indiana). We sorted for statin use as users or nonusers at baseline and year 3. Given that Sattar et al9 found a null effect of lipophilicity among statins, and in the absence of dose information, we determined statin categories by relative potency of action to decrease low-density lipoprotein cholesterol. Accordingly, statins were designated as low (fluvastatin, lovastatin, pravastatin) or high (simvastatin, atorvastatin) potency.24,25

IDENTIFICATION OF DM

At baseline and at each semiannual (CT) or annual (OS) contact, incident treated DM was identified by questionnaire and was defined as a self-report of a new physician diagnosis of treated DM. This method of identification of prevalent and incident DM has been used in prior publications by the WHI investigators.18,2628 The accuracy of self-reported DM in the WHI trials has been assessed using medication and laboratory data, and self-reported DM was found to be reliable.29

COVARIATES

Baseline questionnaires ascertained demographic and health history information, including race/ethnicity, age, educational attainment, family history of DM, family history of depression, self-report of CVD, hormone therapy use, and smoking status. Baseline self-report for CVD has been previously validated in the WHI30,31 and found to have reasonable agreement with hospital discharge International Classification of Diseases, Ninth Revision (ICD-9) codes.

The metabolic equivalents of physical activities and average daily nutrient intake were computed, using detailed methods described elsewhere.32,33 Trained and certified clinic staff measured height using a fixed stadiometer and weight by a calibrated balance-beam scale. Relative weight as BMI was calculated from these values. Blood was analyzed for glucose and insulin for the random 6% WHI-CT blood subsample at baseline, year 1, year 3, year 6, and year 9. Fasting glucose was analyzed using the hexokinase method with interassay coefficients of variation less than 2%.26 Insulin was measured by enzyme-linked immunosorbent assay. The WHI used the homeostasis model assessment of insulin resistance (HOMA-IR), which was developed for application in large epidemiologic investigations as an alternative to the glucose clamp. HOMA-IR = fasting plasma insulin (μIU/mL) × fasting plasma glucose (mmol/L)/22.5.34

STATISTICAL ANALYSIS

Cox proportional hazards (PH) models were used to estimate hazard ratios (HRs) of DM by statin medication use. The dependent variable was time to occurrence of DM determined by self-report (ie, time to event). The time to event was calculated as the interval between enrollment date and the earliest of the following: (1) date of annual medical history update when new DM was ascertained (observed outcome) and (2) date of the last annual medical update during which DM status was ascertained (censored outcome). The primary independent variable in these analyses was statin use at baseline, coded as a binary variable. We present 3 Cox PH models to examine the association between baseline statin use and DM: model 1 estimates the unadjusted HRs (and associated 95% CIs) of the effects of statin use on incident DM; model 2 presents age- and race/ethnicity–adjusted HRs; and model 3 presents HRs adjusted for all potential confounding variables at baseline (age, race/ethnicity, education, cigarette smoking, BMI, physical activity, alcohol intake, energy intake, family history of DM, hormone therapy use, study arm, and self-report of CVD). Similar analyses were conducted for specific type of statin medication use at baseline, categorized as low vs high potency.

Since individuals using statins may have different underlying conditions that could put them at elevated risk for DM, we conducted several subgroup analyses to control confounding by indication. First, we conducted subgroup analyses by age, race/ethnicity, and BMI categories to examine whether the associations of statin use and onset of DM differed by categories of these variables. Age was categorized into 3 groups (50-59 years, 60-69 years, and ≥70 years). Race/ethnicity was assessed according to 4 major groups (white, African American, Hispanic, Asian). Body mass index was categorized into 3 groups (<25.0, 25.0-29.9, ≥30.0). Second, we conducted similar analyses in 2 subgroups of women either with or without self-reported CVD at baseline. Finally, propensity score analysis35 was performed to reduce the confounding effects of other factors in the evaluation of the association between statin use and DM risk within an observational study setting. Participant-specific propensity scores were estimated from a logistic regression model to predict the probability of statin prescription. Covariates considered for inclusion into the logistic regression model included age, BMI, self-report of hypertension, self-report of CVD, family history of DM, smoking status, and physical activity. The final propensity score model retained all covariates noted herein with the exception of physical activity, which was an insignificant predictor of statin use. The association between statin use and DM risk was evaluated in Cox PH models after adjusting for the estimated propensity score.

After exclusion for cases of DM before year 3 (146 women), use of cerivastatin (651 women), and missing medication data at year 3 (2 women), our longitudinal analyses were conducted in a subset of 125 575 women from the OS and the CT arm at baseline and year 3 visits. Statin use was sorted into 4 categories: (1) never took statin; (2) use at both baseline and at the year 3 visit, (3) use only at baseline; and (4) use only at the year 3 visit. The HRs for DM by statin use were estimated similarly based on Cox PH models.

