February 12, 2014

Statin Use Increases the Risk of Diabetes Mellitus in Postmenopausal Women

Recent study confirms already-known association
This study investigated 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).


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;172(2):144-152. 


The study investigated 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).


The WHI recruited 161,808 postmenopausal women aged 50–79 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.


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 of 48%. This association remained after adjusting for other potential confounders and was observed for all types of statin medications.


Statin medication use in postmenopausal women is associated with an increased risk for DM.


This study confirmed an already-known association between statins and type 2 diabetes in women; however, it may have been the final straw that led the FDA to issue an important safety announcement regarding statins.1 This safety announcement should be required reading for all healthcare providers because it offers a view behind the curtain of propaganda that the drug industry has painted on the safety of statins. And, even with the FDA’s best attempt at quelling the safety concerns, the document discloses added risk of adverse effects with statin use. The major outcome is that the FDA now requires a label warning that “increases in glycosylated hemoglobin (HbA1c) and fasting serum glucose levels have been reported with statin use.”
Physicians are faced with a basic question when making a prescription of any drug to a patient: “What are the risks and benefits of this recommendation?” When it comes to statin drugs, the benefits have been grossly overstated, while the risks have continually been swept under the rug. That discussion is much longer than the space available in this commentary. Suffice it to say that it is important to point out that while statins reduce the heart attack risk in women, they do not appear to affect overall risk of death, possibly because an increased risk for diabetes cancels out the reduced heart attack risk. So, let me focus on the study at hand and try to make sense of such a high risk for diabetes in postmenopausal women using statins.
When it comes to statin drugs, the benefits have been grossly overstated, while the risks have continually been swept under the rug.
First, are the results valid? There appears to be little doubt that there is an association between statin use and the development of a new diagnosis of diabetes. Although other studies, such as the Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial reported a lower percentage of risk increase, at a 27%,2 it is still quite significant given the fact that doctors currently write 255 million prescriptions for cholesterol-lowering drugs each year. With an estimated 24 million Americans taking statins every day, the population-attributable risk is of great concern—hence the warning letter from the FDA. Let me put this risk in real numbers: More than 20 million Americans take statins. Based upon the WHI study, a conservative estimate is that the increased risk for DM with statin use would equate to 100,000 new statin-induced diabetics every 5 years. The section of the safety announcement dealing with the diabetes link concluded, “Based on clinical trial meta-analyses and epidemiological data from the published literature, information concerning an effect of statins on incident diabetes and increases in HbA1c and/or fasting plasma glucose was added to statin labels.”
So, here is the next question: If it is now a consensus that statins can lead to diabetes and/or worsen glycemic control, what is the mechanism? My guess is that the answer will point to the fundamental flaw with the action of HMG-CoA reductase inhibitors: The blockade occurs way too far up in the metabolic pathway, and in the process leads to impaired manufacture of at least a dozen important physiological compounds. Yes, coenzyme Q10 gets the most focus, but what about all of the others like the various pyrophosphates, isoprenoids, squalene, and dolichols? Could these somehow be involved in important steps in insulin sensitivity and cell communication? The research seems to suggest so.
Cellular studies have shown that statins can create cellular inflammation by inducing specific pro-inflammatory cytokine production that could impair insulin action3 as well as interfering with beta-cell insulin secretion, either by decreasing Ca2+-dependent insulin secretion or by interfering with isoprenylation of guanosine triphosphate (GTP)–binding proteins.4 Statin inhibition of isoprenoid biosynthesis may lead to lower expression of insulin-signaling proteins in adipocytes and to reduced glucose transporter expression or translocation.5
The bottom line is that statins are not as benign as presented, and although the medical literature is flush with editorials, letters, and opinions all expressing the virtues of statins justifying the continued overprescribing, there is also a growing swell of research indicating that statins may present greater risk than previously thought.

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  1.  United States Food and Drug Administration. FDA Drug Safety Communication: Important safety label changes to cholesterol-lowering statin drugs. http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm
  2.  Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195-2207
  3.  Massonnet B, Normand S, Moschitz R, et al. Pharmacological inhibitors of the mevalonate pathway activate pro-IL-1 processing and IL-1 release by human monocytes. Eur Cytokine Netw. 2009;20(3):112-120.
  4.  Yada T, Nakata M, Shiraishi T, Kakei M. Inhibition by simvastatin, but not pravastatin, of glucose-induced cytosolic Ca2+ signalling and insulin secretion due to blockade of L-type Ca2+ channels in rat islet beta-cells. Br J Pharmacol. 1999;126(5):1205-1213.
  5.  Nakata M, Nagasaka S, Kusaka I, et al. Effects of statins on the adipocyte maturation and expression of glucose transporter 4 (SLC2A4): implications in glycaemic control. Diabetologia. 2006;49(8):1881-1892.