Long Term Effect of Diuretic Based Therapy in Subjects with Isolated Systolic Hypertension With and Without Diabetes Fo

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. Diuretic-based antihypertensive therapy is associated with the development of diabetes but with improved clinical outcomes. A common concern among practitioners is the effect of diuretic-associated diabetes on long-range prognosis, especially since the duration of clinical trials has been considered by many to be too short to detect adverse effects of diabetes. Diuretic-based antihypertensive therapy is associated with the development of diabetes but with improved clinical outcomes. A common concern among practitioners is the effect of diuretic-associated diabetes on long-range prognosis, especially since the duration of clinical trials has been considered by many to be too short to detect adverse effects of diabetes.

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) A group of investigators from the Systolic Hypertension in the Elderly Program (SHEP) used mortality data from the National Death Index to assess the long-term mortality rate of SHEP participants among those with diabetes at baseline (n=384 in the active treatment, 415 placebo treatment group), with incident diabetes at the 1-year or 2-year visit (n=258 active, 169 placebo), and without diabetes (n=1,721 active, 1,785 placebo). A group of investigators from the Systolic Hypertension in the Elderly Program (SHEP) used mortality data from the National Death Index to assess the long-term mortality rate of SHEP participants among those with diabetes at baseline (n=384 in the active treatment, 415 placebo treatment group), with incident diabetes at the 1-year or 2-year visit (n=258 active, 169 placebo), and without diabetes (n=1,721 active, 1,785 placebo).

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). The SHEP was an NHLBI-initiated multi-center, placebo-controlled, randomized clinical trial which reported in 1991 that diuretic-based (chlorthalidone 12.5 to 25.0 mg/day) antihypertensive therapy reduced the rate of fatal or non-fatal stroke by 37%, as well as all major CV events by 33%, in older patients with isolated systolic hypertension.The SHEP was an NHLBI-initiated multi-center, placebo-controlled, randomized clinical trial which reported in 1991 that diuretic-based (chlorthalidone 12.5 to 25.0 mg/day) antihypertensive therapy reduced the rate of fatal or non-fatal stroke by 37%, as well as all major CV events by 33%, in older patients with isolated systolic hypertension.

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. For participants who were alive at the end of SHEP follow-up, additional vital status and cause of death data were gathered from the National Death Index (NDI) through the year 2000. Diabetes was defined based on diabetes history status and on fasting glucose level (>=126 mg/dl). Survival analyses and Cox proportional hazards analyses were carried out for total mortality and CV mortality by initial randomization group and by diabetes status (diabetes at baseline, incident diabetes during the trial, no diabetes).For participants who were alive at the end of SHEP follow-up, additional vital status and cause of death data were gathered from the National Death Index (NDI) through the year 2000. Diabetes was defined based on diabetes history status and on fasting glucose level (>=126 mg/dl). Survival analyses and Cox proportional hazards analyses were carried out for total mortality and CV mortality by initial randomization group and by diabetes status (diabetes at baseline, incident diabetes during the trial, no diabetes).

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 For participants who were alive at the end of SHEP follow-up, additional vital status and cause of death data were gathered from the National Death Index (NDI) through the year 2000. Diabetes was defined based on diabetes history status and on fasting glucose level (>=126 mg/dl). Survival analyses and Cox proportional hazards analyses were carried out for total mortality and CV mortality by initial randomization group and by diabetes status (diabetes at baseline, incident diabetes during the trial, no diabetes).For participants who were alive at the end of SHEP follow-up, additional vital status and cause of death data were gathered from the National Death Index (NDI) through the year 2000. Diabetes was defined based on diabetes history status and on fasting glucose level (>=126 mg/dl). Survival analyses and Cox proportional hazards analyses were carried out for total mortality and CV mortality by initial randomization group and by diabetes status (diabetes at baseline, incident diabetes during the trial, no diabetes).

7. Length of Follow-up and Active / Placebo Hazard Ratios* for Total and CVD Mortality Results comparing the placebo and active groups for total mortality with the extended follow-up were similar to those obtained during the trial. The results for deaths due to CVD causes with the longer follow-up were now significant in favor of the active treatment (chlorthalidone) group.Results comparing the placebo and active groups for total mortality with the extended follow-up were similar to those obtained during the trial. The results for deaths due to CVD causes with the longer follow-up were now significant in favor of the active treatment (chlorthalidone) group.

8. Comparing active treatment with placebo, there is an advantage in favor of active treatment among participants who have diabetes at baseline.Comparing active treatment with placebo, there is an advantage in favor of active treatment among participants who have diabetes at baseline.