PARTICIPANTS’ CHARACTERISTICS

Participant characteristics are listed in Table 1. At baseline, the mean (SD) age of women included in our sample was 63.2 (7.3) years. Approximately 16.30% of the women were from racial/ethnic groups other than white, of which the largest representation was African American (8.32%). Only 2.56% (3922 women) were Asian. At baseline, 7.04% of participants took statin medication. Of these, 30.29% took simvastatin; 27.29%, lovastatin; 22.52%, pravastatin; 12.15%, fluvastatin; and 7.74%, atorvastatin. Comparison between statin users and nonusers showed significant differences in baseline characteristics.

Table Graphic Jump LocationTable 1. Characteristics of 153 840 Study Participants, Women's Health Initiativea
STATIN USE AT BASELINE AND DM INCIDENCE

A total of 10 242 incident cases of DM were reported over 1 004 466 person-years of follow-up. Table 2 presents results regarding the association between statin use at baseline and risk of incident DM. In unadjusted models, statin use at baseline was significantly associated with an increased DM risk (HR, 1.71; 95% CI, 1.61-1.83) when compared with nonuse. This association was decreased but remained significant after adjusting for potential confounders (HR, 1.48; 95% CI, 1.38-1.59). This association was observed for all types of statin. Similar risk associations were found in use of either high- or low-potency statins, with multivariate-adjusted HRs of 1.45 (95% CI, 1.36-1.61) and 1.48 (95% CI, 1.36-1.61) compared with nonusers, respectively. Table 3 shows subgroup analyses by race/ethnicity, BMI category, and age group. In both unadjusted and adjusted models, statin use was consistently associated with increased risk of DM across subgroups by age. We observed significantly increased risk of DM by statin use within subgroups of white, Hispanic, and Asian women in both unadjusted and adjusted models. In adjusted models, we observed HRs of 1.49 (95% CI, 1.38-1.62), 1.18 (95% CI, 0.96-1.45), 1.57 (95% CI, 1.14-2.17), and 1.78 (95% CI, 1.32-2.40) among whites, African Americans, Hispanics, and Asians, respectively. Statin use was also associated with a significantly increased risk of DM within 3 subgroups according to BMI (<25.0, 25.0-29.9, ≥30.0). Moreover, a significantly increased risk of DM associated with statin use was observed among women with BMI lower than 25.0 when compared with women with BMI of 30.0 or higher after adjusting for all potential confounders. In adjusted models, the HRs were 1.89 (95% CI, 1.57-2.29), 1.66 (95% CI, 1.48-1.87), and 1.20 (95% CI, 1.09-1.33) within the groups of women with BMI of less than 25.0, 25.0 to 29.9, and 30.0 or higher, respectively.

Table Graphic Jump LocationTable 2. Association Between Diabetes Mellitus (DM) Risk and Statin Use Status at Baseline in 153840 Participants
Table Graphic Jump LocationTable 3. Association Between Diabetes Mellitus (DM) Risk and Statin Use Status at Baseline, Within Age, Race/Ethnicity, and BMI Subgroups in 153840 Participants
STATIN USE AT BASELINE AND RISK OF DM AMONG POSTMENOPAUSAL WOMEN WITH AND WITHOUT HISTORY OF CVD

To address potential confounding and selection bias, we conducted subgroup analyses among postmenopausal women with and without a history of CVD (Table 4). Among a subset of 24 842 women who self-reported CVD at baseline, we found that statin use was associated with an increased risk of DM (HR, 1.52; 95% CI, 1.36-1.71). These associations remained significant after adjusting for potential confounders (HR, 1.46; 95% CI, 1.29-1.65). Similar findings were observed among women without CVD at baseline.

Table Graphic Jump LocationTable 4. Risk of Diabetes Mellitus (DM) by Statin Use Among Women With and Without Medical History of Cardiovascular Disease (CVD) at Baseline
PROPENSITY SCORE ANALYSES

In unadjusted models, statin use was significantly related to DM risk (HR, 1.71; 95% CI, 1.61-1.83). When the propensity score was included, the estimated HR attenuated to 1.38 (95% CI, 1.29-1.47). On inclusion of other confounders in the model, the HR was essentially unaltered (HR, 1.40; 95% CI, 1.31-1.51). Propensity score adjusted models yielded HRs of 1.38 (95% CI, 1.23-1.54) and 1.40 (95% CI, 1.29-1.53) for respective increased risk with either high- or low-potency statin use at baseline compared with nonuse.

LONGITUDINAL MEASURES OF STATIN USE AND RISK OF DM

When compared with those who never received statin therapy, unadjusted HRs of 1.82 (95% CI, 1.65-2.00), 1.75 (95% CI, 1.43-2.14), and 1.81 (95% CI, 1.67-1.97) were observed for the groups of women who reported statin use at both baseline and at the year 3 visit, reported statin use only at baseline, and reported statin use only at the year 3 visit, respectively (Table 5). The risk associations remained significant after adjusting for age, race/ethnicity, other potential confounders, and propensity score. The multivariate adjusted HRs were 1.47 (95% CI, 1.32-1.64), 1.44 (95% CI, 1.15-1.80), and 1.60 (95% CI, 1.47-1.75), respectively.

