Lan Shen, MD; Bimal R. Shah, MD, MBA; Eric M. Reyes, Ph.D.; Laine Thomas, Ph.D.; Peter Diem, MD; Lawrence A. Leiter, MD; Bernard Charbonnel, MD; Viacheslav Mareev, MD; Edward Horton, MD; Steven M. Haffner, MD; Vladimir Soska, MD; Rury Holman, MD; Angelyn Bethel, MD; Frank Schaper, MD; Jie Lena Sun, MS; John McMurray, MD; Robert Califf, MD; Henry Krum, MBBS, Ph.D. Diuretics, Beta-blockers and Statins Increase the Risk of Diabetes in Patients with Impaired Glucose Tolerance: Insights from the NAVIGATOR study

Disclosures L. Shen: None. B. Shah: None. E. Reyes: None. L. Thomas: None. P. Diem: Research Grant; Significant; Novartis. Consultant/Advisory Board; Modest; Novartis.L. Leiter: Research Grant; Significant; Novartis. Consultant/Advisory Board; Modest; Novartis. B. Charbonnel: Consultant/Advisory Board; Modest; Novartis. V. Mareev: Speakers Bureau; Modest; Novartis. Consultant/Advisory Board; Modest; Novartis. E. Horton: Consultant/Advisory Board; Modest; Novartis. S. Haffner: None. V. Soska: None. R. Holman: Research Grant; Significant; Novartis. Consultant/Advisory Board; Modest; Novartis. M. Bethel: Research Grant; Modest; Novartis, Bayer, Merck, Amylin, Lilly. F. Schaper: Research Grant; Significant; Novartis. J. Sun: None. J. McMurray: Other; Modest; Employer (Glasgow University) paid for time as member of executive committee of NAVIGATOR and travel and accommodations for NAVIGATOR executive/steering committee meetings. R. Califf: Research Grant; Significant; Novartis. Consultant/Advisory Board; Modest; Novartis. H. Krum: Research Grant; Significant; Novartis.

Background Diuretics, β-blockers, and statins are the cornerstone of therapy in patients with CVD Even with their robust evidence of benefit, more recent data suggests that the long-term use may increase fasting glucose levels These concerns have led the US FDA to mandate a label change for statins in 2012 However, there are limited large scale studies using serial glucose measures that have linked these medications to new onset diabetes (NOD)

Objective To examine the association of new onset diabetes (NOD) with the initiation of β- blockers, thiazide diuretics, or statins in high risk, treatment naïve patients.

NAVIGATOR Study A multinational, randomized design study testing the efficacy and safety of long term administration of nateglinide and valsartan in the prevention of diabetes and cardiovascular outcomes Study population is 9518 patients with impaired glucose tolerance (IGT) and at least one other CV risk factor enrolled between January 4, 2002 to January 29, NAVIGATOR excluded patients with diabetes at baseline

Methods Therefore, we evaluated treatment initiation of the following medications on naïve patients. β-blockers Diuretics Statins CCBs – (metabolically negative control) Median follow-up time: 5.0 years

Methods Endpoint: New onset diabetes (NOD) NOD defined as: Fasting plasma glucose >126 mg/dl (7.0mmol/L) OR Glucose level >200 mg/dl (11.1 mmol/L) 2 hours after OGTT AND Confirmed by OGTT 12 weeks after the elevated glucose value was recorded Glucose testing frequency: Fasting plasma glucose level was measured every 6 months for the first 3 years and then annually Oral glucose tolerance tests were performed annually

Methods We examined the timing of the starting of each medication during study period We estimated the effect of receiving treatment on progression to NOD using Marginal Structural Models –In short, this is a Cox Proportional Hazard model adjusting cofounders that change over time –We present a single hazard ratio for treatment that represents the difference in rate of progression to NOD between someone who receives these medications and someone who does not

Results N=5637N=6343N=6143N=6290 Medication Initiation

Results Baseline Characteristics β –blockersDiureticsStatins Yes n=993 No n=4644 Yes n=1425 No n=4918 Yes n=1474 No n=4669 Age (Median) Hypertension (%) Congestive Heart Failure (%) Hx CV events (%) Hx stroke (%) Hx Heart Failure (%) Fasting Glucose HbA1c5.8

Results Incidence of New Onset Diabetes Unadjusted HR (95% CI) Adjusted HR (95% CI) Diuretics 1.48 (1.30,1.68) 1.35 (1.12,1.61) Statins 1.38 (1.21, 1.57) 1.30 (1.09, 1.55) β-blockers 1.35 (1.16, 1.57) 1.19 (0.97,1.46) CCBs 1.31 (0.97, 1.31) 1.14 (0.91, 1.42)

Limitations Post-hoc analysis of a clinical trial so residual confounders cannot be excluded No information on dose-response for medication No information on the adherence to specified medication Small size of population in β-blocker subgroup contributes to the limited power of the association in the β-blocker subgroup

Conclusion In high-risk patients with IGT, the use of diuretic and statin therapy is associated with NOD β-blocker therapy has a borderline effect towards the development of NOD, but the effect was not significant after adjustment Surveillance of glucose levels should be considered in high risk patients taking these medications Future studies are warranted to examine net benefit/risk profile of those medications in high risk CVD patients

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