9. At a mean follow-up of 14.3 years, cardiovascular (CV) mortality rate was significantly lower in the chlorthalidone group (19%) than in the placebo group (22%; adjusted hazard ratio [HR] 0.854, 95% confidence interval [CI] 0.751 to 0.972). Diabetes at baseline (n=799) was associated with increased CV mortality rate (adjusted HR 1.659, 95% CI 1.413 to 1.949). Diabetes that developed during the trial among subjects on placebo (n=169) was also associated with increased CV adverse outcome (adjusted HR 1.562, 95% CI 1.117 to 2.184). However, diabetes that developed among subjects during diuretic therapy (n=258) did not have a significant association with CV mortality rate (adjusted HR 1.043, 95% CI 0.745 to 1.459). Diuretic treatment in subjects who had diabetes was strongly associated with lower long-term CV mortality rate (adjusted HR 0.688, 95% CI 0.526 to 0.848). At a mean follow-up of 14.3 years, cardiovascular (CV) mortality rate was significantly lower in the chlorthalidone group (19%) than in the placebo group (22%; adjusted hazard ratio [HR] 0.854, 95% confidence interval [CI] 0.751 to 0.972). Diabetes at baseline (n=799) was associated with increased CV mortality rate (adjusted HR 1.659, 95% CI 1.413 to 1.949). Diabetes that developed during the trial among subjects on placebo (n=169) was also associated with increased CV adverse outcome (adjusted HR 1.562, 95% CI 1.117 to 2.184). However, diabetes that developed among subjects during diuretic therapy (n=258) did not have a significant association with CV mortality rate (adjusted HR 1.043, 95% CI 0.745 to 1.459). Diuretic treatment in subjects who had diabetes was strongly associated with lower long-term CV mortality rate (adjusted HR 0.688, 95% CI 0.526 to 0.848).

10. Diabetes at baseline (n=799) was associated with increased total mortality rate (adjusted HR 1.510, 95% CI 1.347 to 1.693). Diabetes that developed during the trial among subjects on placebo (n=169) was also associated with increased total mortality rate (adjusted HR 1.348, 95% CI 1.051 to 1.727). However, diabetes that developed among subjects during diuretic therapy (n=258) did not have significant associations with total mortality rate (adjusted HR 1.151, 95% CI 0.925 to 1.433). Diuretic treatment in subjects who had diabetes was strongly associated with lower long-term total mortality rate (adjusted HR 0.805, 95% CI 0.680 to 0.952). Diabetes at baseline (n=799) was associated with increased total mortality rate (adjusted HR 1.510, 95% CI 1.347 to 1.693). Diabetes that developed during the trial among subjects on placebo (n=169) was also associated with increased total mortality rate (adjusted HR 1.348, 95% CI 1.051 to 1.727). However, diabetes that developed among subjects during diuretic therapy (n=258) did not have significant associations with total mortality rate (adjusted HR 1.151, 95% CI 0.925 to 1.433). Diuretic treatment in subjects who had diabetes was strongly associated with lower long-term total mortality rate (adjusted HR 0.805, 95% CI 0.680 to 0.952).

11. Participants with diabetes at baseline have increased risk of all-cause mortality and CVD mortality compared to those without diabetes at baseline or during follow-up. Participants who develop diabetes during follow-up have increased risks for those events only among participants in the placebo group. Those on active treatment do not have increased risk compared to those without diabetes. Participants with diabetes at baseline have increased risk of all-cause mortality and CVD mortality compared to those without diabetes at baseline or during follow-up. Participants who develop diabetes during follow-up have increased risks for those events only among participants in the placebo group. Those on active treatment do not have increased risk compared to those without diabetes.

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. Thus, chlorthalidone-based treatment improved long-term outcomes, especially among subjects who had diabetes. Subjects who had diabetes associated with chlorthalidone treatment had no significant increase in CV events and had a better prognosis than did those who had preexisting diabetes. One explanation for this is that diuretic-induced hypokalemia, which inhibits pancreatic insulin release, may have been subsequently corrected, leading to improved glucose tolerance, while any efforts to improve glucose intolerance related to weight gain and sedentary habits may have been less successful. The much longer follow-up in the SHEP post-trial experience provides the strongest evidence for the benign nature of diuretic-associated hyperglycemia, and should reinforce the recommendations on drug choice from the 7th Report of the Joint National Committee (JNC7). Thus, chlorthalidone-based treatment improved long-term outcomes, especially among subjects who had diabetes. Subjects who had diabetes associated with chlorthalidone treatment had no significant increase in CV events and had a better prognosis than did those who had preexisting diabetes. One explanation for this is that diuretic-induced hypokalemia, which inhibits pancreatic insulin release, may have been subsequently corrected, leading to improved glucose tolerance, while any efforts to improve glucose intolerance related to weight gain and sedentary habits may have been less successful. The much longer follow-up in the SHEP post-trial experience provides the strongest evidence for the benign nature of diuretic-associated hyperglycemia, and should reinforce the recommendations on drug choice from the 7th Report of the Joint National Committee (JNC7).