Table Graphic Jump LocationTable 5. Risk of Diabetes Mellitus (DM) by Statin Use at Baseline and 3-Year Follow-up in 125575 Participants
SENSITIVITY ANALYSIS

A sensitivity analysis was conducted on a subset of 3706 women without DM at baseline and enrolled in the WHI CT for whom fasting glucose measurements were available at baseline and at least 1 additional follow-up visit. Diabetes mellitus was identified based on fasting glucose levels of 126 mg/dL (6.99 mmol/L) or higher. In unadjusted models, statin use at baseline was not significantly related to DM risk (HR, 1.06; 95% CI, 0.61-1.86). However, using baseline through year 6 data in the CT arm, we found that the statin users had higher fasting glucose levels and HOMA-IR compared with non–statin users, with increasing values from baseline to year 6 follow-up.

The results of this study imply that statin use conveys an increased risk of new-onset DM in postmenopausal women. In keeping with the findings of other studies,9,13,36 our results suggest that statin-induced DM is a medication class effect and not related to potency or to individual statin. However, the data set contains unequal representation of statins that may have influenced the outcomes. In addition, women who took statins may have changed statin type prior to incident DM. Results may actually reflect a changing market and demand and include those statins that were not available at baseline. For example, rosuvastatin was not available until 2003, after the baseline and year 3 capture points, and may affect follow-up results. Rosuvastatin was associated with increased risk for DM in the postmenopausal women in the JUPITER trial (HR, 1.49; 95% CI, 1.11-2.01).10 In the absence of dose information, we could not explore further comparisons.

Women with a BMI lower than 25.0 were at greater risk for new-onset DM than those with BMI of 30.0 or higher, who seem to be at lowest relative risk among BMI categories. Given no other reports of this incidence pattern in other studies, we can only speculate that differences in phenotype, such as weight distribution, may contribute to this finding. Native hormonal changes in menopause permit a redistribution of weight in favor of visceral fat that may be independent of BMI as a risk factor for DM.37 Weight gain within a BMI category may also increase risk for DM.38 Alternatively, there may be some paradoxical protection against DM among postmenopausal women, akin to that reported for recurrent coronary artery events. This may in fact be a sign of index event bias.15 This is an area to explore further.

Overlaps in 95% CIs erase significant ethnic differences, although the trend for greater risk among Asian women compared with others agrees with evidence for increased sensitivity to statin effects in this group.8,12,34,35 Our sample size urges cautious interpretation.

Overlapping 95% CIs indicate similar risk for incident DM with statin use for women with CVD (adjusted HR, 1.46; 95% CI, 1.29-1.65) and without CVD (adjusted HR, 1.48; 95% CI, 1.36-1.62). Given that specific indications for statin use was not available among all women, and that our analysis did not include cardiovascular outcomes, we could not compare risk and benefit for statins in primary or secondary prevention in this population. Current and impending guidelines for cardiometabolic risk assessment and statin therapy include monitoring for DM and DM risk,39,40 which seems prudent.

Several strengths are worth noting: the WHI includes a large, racially diverse cohort of postmenopausal women, and its prospective design enables an examination of temporal associations. When the WHI began, statin use in women with CHD risk factors was not prevalent, allowing comparative study of statin use and nonuse in women with similar risk factors. Our study was also uniform in terms of ascertainment of DM and consistent with data collection for confounders and risk factors over several years.

There are several limitations. First, as this was a observation study, we could not control all confounding factors. While our subgroup analyses in women either with or without CVD found that statin use remains a significant risk for DM, we cannot rule out variations in health care. The sensitivity analyses also attempt to discover and resolve detection and/or selection bias, but it is possible that such biases remain. Second, we did not have data on blood lipid, C-reactive protein, or hemoglobin A1c levels to distinguish if those using statins were at higher risk than those not using statins. Third, although incident DM in older women is likely of the type 2 variety, the WHI question did not specify for type.26,27,29 Despite a lower sensitivity in self-reports for newly incident DM, statin users and nonusers should have a similar bias of underreporting.41,42 Fourth, the inability to track intermittent or inconsistent medication use limits analysis.43 We cannot reliably say that women who reported statin use at 1 or both collection points continued therapy in a way that was likely to provide the intended effect. Moreover, the WHI data up to 2005 reveal that only 7.4% of women used statins, and this proportion may not reflect attributable risk patterns of greater use. Finally, we could not measure drug-drug or drug-disease interactions.

Clearly, statins address the cardiovascular consequences of DM, and current American Diabetes Association guidelines for primary and secondary prevention should not change.44 The Cholesterol Treatment Trialists' Collaboration found that statins significantly benefit vascular mortality and morbidity and all-cause mortality in diabetic populations with rates comparable with those without DM.45 Likewise, guidelines for statin use in nondiabetic populations should not change.39,40 However, the consequences of statin-induced DM have not been specifically defined and deserve more attention. Given the wide use of statins in the aging population, further studies among women, men, and diverse ethnicities will clarify DM risk and risk management to optimize therapy.

Correspondence: Yunsheng Ma, MD, PhD, Division of Preventive and Behavioral Medicine, Department of Medicine, University of Massachusetts Medical School, 55 Lake Ave North, Worcester, MA 01655 (Yunsheng.Ma@umassmed.edu).

