lan shen, md; bimal r. shah, md, mba; eric m. reyes, ph.d.; laine thomas, ph.d.; peter diem, md;...
TRANSCRIPT
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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
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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.
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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)
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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.
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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
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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
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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
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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
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Results
N=5637 N=6343 N=6143 N=6290
Medication Initiation
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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
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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)
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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
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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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Thank you