STATINS AND THE RISK OF DEVELOPING DIABETES

G.B. John Mancini, MD, FRCPC, FACP, FACC Professor of Medicine University of British Columbia Department of Medicine, Division of Cardiology President, Vancouver Hospital Medical, Dental and Allied Staff Director, Cardiovascular Imaging Research Core Laboratory (CIRCL) Staff Cardiologist, VH Cardiology Clinics and Cardiac Computed Tomographic Angiography Program Staff Cardiologist, St. Paul’s Hospital Healthy Heart/Prevention Clinic Vancouver, British Columbia

Statins and the Risk of Developing Diabetes

Or

Statin: From Hero to Villain

Disclosure

• Honoraria: Valeant, Amgen, Regeneron, Sanofi-Aventis

• Advisory Board: Amgen, Valeant

• Grants: NIH –ISCHEMIA Trial

Statins and the Risk of Developing Diabetes

Key Questions

• Why are statins of interest in diabetes?

• How has the evidence emerged?

• What are the underlying mechanisms linking statins and diabetes?

• How should this information change your practice?

Answers

• DM diagnosed as blood glucose > 7.0 mmol/L

• 139 of 5974 patients became diabetic

• Multivariate positive and negative predictors: BMI (+), log TG (+), glucose (+) and pravastatin (-)

• Pravastatin associated with a 30% risk reduction

• A pleiotropic benefit of statin?

Freeman et al: Circulation 2001;103:357-362.

NB: rosuva study was in CHF

Coleman et al: The effect of statins on the development of new-onset T2D: a meta-analysis of randomized controlled trials. Curr Med Research and Opinion. 2008;24: 1359 - 1362

JUPITER: Measured Laboratory Values, and Other Reported Events of Interest during the Follow-up Period

Ridker PM, et al. N Engl J Med 2008;359:2195-207

Statins and the Development of Diabetes

Rajpathak et al: Statin therapy and risk of developing T2D: a meta-analysis. Diabetes Care 2009;32:1924– 9.

Association Between Statin Therapy and Incident Diabetes: Trials

Sattar, Lancet 2010

Association Between Statin Therapy and Incident Diabetes: Specific Statins

Sattar, Lancet 2010

Association Between Diabetes Risk and Statin Use in 153,840 Postmenopausal Women in the Women’s Health Initiative

Variable Multivariate-Adjusted HR

Taking statin medications at baseline 1.48 (1.38-1.59)

Years of statin medication use

<1.0 1.46 (1.30-1.64)

1.0-2.9 1.42 (1.26-1.59)

≥ 3.0 1.57 (1.40-1.77)

Type of statin medications at baseline

Lovastatin 1.35 (1.19-1.55)

Simvastatin 1.41 (1.25-1.61)

Fluvastatin 1.61 (1.35-1.92)

Atorvastatin 1.61 (1.26-2.06)

Pravastatin 1.63 (1.43-1.87)

Potency of statin at baseline

Low potency: lovastatin, fluvastatin and pravastatin 1.48 (1.36-1.61)

High-potency: simvastatin and atorvastatin 1.45 (1.36-1.61)

Culver AL, et al. Arch Intern Med 2012;172:144-52

Comparative tolerability and harms of individual statins: A study-level network meta-analysis of 246,955 participants

from 135 randomized controlled trials Naci et al: Circ Cardiovasc Qual Outcomes 2013;6

• Examined Discontinuations, Myalgia, CK Elevation, Transaminases, Cancer, & Diabetes

• Odds Ratio for Diabetes on statin vs control was 1.09 (1.02 – 1.31)

• Unable to detect differences among statins or doses

Fasting Glucose and Features of Metabolic Syndrome are More Consistent Determinants of Diabetes Than Statin Use

Waters DD, et al. J Am Coll Cardiol 2011;57:1535-45

Incident Diabetes in the TNT (Treating to New Targets) Trial According to Baseline Clinical Predictors

Presence versus absence of Risk Factor

Fasting Glucose and Features of Metabolic Syndrome are More Consistent Determinants of Diabetes Than Statin Use

Waters DD, et al. J Am Coll Cardiol 2011;57:1535-45

Incident Diabetes in the TNT (Treating to New Targets) Trial According to Number of Risk Factors and Treatment Group

The Potential Diabetogenic Effects of Statins May Be Dose Related

Data marker size indicates relative weight of the studies; OR, odds ratio; and CI, confidence interval.

Preiss, JAMA 2011

The Potential Diabetogenic Effects of Statins May Be Dose Related

Preiss, JAMA 2011

NNT to reduce CVE = 38 NNH to see one new-onset case of DM = 125 3.3:1 ratio NNT to reduce CVE and AVOID new-onset case of DM = Unqualified Success = 39 NNH to see one new onset case of DM while failing to prevent CVE = Unmitigated Failure = 654 16.8:1 ratio

Preiss D, et al. JAMA 2011;305:2556-64

CV Event Reduction Versus New-Onset Diabetes During Atorvastatin Therapy: Effect of Baseline Risk

Factors for Diabetes Waters DD et al. JACC 2012;61:148-52

NNT = 66.7 NNH = 111 Unqualified Success = 67.2 (event prevented, no NODM) Unmitigated Failure = 1208 (NODM and CVE occurs)

Efficacy of cholesterol-

lowering therapy in 18,686 people with diabetes in 14 randomised

trials of statin: a meta-analysis.

Cholesterol Treatment Trialists’ Collaborators Lancet 2008;371:117 – 25.

Cholesterol Treatment

Trialists’ Collaborators

Lancet

2008;371:117 – 25.

Hypothetical paradigm for statin-induced impairment of glucose metabolism

ATP, adenosine triphosphate; CHOL, cholesterol (de-novo synthesized); Glut2, glucose transporter 2; Glut4, glucose transporter 4; HMG-CoA, 3-hydroxy-methylglutaryl coenzyme A; LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol (plasma-derived); LDL-R, LDL receptor; OxLDL, oxidized LDL; NO, nitric oxide.

Sattar, Atherosclerosis Supplements (2012)

Metabolic Effects of Statins

Effect on glucose

metabolism

Main observation Statin studied

Decreased insulin

secretion

Blocks L-type Ca2+ channels Simvastatin

HMG-CoA inhibition/cytotoxicity Simvastatin, atorvastatin

Decreased insulin

sensitivity

Reduction in insulin sensitivity without reduction in

insulin secretion

Atorvastatin

Inhibition of isoprenoid synthesis/GLUT-4 expression Atorvastatin, lovastatin

Increased insulin

sensitivity

Induction of insulin sensitivity in lean and fatty rats Atorvastatin

Increased adiponectin secretion Pravastatin

No effect on glucose

metabolism

No effect on L-type Ca2+ channels Pravastatin

No HMG-CoA inhibition/cytotoxicity Pravastatin

Does not inhibit isoprenoid synthesis/GLUT-4

expression

Pravastatin

Does not decrease insulin sensitivity Pravastatin

No effect on adiponectin secretion Simvastatin

Colbert J, et al. Can J Cardiol 2012;28:581-9

Statins and the Risk of Developing Diabetes

Key Questions

• Why are statins of interest in diabetes?

• How has the evidence emerged?

• What are the underlying mechanisms linking statins and diabetes?

• How should this information change your practice?

Answers • Pleiotropic effects of statins may

be beneficial • RCT’s, meta-analyses, cohort

studies • Multiple mechanisms both pro

and con for a diabetogenic effect • CV risk reduction through use of

statin outweighs any putative diabetogenic effect. Use the right dose (not more, not less). Pay attention to elements predisposing to diabetes in order to achieve maximal, global CV risk reduction.