Accepted for Publication: October 17, 2011.

Published Online: January 9, 2012. doi:10.1001/archinternmed.2011.625

Author Contributions:Study concept and design: Culver, I. S. Ockene, Olendzki, Sepavich, Wactawski-Wende, Manson, Liu, Curb, and Ma. Acquisition of data: Sepavich, Wactawski-Wende, Manson, Liu, Merriam, J. K. Ockene, Curb, and Ma. Analysis and interpretation of data: I. S. Ockene, Balasubramanian, Wactawski-Wende, Manson, Qiao, Liu, Rahilly-Tierny, Thomas, Berger, and Ma. Drafting of the manuscript: Culver, Balasubramanian, Olendzki, Qiao, and Ma. Critical revision of the manuscript for important intellectual content: Culver, I. S. Ockene, Balasubramanian, Olendzki, Sepavich, Wactawski-Wende, Manson, Liu, Merriam, Rahilly-Tierny, Thomas, Berger, J. K. Ockene, Curb, and Ma. Statistical analysis: Balasubramanian, Qiao and Liu. Obtained funding: Wactawski-Wende, Manson, Liu, Merriam, Curb, and Ma. Administrative, technical, and material support: Culver, Olendzki, Sepavich, Wactawski-Wende, Liu, J. K. Ockene, and Curb. Study supervision: Culver, I. S. Ockene, Olendzki, Sepavich, Wactawski-Wende, Manson, Liu, and Curb. Background literature search: Culver.

Financial Disclosure: None reported.

Funding/Support: This research was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant No. 1 R21 DK083700-01A1 to Dr Ma. It was also supported in part by the University of Massachusetts Diabetes and Endocrinology Research Center grant 5 P30 DK32520 from the NIDDK to Drs Ma and I. S. Ockene. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services, through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221.

Disclaimer: The article's contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIDDK.

Additional Contributions: We thank the principal investigators of all WHI clinical centers and the data coordinating center for their contribution to the study, and we are indebted to the dedicated and committed participants of the WHI.

