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.

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, 2004.

• 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=5637 N=6343 N=6143 N=6290

Medication Initiation

ResultsBaseline Characteristics

β –blockers Diuretics Statins

Yesn=993

Non=4644

Yesn=1425

Non=4918

Yesn=1474

Non=4669

Age (Median) 64 62 64 62 63 63

Hypertension (%) 80 69 84 65 77 84

Congestive Heart Failure (%) 4 2 3 2 3 4

Hx CV events (%) 30 19 34 32 31 29

Hx stroke (%) 5 3 6 3 4 3

Hx Heart Failure (%) 4 2 3 2 3 4

Fasting Glucose 6 6 6 6 6 6

HbA1c 5.8 5.8 5.8 5.8 5.8 5.8

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)

CCBs1.31

(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

Thank you