What to Tell Patients about Statins and the Risk of Diabetes?
The Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin or JUPITER trial randomly assigned 17,603 subjects over age 65 with high sensitivity C-reactive protein levels (hsCRP) > 2 to 20 mg of rosuvastatin or placebo.(1) New onset diabetes (NOD) was a prespecified secondary outcome because the West of Scotland Coronary Prevention Study had suggested a reduction in NOD with 40 mg of pravastatin treatment. (2) In contrast, JUPITER documented 54 more cases of NOD in the rosuvastatin-treated subjects, but 134 fewer cardiac events.(1) This number of diabetic subjects is extremely low given that there were 8901 subjects in the rosuvastatin treated group, but subsequent observational and meta-analytic studies demonstrate that statins increase the risk of NOD about 10%.(3) The increased risk for NOD is greatest in those subjects with either prediabetes or risk factors for the metabolic syndrome such as elevated glucose or A1c levels or increased body weight. We have speculated that JUPITER documented that statins increase NOD because JUPITER selected subjects for an increased hsCRP.(4) hsCRP is a marker of increased risk for the metabolic syndrome (5) and therefore a marker of insulin resistance. Indeed, >40% of the JUPITER subjects met criteria for the metabolic syndrome. The overall absolute risk for NOD in statin-treated patients is low at only 1/1000 patients treated per year, (3) and the reductions in cardiovascular events exceed the risks of NOD. Nevertheless, patients are very concerned about NOD so clinicians need to be knowledgeable to address their concern.
So far statins are the only LDL reducing agents proven to increase NOD, and the mechanism is not clear, but the best evidence suggests that NOD is directly related to the reduction in cholesterol. That suggests that other LDL-reducing agents will also increase NOD. Statins block 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA R), which reduces hepatic intracellular cholesterol and thereby stimulates increased hepatic production of LDL receptors. The theory is that blocking HMG-CoA R also increases pancreatic beta-cell LDL receptor activity which increases intracellular cholesterol and somehow interferes with insulin secretion. (3) This theory is not totally satisfactory because one would expect that the increased beta-cell LDL levels and intracellular cholesterol levels would eventually reduce LDL receptor activity and restore normal insulin activity. Consequently, there are other theories including the observation that statins reduce glucose transporters (GLUT) 2 and 4 or that the effect is mediated by the reductions in coenzyme Q10 that occur with stains. (3)
Whatever the mechanism, other studies clearly indicate that the increased incidence of NOD is related to the reduction in LDL-C. Studies of Dutch individuals with inherited hypercholesterolemia of different severities demonstrate that the risk of NOD goes down as the cholesterol level goes up.(6) Such results clearly implicate reduced LDL as the culprit for the increase in NOD. So, we suspect that other agents that lower LDL such as ezetimibe and PCSK9 inhibitors will also increase NOD.
These observations have several possible implications for clinical practice. First statins should not be in everyone’s water, but only in the water of those with increased risk for CVD. Statins’ benefits are so great and the risks of DM so low, however, that clinicians must be certain that the risk for CVD is low before not using these drugs. I prefer using lifetime risk to assess the possibility of statin benefit, and also make sure that atypical risk factors such as lipoprotein a (7) are also low before I decide not to treat someone. Second, all patients on statins should be encouraged to exercise and to keep their weight down so that their lifestyle does not contribute to their risk of NOD. The folks most likely to develop NOD with statins were those individuals with risk factors for diabetes. Third, clinicians should be aware of the documented diabetes risk with statins and the possible risk with other LDL reducing agents. Many patients are aware of these risks so it behooves clinicians to be knowledgeable so that we can engage in a frank discussion of the risks and benefits or reducing LDL-C.
1. 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(21):2195–2207.
2. Shepherd J. Prevention of coronary heart disease with pravastatin in west of scotland prevention study group. NEJM. 1995;333:1301–1307.
3. Carmena R, Betteridge DJ. Diabetogenic action of statins: Mechanisms. Curr Atheroscler Rep. 2019;21(6):23.
4. Thompson PD, Panza G, Zaleski A, Taylor B. Statin-associated side effects. J Am Coll Cardiol. 2016;67(20):2395–2410. doi: S0735–1097(16)01692–2 [pii].
5. Mirhafez S, Ebrahimi M, Karimian MS, et al. Serum high-sensitivity C-reactive protein as a biomarker in patients with metabolic syndrome: Evidence-based study with 7284 subjects. Eur J Clin Nutr. 2016;70(11):1298.
6. Besseling J, Kastelein JJ, Defesche JC, Hutten BA, Hovingh GK. Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus. JAMA. 2015;313(10):1029–1036. doi: 10.1001/jama.2015.1206 [doi].
7. Tsimikas S. A test in context: Lipoprotein(a): Diagnosis, prognosis, controversies, and emerging therapies. J Am Coll Cardiol. 2017;69(6):692–711. doi: S0735–1097(16)37254–0 [pii].