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Women's Health Initiative Study Group.  Design of the Women's Health Initiative clinical trial and observational study.  Control Clin Trials. 1998;19(1):61-109
PubMed   |  Link to Article
Ritenbaugh C, Patterson RE, Chlebowski RT,  et al.  The Women's Health Initiative Dietary Modification trial: overview and baseline characteristics of participants.  Ann Epidemiol. 2003;13(9):(suppl)  S87-S97
PubMed   |  Link to Article
Stefanick ML, Cochrane BB, Hsia J, Barad DH, Liu JH, Johnson SR. The Women's Health Initiative postmenopausal hormone trials: overview and baseline characteristics of participants.  Ann Epidemiol. 2003;13(9):(suppl)  S78-S86
PubMed   |  Link to Article
Langer RD, White E, Lewis CE, Kotchen JM, Hendrix SL, Trevisan M. The Women's Health Initiative Observational Study: baseline characteristics of participants and reliability of baseline measures.  Ann Epidemiol. 2003;13(9):(suppl)  S107-S121
PubMed   |  Link to Article
Vaughan CJ, Gotto AM Jr. Update on statins: 2003.  Circulation. 2004;110(7):886-892
PubMed   |  Link to Article
Igel M, Sudhop T, von Bergmann K. Pharmacology of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins), including rosuvastatin and pitavastatin.  J Clin Pharmacol. 2002;42(8):835-845
PubMed   |  Link to Article
de Boer IH, Tinker LF, Connelly S,  et al; Women's Health Initiative Investigators.  Calcium plus vitamin D supplementation and the risk of incident diabetes in the Women's Health Initiative.  Diabetes Care. 2008;31(4):701-707
PubMed   |  Link to Article
Bonds DE, Lasser N, Qi L,  et al.  The effect of conjugated equine oestrogen on diabetes incidence: the Women's Health Initiative randomised trial.  Diabetologia. 2006;49(3):459-468
PubMed   |  Link to Article
Margolis KL, Bonds DE, Rodabough RJ,  et al; Women's Health Initiative Investigators.  Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women's Health Initiative Hormone Trial.  Diabetologia. 2004;47(7):1175-1187
PubMed   |  Link to Article
Margolis KL, Lihong Qi , Brzyski R,  et al; Women Health Initiative Investigators.  Validity of diabetes self-reports in the Women's Health Initiative: comparison with medication inventories and fasting glucose measurements.  Clin Trials. 2008;5(3):240-247
PubMed   |  Link to Article
Heckbert SR, Kooperberg C, Safford MM,  et al.  Comparison of self-report, hospital discharge codes, and adjudication of cardiovascular events in the Women's Health Initiative.  Am J Epidemiol. 2004;160(12):1152-1158
PubMed   |  Link to Article
Conen D, Ridker PM, Mora S, Buring JE, Glynn RJ. Blood pressure and risk of developing type 2 diabetes mellitus: the Women's Health Study.  Eur Heart J. 2007;28(23):2937-2943
PubMed   |  Link to Article
Patterson RE, Kristal AR, Tinker LF, Carter RA, Bolton MP, Agurs-Collins T. Measurement characteristics of the Women's Health Initiative food frequency questionnaire.  Ann Epidemiol. 1999;9(3):178-187
PubMed   |  Link to Article
McTiernan A, Kooperberg C, White E,  et al; Women's Health Initiative Cohort Study.  Recreational physical activity and the risk of breast cancer in postmenopausal women: the Women's Health Initiative Cohort Study.  JAMA. 2003;290(10):1331-1336
PubMed   |  Link to Article
Song Y, Manson JE, Tinker L,  et al.  Insulin sensitivity and insulin secretion determined by homeostasis model assessment and risk of diabetes in a multiethnic cohort of women: the Women's Health Initiative Observational Study.  Diabetes Care. 2007;30(7):1747-1752
PubMed   |  Link to Article
Rubin DB. Estimating causal effects from large data sets using propensity scores.  Ann Intern Med. 1997;127(8, pt 2):757-763
PubMed
Rajpathak SN, Kumbhani DJ, Crandall J, Barzilai N, Alderman M, Ridker PM. Statin therapy and risk of developing type 2 diabetes: a meta-analysis.  Diabetes Care. 2009;32(10):1924-1929
PubMed   |  Link to Article
Janssen I, Powell LH, Kazlauskaite R, Dugan SA. Testosterone and visceral fat in midlife women: the Study of Women's Health Across the Nation (SWAN) fat patterning study.  Obesity (Silver Spring). 2010;18(3):604-610
PubMed   |  Link to Article
Biggs ML, Mukamal KJ, Luchsinger JA,  et al.  Association between adiposity in midlife and older age and risk of diabetes in older adults.  JAMA. 2010;303(24):2504-2512
PubMed   |  Link to Article
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.  Executive Summary of The Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).  JAMA. 2001;285(19):2486-2497
PubMed   |  Link to Article
Brunzell JD, Davidson M, Furberg CD,  et al; American Diabetes Association; American College of Cardiology Foundation.  Lipoprotein management in patients with cardiometabolic risk: consensus statement from the American Diabetes Association and the American College of Cardiology Foundation.  Diabetes Care. 2008;31(4):811-822
PubMed   |  Link to Article
Oksanen T, Kivimäki M, Pentti J, Virtanen M, Klaukka T, Vahtera J. Self-report as an indicator of incident disease.  Ann Epidemiol. 2010;20(7):547-554
PubMed   |  Link to Article
Okura Y, Urban LH, Mahoney DW, Jacobsen SJ, Rodeheffer RJ. Agreement between self-report questionnaires and medical record data was substantial for diabetes, hypertension, myocardial infarction and stroke but not for heart failure.  J Clin Epidemiol. 2004;57(10):1096-1103
PubMed   |  Link to Article
Simpson RJ Jr, Mendys P. The effects of adherence and persistence on clinical outcomes in patients treated with statins: a systematic review.  J Clin Lipidol. 2010;4(6):462-471
PubMed   |  Link to Article
American Diabetes Association.  Standards of medical care in diabetes: 2011.  Diabetes Care. 2011;34:(suppl 1)  S11-S61
PubMed   |  Link to Article
Cholesterol Treatment Trialists' Collaboration (CTT).  Accessed September 30, 2011. http://www.ctsu.ox.ac.uk/projects/ctt

Figures

Place holder to copy figure label and caption
Graphic Jump Location

Figure. Flowchart for statin users and diabetes mellitus (DM) analyses using data sets from the Women's Health Initiative.

Tables

Table Graphic Jump LocationTable 1. Characteristics of 153 840 Study Participants, Women's Health Initiativea
Table Graphic Jump LocationTable 2. Association Between Diabetes Mellitus (DM) Risk and Statin Use Status at Baseline in 153840 Participants
Table Graphic Jump LocationTable 3. Association Between Diabetes Mellitus (DM) Risk and Statin Use Status at Baseline, Within Age, Race/Ethnicity, and BMI Subgroups in 153840 Participants
Table Graphic Jump LocationTable 4. Risk of Diabetes Mellitus (DM) by Statin Use Among Women With and Without Medical History of Cardiovascular Disease (CVD) at Baseline
Table Graphic Jump LocationTable 5. Risk of Diabetes Mellitus (DM) by Statin Use at Baseline and 3-Year Follow-up in 125575 Participants

