Skip to main content
Top

02-02-2017 | Cardiovascular disorders | Review | Article

Diabetes Secondary to Treatment with Statins

Journal: Current Diabetes Reports

Authors: Markku Laakso, Johanna Kuusisto

Publisher: Springer US

Abstract

Purpose of Review

This review summarizes the recent population-based studies, clinical trials, clinical metabolic studies, and genetic studies reporting the effects of statin therapy on the risk of diabetes. Recent studies aiming to explain the mechanisms how statin treatment affects insulin sensitivity and insulin secretion are also reviewed.

Recent Findings

Statin therapy increases the risk of diabetes by 9%–12% in the two meta-analyses of statin trials and by 18%–99% in five population-based studies. Statin therapy impairs insulin sensitivity and insulin secretion based on clinical and epidemiologic studies. In vitro studies demonstrate that the most diabetogenic statins impair insulin sensitivity and insulin secretion by multiple mechanisms. Recent genetic studies suggest that the increased risk of type 2 diabetes may be partially explained by gene variants in the target genes for low-density lipoprotein cholesterol lowering drugs.

Summary

Population-based studies report higher incidence rates for diabetes in individuals on statin treatment compared with clinical trials. Incident diabetes has not been a prespecified endpoint in statin trials and glucose and/or HbA1c have not been routinely measured. Therefore, it is possible that the risk of diabetes in individuals on statin treatment has been underestimated in previous statin trials. Accumulating evidence from several statin trials, population-based studies, clinical studies, and in vitro studies suggests that pravastatin is the least diabetogenic statin, and simvastatin, atorvastatin, and rosuvastatin the most diabetogenic statins. In vitro studies have reported new findings on mechanisms how statin treatment affects insulin sensitivity and insulin secretion. In spite of diabetogenicity of different statins, the consensus is that the benefits of statins in reducing cardiovascular events clearly outweigh the risk of diabetes.
Literature
1.
Tobert JA. New developments in lipid-lowering therapy: the role of inhibitors of hydroxymethylglutaryl-coenzyme A reductase. Circulation. 1987;76:534–8.CrossRefPubMed
2.
•• Collins R, Reith C, Emberson J, Armitage J, Baigent C, Blackwell L, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet. 2016. An extensive and updated review on the evidence for the efficacy and safety of statin therapy.
3.
Freeman DJ, Norrie J, Sattar N, et al. Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation. 2001;103:357–62.CrossRefPubMed
4.
Betteridge DJ, Carmena R. The diabetogenic action of statins—mechanisms and clinical implications. Nat Rew Endocrinol. 2016;12:99–110.
5.
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;172:144–52.CrossRefPubMed
6.
Zaharan NL, Williams D, Bennett K. Statins and risk of treated incident diabetes in a primary care population. Br J Clin Pharmacol. 2013;75:1118–24.CrossRefPubMed
7.
Macedo AF, Douglas I, Smeeth L, Forbes H, Ebrahim S. Statins and the risk of type 2 diabetes mellitus: cohort study using the UK clinical practice pesearch datalink. BMC Cardiovasc Disord. 2014;14:85.CrossRefPubMedPubMedCentral
8.
Cederberg H, Stančáková A, Yaluri N, Modi S, Kuusisto J, Laakso M. Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion: a 6 year follow-up study of the METSIM cohort. Diabetologia. 2015;58:1109–17.CrossRefPubMed
9.
Rha SW, Choi BG, Seo HS, et al. Impact of statin use on development of new-onset diabetes mellitus in Asian population. Am J Cardiol. 2016;117:382–7.CrossRefPubMed
10.
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;359:2195–207.CrossRefPubMed
11.
Kjekshus J, Apetrei E, Barrios V, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med. 2007;357:2248–61.CrossRefPubMed
12.
Tavazzi L, Maggioni AP, Marchioli R, et al. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:1231–9.CrossRefPubMed
13.
• Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375:735–42. The first meta-analysis to demonstrate that statin treatments is associated with the risk of diabetes.CrossRefPubMed
14.
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;305:2556–64.CrossRefPubMed
15.
Navarese EP, Buffon A, Andreotti F, et al. Meta-analysis of impact of different types and doses of statins on new-onset diabetes mellitus. Am J Cardiol. 2013;111:1123–30.CrossRefPubMed
16.
•• Swerdlow DI, Preiss D, Kuchenbaecker KB, et al. HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Lancet. 2015;385:351–61. The first study to show that the increased risk of type 2 diabetes associated with statins is at least partially explained by HMGCR inhibition.CrossRefPubMedPubMedCentral
17.
•• Lotta LA, Sharp SJ, Burgess S, et al. Association between low-density lipoprotein cholesterol-lowering genetic variants and risk of type 2 diabetes: a meta-analysis. JAMA. 2016;316:1383–91. This meta-analysis shows that LDL-C-lowering genetic variants in or near NPC1L1 and PCSK9 genes were associated with a higher risk of type 2 diabetes. These data provide insights into potential adverse effects of LDL-C-lowering therapy.CrossRefPubMed
