Long Term Effect of Diuretic Based Therapy in Subjects with Isolated Systolic Hypertension With and

1
Long Term Effect of Diuretic Based Therapy in
Subjects with Isolated Systolic Hypertension With
and Without DiabetesFourteen-Year Follow-up of
the Systolic Hypertension in the Elderly Program
(SHEP)

• Kostis JB, Wilson AC, Freudenberger RS, Cosgrove
  NM, Pressel SL, Davis BR.
  
• SHEP Investigators
• UMDNJ-Robert Wood Johnson Medical School (J.B.K.,
  A.C.W., R.S.F., N.M.C.)
  
• and the University of Texas School of Public
  Health at Houston (S.L.P., B.R.D.)

2
Context

• In randomized clinical trials diuretic based
  antihypertensive therapy has resulted in improved
  cardiovascular outcomes.
  
• In these trials diuretic therapy has also been
  associated with the development of new onset
  diabetes.
  
• It has been speculated that this diabetes did
  not result in worse outcomes because of
  relatively short periods of observation.

3
Objective

• To assess the long term (14.3 years) mortality
  of Systolic Hypertension in Elderly Program
  (SHEP) participants by diabetes status
  
• No diabetes
• Diabetes at baseline
• New onset diabetes (during SHEP)

4
SHEP Design Results

• Double blind randomized placebo controlled
  stepped care therapy with chlorthalidone
  12.5-25.0 mg daily and double blind atenolol
  25-50 mg or reserpine as step 2 drug (4.4 yrs).
• At the end of SHEP all were advised to receive
  active Rx (14.3 yrs total follow up).

5
Methods

• Determination of vital status and cause of death
  of SHEP participants through the year 2000, by
  National Death Index matching.
  
• Cardiovascular and total mortality.
• Diabetes defined as DM Rx or fasting glucose
  level ?126 mg/dL at baseline or 1st or 2nd annual
  visit.

6
Methods

• Survival and Cox proportional hazards analysis
  according to initial randomization and diabetes
  status
  
• 799 with diabetes at baseline
• 427 new onset diabetes
• 3506 without diabetes

7
Length of Follow-up and Active / Placebo Hazard
Ratios for Total and CVD Mortality
8
CV Death () 14.3 yrs Follow up

pand no BL DM are not significantly different
Kostis JB, Wilson AC, Freudenberger RS, et al. Am
J Cardiol 20059529-35
9
CV Death () 14.3 yrs Follow up
pKostis JB, Wilson AC, Freudenberger RS, et al. Am
J Cardiol 20059529-35
10
Total Mortality () 14.3 yrs Follow up
pKostis JB, Wilson AC, Freudenberger RS, et al. Am
J Cardiol 20059529-35
11
Effect of DM on Mortality 14.3 Years Follow-Up
Baseline diabetes / No diabetes
Adjusted RR (95 CI)
1.38 (1.16 1.63)
Active
All-cause mortality
Placebo
1.63 (1.40 1.91)
1.46 (1.14 1.87)
Active
CVD mortality
1.84 (1.48 2.28)
Placebo
Follow-up diabetes / No diabetes
1.15 (0.93 1.43)
Active
All-cause mortality
1.35 (1.05 1.73)
Placebo
1.04 (0.75 1.46)
Active
CVD mortality
1.56 (1.12 2.18)
Placebo
Survival better Survival worse
0.50
1
2
3
12
Limitations

• Hypotheses for SHEP extended not pre-specified
• Only mortality data
• Rx and BP during follow up unknown
• No metabolic data (HbA1c, serum potassium,
  weight/BMI/abdominal fat) to evaluate mechanisms
  
• Diabetes development after SHEP unknown

13
Interpretation

• Milder long-term course of diabetes that occurred
  during diuretic therapy is likely related to
  lesser degree of metabolic disturbance.
  
• Different underlying mechanisms for diabetes due
  to diuretic and diabetes occurring in the placebo
  group

14
Conclusions

• Chlorthalidone based treatment of hypertension
  results in improved long-term outcomes.
  
• The diabetes related to chlorthalidone therapy
  has better prognosis than diabetes at baseline.
  
• The benefit of chlorthalidone-based therapy on
  long-term total and CV mortality is most
  pronounced in hypertensive patients with diabetes.