References

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Pedersen TR, Kjekshus J, Berg K,  et al; Scandinavian Simvastatin Survival Study Group.  Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).  Atheroscler Suppl. 2004;5(3):81-87
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Collins R, Armitage J, Parish S, Sleigh P, Peto R.Heart Protection Study Collaborative Group.  MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial.  Lancet. 2003;361(9374):2005-2016
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Mann D, Reynolds K, Smith D, Muntner P. Trends in statin use and low-density lipoprotein cholesterol levels among US adults: impact of the 2001 National Cholesterol Education Program guidelines.  Ann Pharmacother. 2008;42(9):1208-1215
PubMed   |  Link to Article
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Sattar N, Preiss D, Murray HM,  et al.  Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials.  Lancet. 2010;375(9716):735-742
PubMed   |  Link to Article
Mora S, Glynn RJ, Hsia J, MacFadyen JG, Genest J, Ridker PM. Statins for the primary prevention of cardiovascular events in women with elevated high-sensitivity C-reactive protein or dyslipidemia: results from the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) and meta-analysis of women from primary prevention trials.  Circulation. 2010;121(9):1069-1077
PubMed   |  Link to Article
Yokote K, Saito Y.CHIBA.  Influence of statins on glucose tolerance in patients with type 2 diabetes mellitus: subanalysis of the collaborative study on hypercholesterolemia drug intervention and their benefits for atherosclerosis prevention (CHIBA study).  J Atheroscler Thromb. 2009;16(3):297-298
PubMed   |  Link to Article
Chan JC, Malik V, Jia W,  et al.  Diabetes in Asia: epidemiology, risk factors, and pathophysiology.  JAMA. 2009;301(20):2129-2140
PubMed   |  Link to Article
Waters DD, Ho JE, DeMicco DA,  et al.  Predictors of new-onset diabetes in patients treated with atorvastatin: results from 3 large randomized clinical trials.  J Am Coll Cardiol. 2011;57(14):1535-1545
PubMed   |  Link to Article
Baker WL, Talati R, White CM, Coleman CI. Differing effect of statins on insulin sensitivity in non-diabetics: a systematic review and meta-analysis.  Diabetes Res Clin Pract. 2010;87(1):98-107
PubMed   |  Link to Article
Dahabreh IJ, Kent DM. Index event bias as an explanation for the paradoxes of recurrence risk research.  JAMA. 2011;305(8):822-823
PubMed   |  Link to Article
Mills EJ, Wu P, Chong G,  et al.  Efficacy and safety of statin treatment for cardiovascular disease: a network meta-analysis of 170,255 patients from 76 randomized trials.  QJM. 2011;104(2):109-124
PubMed   |  Link to Article
Preiss D, Seshasai SR, Welsh P,  et al.  Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis.  JAMA. 2011;305(24):2556-2564
PubMed   |  Link to Article
Liu S, Tinker L, Song Y,  et al.  A prospective study of inflammatory cytokines and diabetes mellitus in a multiethnic cohort of postmenopausal women.  Arch Intern Med. 2007;167(15):1676-1685
PubMed   |  Link to Article
Ding EL, Song Y, Malik VS, Liu S. Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis.  JAMA. 2006;295(11):1288-1299
PubMed   |  Link to Article
Women's Health Initiative Study Group.  Design of the Women's Health Initiative clinical trial and observational study.  Control Clin Trials. 1998;19(1):61-109
PubMed   |  Link to Article
Ritenbaugh C, Patterson RE, Chlebowski RT,  et al.  The Women's Health Initiative Dietary Modification trial: overview and baseline characteristics of participants.  Ann Epidemiol. 2003;13(9):(suppl)  S87-S97
PubMed   |  Link to Article
Stefanick ML, Cochrane BB, Hsia J, Barad DH, Liu JH, Johnson SR. The Women's Health Initiative postmenopausal hormone trials: overview and baseline characteristics of participants.  Ann Epidemiol. 2003;13(9):(suppl)  S78-S86
PubMed   |  Link to Article
Langer RD, White E, Lewis CE, Kotchen JM, Hendrix SL, Trevisan M. The Women's Health Initiative Observational Study: baseline characteristics of participants and reliability of baseline measures.  Ann Epidemiol. 2003;13(9):(suppl)  S107-S121
PubMed   |  Link to Article
Vaughan CJ, Gotto AM Jr. Update on statins: 2003.  Circulation. 2004;110(7):886-892
PubMed   |  Link to Article
Igel M, Sudhop T, von Bergmann K. Pharmacology of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins), including rosuvastatin and pitavastatin.  J Clin Pharmacol. 2002;42(8):835-845
PubMed   |  Link to Article