18.
• Besseling J, Kastelein JJ, Defesche JC, Hutten BA, Hovingh GK. Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus. JAMA. 2015;313:1029–36. This study showed that the prevalence of type 2 diabetes among patients with familial hypercholesterolemia was significantly lower than among unaffected relatives.CrossRefPubMed
19.
Baker WL, Talati R, White CM, Coleman CI. Differing effect of statins on insulin sensitivity in nondiabetics: a systematic review and meta-analysis. Diabetes Res Clin Pract. 2010;87:98–107.CrossRefPubMed
20.
Puurunen J, Piltonen T, Puukka K, et al. Statin therapy worsens insulin sensitivity in women with polycystic ovary syndrome (PCOS): a prospective, randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2013;98:4798–807.CrossRefPubMed
21.
Moutzouri E, Liberopoulos E, Mikhailidis DP, et al. Comparison of the effects of simvastatin vs. rosuvastatin vs. simvastatin/ezetimibe on parameters of insulin resistance. Int J Clin Pract. 2011;65:1141–8.CrossRefPubMed
22.
Paniagua JA, López-Miranda J, Escribano A, et al. Cerivastatin improves insulin sensitivity and insulin secretion in early-state obese type 2 diabetes. Diabetes. 2002;51:2596–603.CrossRefPubMed
23.
Yaluri N, Modi S, Kokkola T. Simvastatin induces insulin resistance in L6 skeletal muscle myotubes by suppressing insulin signaling, GLUT4 expression and GSK-3β phosphorylation. Biochem Biophys Res Commun. 2016. doi:10.​1016/​j.​bbrc.​2016.​10.​026.PubMed
24.
Kain V, Kapadia B, Misra P, Saxena U. Simvastatin may induce insulin resistance through a novel fatty acid mediated cholesterol independent mechanism. Sci Rep. 2015;5:13823. doi:10.​1038/​srep13823.CrossRefPubMedPubMedCentral
25.
Henriksbo BD, Lau TC, Cavallari JF, et al. Fluvastatin causes NLRP3 inflammasome-mediated adipose insulin resistance. Diabetes. 2014;63:3742–7.CrossRefPubMed
26.
Ashcroft FM, Rorsman P. Diabetes mellitus and the β cell: the last ten years. Cell. 2012;148:1160–71.CrossRefPubMed
27.
Yaluri N, Modi S, López Rodríguez M, et al. Simvastatin impairs insulin secretion by multiple mechanisms in MIN6 cells. PLoS One. 2015;10, e0142902.CrossRefPubMedPubMedCentral
28.
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;126:1205–13.CrossRefPubMedPubMedCentral
29.
Zhou J, Li W, Xie Q, et al. Effects of simvastatin on glucose metabolism in mouse MIN6 cells. J Diabetes Res. 2014;2014:376570.PubMedPubMedCentral
30.
Ishikawa M, Okajima F, Inoue N, et al. Distinct effects of pravastatin, atorvastatin, and simvastatin on insulin secretion from a beta-cell line, MIN6 cells. J Atheroscler Thromb. 2006;13:329–35.CrossRefPubMed
31.
Zhao W, Zhao SP. Different effects of statins on induction of diabetes mellitus: an experimental study. Drug Des Devel Ther. 2015;9:6211–23.CrossRefPubMedPubMedCentral
32.
Lorza-Gil E, Salerno AG, Wanschel AC, et al. Chronic use of pravastatin reduces insulin exocytosis and increases β-cell death in hypercholesterolemic mice. Toxicology. 2016;17(344-346):42–52.CrossRef
33.
Abe M, Toyohara T, Ishii A, et al. Drug Metab Pharmacokinet. 2010;25:274–82.CrossRefPubMed
34.
Salunkhe VA, Mollet IG, Ofori JK, et al. Dual Effect of Rosuvastatin on glucose homeostasis through improved insulin sensitivity and reduced insulin secretion. EBioMedicine. 2016;10:185–94.CrossRefPubMedPubMedCentral
35.
Salunkhe VA, Elvstam O, Eliasson L, Wendt A. Rosuvastatin treatment affects both basal and glucose-induced insulin secretion in INS-1 832/13 Cells. PLoS One. 2016;11, e0151592.CrossRefPubMedPubMedCentral
36.
Mabuchi H, Higashikata T, Kawashiri M, et al. Reduction of serum ubiquinol-10 and ubiquinone-10 levels by atorvastatin in hypercholesterolemic patients. J Atheroscler Thromb. 2005;12:111–9.CrossRefPubMed
37.
McCarty M. Can correction of sub-optimal coenzyme Q status improve beta-cell function in type II diabetics? Med Hypotheses. 1999;52:397–400.CrossRefPubMed
38.
Hao M, Head WS, Gunawardana SC, Hasty AH, Piston DW. Direct effect of cholesterol on insulin secretion: a novel mechanism for pancreatic beta-cell dysfunction. Diabetes. 2007;56:2328–38.CrossRefPubMed
39.
Fizelova M, Miilunpohja M, Kangas AJ, et al. Associations of multiple lipoprotein and apolipoprotein measures with worsening of glycemia and incident type 2 diabetes in 6607 non-diabetic Finnish men. Atherosclerosis. 2015;240:272–7.CrossRefPubMed
40.
Laakso M, Kuusisto J. Insulin resistance and hyperglycaemia in cardiovascular disease development. Nat Rev Endocrinol. 2014;10:293–302.CrossRefPubMed
41.
Nielsen SF, Nordestgaard BG. Statin use before diabetes diagnosis and risk of microvascular disease: a nationwide nested matched study. Lancet Diabetes Endocrinol. 2014;2:894–900.CrossRefPubMed

Be confident that your patient care is up to date

Medicine Matters is being incorporated into Springer Medicine, our new medical education platform. 

Alongside the news coverage and expert commentary you have come to expect from Medicine Matters diabetes, Springer Medicine's complimentary membership also provides access to articles from renowned journals and a broad range of Continuing Medical Education programs. Create your free account »