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    4 Comments for this article
    Statins may Increase Diabetes Type 2 by Lowering Testosterone
    James M. Howard, BS | Independent
    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.
    Lisa W. Martin, MD | George Washington University
    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?
    Alice C. Ceacareanu, PharmD, PhD | SUNY School of Pharmacy and Pharmaceutical Sciences
    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?
    Claudia Gragnoli, MD, PhD | Penn State Hershey Medical Center
    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
    Original Investigation
    Jan 23, 2012

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

    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

    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.