de Boer IH, Tinker LF, Connelly S,  et al; Women's Health Initiative Investigators.  Calcium plus vitamin D supplementation and the risk of incident diabetes in the Women's Health Initiative.  Diabetes Care. 2008;31(4):701-707
PubMed   |  Link to Article
Bonds DE, Lasser N, Qi L,  et al.  The effect of conjugated equine oestrogen on diabetes incidence: the Women's Health Initiative randomised trial.  Diabetologia. 2006;49(3):459-468
PubMed   |  Link to Article
Margolis KL, Bonds DE, Rodabough RJ,  et al; Women's Health Initiative Investigators.  Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women's Health Initiative Hormone Trial.  Diabetologia. 2004;47(7):1175-1187
PubMed   |  Link to Article
Margolis KL, Lihong Qi , Brzyski R,  et al; Women Health Initiative Investigators.  Validity of diabetes self-reports in the Women's Health Initiative: comparison with medication inventories and fasting glucose measurements.  Clin Trials. 2008;5(3):240-247
PubMed   |  Link to Article
Heckbert SR, Kooperberg C, Safford MM,  et al.  Comparison of self-report, hospital discharge codes, and adjudication of cardiovascular events in the Women's Health Initiative.  Am J Epidemiol. 2004;160(12):1152-1158
PubMed   |  Link to Article
Conen D, Ridker PM, Mora S, Buring JE, Glynn RJ. Blood pressure and risk of developing type 2 diabetes mellitus: the Women's Health Study.  Eur Heart J. 2007;28(23):2937-2943
PubMed   |  Link to Article
Patterson RE, Kristal AR, Tinker LF, Carter RA, Bolton MP, Agurs-Collins T. Measurement characteristics of the Women's Health Initiative food frequency questionnaire.  Ann Epidemiol. 1999;9(3):178-187
PubMed   |  Link to Article
McTiernan A, Kooperberg C, White E,  et al; Women's Health Initiative Cohort Study.  Recreational physical activity and the risk of breast cancer in postmenopausal women: the Women's Health Initiative Cohort Study.  JAMA. 2003;290(10):1331-1336
PubMed   |  Link to Article
Song Y, Manson JE, Tinker L,  et al.  Insulin sensitivity and insulin secretion determined by homeostasis model assessment and risk of diabetes in a multiethnic cohort of women: the Women's Health Initiative Observational Study.  Diabetes Care. 2007;30(7):1747-1752
PubMed   |  Link to Article
Rubin DB. Estimating causal effects from large data sets using propensity scores.  Ann Intern Med. 1997;127(8, pt 2):757-763
PubMed
Rajpathak SN, Kumbhani DJ, Crandall J, Barzilai N, Alderman M, Ridker PM. Statin therapy and risk of developing type 2 diabetes: a meta-analysis.  Diabetes Care. 2009;32(10):1924-1929
PubMed   |  Link to Article
Janssen I, Powell LH, Kazlauskaite R, Dugan SA. Testosterone and visceral fat in midlife women: the Study of Women's Health Across the Nation (SWAN) fat patterning study.  Obesity (Silver Spring). 2010;18(3):604-610
PubMed   |  Link to Article
Biggs ML, Mukamal KJ, Luchsinger JA,  et al.  Association between adiposity in midlife and older age and risk of diabetes in older adults.  JAMA. 2010;303(24):2504-2512
PubMed   |  Link to Article
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.  Executive Summary of The Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).  JAMA. 2001;285(19):2486-2497
PubMed   |  Link to Article
Brunzell JD, Davidson M, Furberg CD,  et al; American Diabetes Association; American College of Cardiology Foundation.  Lipoprotein management in patients with cardiometabolic risk: consensus statement from the American Diabetes Association and the American College of Cardiology Foundation.  Diabetes Care. 2008;31(4):811-822
PubMed   |  Link to Article
Oksanen T, Kivimäki M, Pentti J, Virtanen M, Klaukka T, Vahtera J. Self-report as an indicator of incident disease.  Ann Epidemiol. 2010;20(7):547-554
PubMed   |  Link to Article
Okura Y, Urban LH, Mahoney DW, Jacobsen SJ, Rodeheffer RJ. Agreement between self-report questionnaires and medical record data was substantial for diabetes, hypertension, myocardial infarction and stroke but not for heart failure.  J Clin Epidemiol. 2004;57(10):1096-1103
PubMed   |  Link to Article
Simpson RJ Jr, Mendys P. The effects of adherence and persistence on clinical outcomes in patients treated with statins: a systematic review.  J Clin Lipidol. 2010;4(6):462-471
PubMed   |  Link to Article
American Diabetes Association.  Standards of medical care in diabetes: 2011.  Diabetes Care. 2011;34:(suppl 1)  S11-S61
PubMed   |  Link to Article
Cholesterol Treatment Trialists' Collaboration (CTT).  Accessed September 30, 2011. http://www.ctsu.ox.ac.uk/projects/ctt

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Submit a Comment
Statins may Increase Diabetes Type 2 by Lowering Testosterone
Posted on January 11, 2012
James M. Howard, BS
Independent
Conflict of Interest: None Declared
A case may be made that loss of testosterone of old age may result in diabetes type 2. Statins are known to reduce testosterone levels. It is my hypothesis that testosterone is increasing within the population. This increase causes an earlier peak, followed by an earlier decline, in testosterone within the population. This may explain why diabetes type 2 is increasing.

Conflict of Interest: None declared
Statin Use and Risk of Diabetes Mellitus: Statins did not cause the excess cases.
Posted on February 13, 2012
Lisa W. Martin, MD
George Washington University
Conflict of Interest: None Declared
The study as presented was observational, and one cannot conclude that statins cause diabetes from this study. An association was found between diagnosis of diabetes and taking statin therapy, but the authors could not fully account for underlying selection bias, particularly since they did not have lipid data. I don't think that the authors intended to imply a causal relationship. Patients with lipid disorders may have had a pre-diabetes, or metabolic syndrome, which includes abnormalities of HDL cholesterol and triglycerides. They may have been more likely to have been prescribed statins. These participants could have been predisposed to diabetes even before they started statin therapy. The authors stated that a “propensity score analysis was performed to reduce the confounding effects of other factors in the evaluation of the association between statin use and DM risk within an observational study setting.”(1) However, it would be impossible to fully correct for the fact that the lipid values were not available. A meta-analysis of randomized trials demonstrated a 9% increased risk of diabetes, or an extra case of diabetes in one patient out of 253 patients treated with statins for 4 years.(2) Another meta-analysis of randomized trials found the same hazard for the development of diabetes in patients on statins versus those randomized to placebo. (3) This assessment is likely more reliable in determining an effect of statins on occurrence of diabetes.
The hazard ratio of 1.71 (1.48 after adjusting for potential confounders that could be assessed) found in this current study (1) is dramatically higher, and raised concerns for increased risk of diabetes. I agree that the study shows that “when a statin is indicated, it’s very important to continue to monitor for diabetes as well as for the statin effects,” (4) because the identification of diabetes will therefore lead to proper treatment for this chronic disease as well. One would not want patients to stop statins as a result of this study, as statins are particularly effective in preventing cardiovascular disease in diabetics.
1. Culver AL, Ockene IS, Balasubramanian R. Statin Use and Risk of Diabetes Mellitus in Postmenopausal Women in the Women’s Health Initiative. Arch Intern Med. Jan 23, 2012; 172(2): 144-152.
2. Sattar N, Preiss D, Murray HD, et al. Statins and risk of incident diabetes: A collaborative meta-analysis of randomised statin trials. Lancet 2010;375(9716):735-42.
3. Mills EJ, Wu P, Chong G et al. Efficacy and safety of statin treatment for cardiovascular disease: A network meta-analysis of 170,255 patients from 76 randomized trials. QJM 2011; 104(2): 109-124.
4. http://www.medpagetoday.com/tbprint.cfm?tbid=30575. Kristina Fiore staff writer, interviewing Yunsheng Ma January 9, 2012.

Conflict of Interest: None declared
Is there a role for statins in the development of diabetes mellitus?
Posted on March 6, 2012
Alice C. Ceacareanu, PharmD, PhD
SUNY School of Pharmacy and Pharmaceutical Sciences
Conflict of Interest: None Declared
The recently reported findings by Culver et al (1) and Dr. Johansen’s editorial note trigger a few comments for consideration when evaluating statins use. Among several pleiotropic effects of this drug class, the lowering of C-reactive protein (2) and leptin levels (3), as well as the recently reported inhibitory effect on the histone deacetylase (HDAC) activity (4), suggest that statins may create an environment which has the potential to improve insulin resistance. HDAC inhibitors are now evaluated as a novel treatment for diabetes mellitus (5), thus, as inhibitors of HDAC, statins may delay the occurrence of diabetes in users as compared to non-users having similar clinical characteristics at baseline. Additional studies are needed to address the knowledge gap created by this intriguing evidence. REFERENCES
1 Culver AL, Ockene IS, Balasubramanian R, et al. Statin Use and Risk of Diabetes Mellitus in Postmenopausal Women in the Women's Health Initiative. Arch Intern Med. 2012 Jan 23;172(2):144-52.
2 Ridker PM, Danielson E, Fonseca FA, et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet. 2009 Apr 4;373(9670):1175-82.
3 Takahashi Y, Satoh M, Tabuchi T, Nakamura M. Prospective, randomized, single-blind comparison of effects of 6 months' treatment with atorvastatin versus pravastatin on leptin and angiogenic factors in patients with coronary artery disease. Heart and vessels. 2011 Jun 4.
4 Lin YC, Lin JH, Chou CW, Chang YF, Yeh SH, Chen CC. Statins increase p21 through inhibition of histone deacetylase activity and release of promoter -associated HDAC1/2. Cancer Res. 2008 Apr 1;68(7):2375-83.
5 Christensen DP, Dahllof M, Lundh M, et al. Histone deacetylase (HDAC) inhibition as a novel treatment for diabetes mellitus. Mol Med. 2011 May- Jun;17(5-6):378-90.

Conflict of Interest: None declared
What about co-inheritance risk of dyslipidemia and type 2 diabetes?
Posted on January 25, 2012
Claudia Gragnoli, MD, PhD
Penn State Hershey Medical Center
Conflict of Interest: None Declared
Dear Editor, The findings about statin use and associated risk of type 2 diabetes in postmenopausal women are certainly meritorious of attention and further studies. However, I would like to raise a concern about the interpretation of the data. Statin use indicates that the subjects had high cholesterol levels and/or high lipid levels. The authors did not report data on cholesterol or lipids levels in the women who are not on statin therapy. I believe this introduces a strong potential bias. In fact, women with high lipid levels may per se be genetically subsceptible to type 2 diabetes, which is commonly associated with dyslipidemia, and this associated risk for type 2 diabetes is likely higher than the type 2 diabetes risk for women without dyslipidemia. In other words, we ought to introduce the concept of co-inheritance of dyslipidemia and type 2 diabetes, which could manifest independently of the use of statin medications. The two populations of women studied, either those on statin therapy or those not on statin therapy, may well represent two genetically distinct groups regarding the vulnerability to development of type 2 diabetes.

Conflict of Interest: None declared
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