1. 10/11/2006 1 Fasting Glucose Levels & Incident Diabetes Mellitus in Older Non-Diabetic Adults Randomized to Three Different Classes of Antihypertensive Treatment A Report from ALLHAT J. Barzilay, M. Alderman, B. R. Davis, J. A. Cutler, S. L. Pressel, P. K. Whelton, J. Basile, K. L. Margolis, S. T. Ong, L. S. Sadler, J. Summerson ALLHAT Archives of Internal Medicine – In Press

2. 10/11/2006 2 Context Elevated glucose levels have been reported with use of diuretic therapy in the treatment of hypertension. The clinical significance of this is uncertain.

3. 10/11/2006 3 Objective Among participants who are non-diabetic at baseline: Compare the effects of 1 st -step antihyper- tensive drug therapy with chlorthalidone, amlodipine, or lisinopril on fasting glucose (FG) levels and incident diabetes Determine risks for CV and renal disease associated with elevated FG and incident diabetes in the three treatment groups.

4. 10/11/2006 4 Design & Population Post hoc analyses of ALLHAT population (hypertensive, age  55 years, >1 other CVD risk factor) Subgroup that was nondiabetic by history at baseline, plus: –FG < 126 mg/dl, or –Random glucose <110 mg/dl Follow-up mean 4.9 years

5. 10/11/2006 5 Derivation of Cohort for Analysis 18,411 FG<126* or RG<110 mg/dl 14,005 1+ follow-up blood samples (fasting* or nonfasting) 21,294 Nondiabetic by history 33,357 Randomized to C, A, or L 42,418Total ALLHAT Participants ALLHAT 9,802 1+ follow-up FG values* *Duration of at least 8 hours

6. 10/11/2006 6 Baseline Characteristics ALLHAT ChlorAmlodLisin N4,5432,6922,567 Age, mean66.466.666.4 Black, %28.128.227.7 Women, %40.943.5*41.2 Smoking, %26.824.925.7 SBP / DBP146 / 85 BMI, mean29.028.8 FG, mg/dl949394 p<.05 compared with chlorthalidone

7. 10/11/2006 7 Fasting Glucose * * * * * p<.05 compared to chlorthalidone ALLHAT

8. 10/11/2006 8 Changes in Fasting Glucose * p<.05 compared to chlorthalidone * * * * ALLHAT

9. 10/11/2006 9 Follow-up Fasting Glucose 126+ mg/dL * * p<.05 compared to chlorthalidone ** * ALLHAT

10. 10/11/2006 10 Potential Confounders and Mediators β-blockers decrease insulin sensitivity and therefore may increase the risk of DM. Potassium depletion appears to be a major intervening factor between thiazide treatment and dysglycemia. Statin therapy may decrease risk of incident DM. ALLHAT

11. 10/11/2006 11 Medication at 2 Years ALLHAT ChlorAmlodLisin N4,4782,6542,527 Blinded or equivalent91%92%85%* Atenolol25%24%27% K supplement12%5%*3%* Statin32%31%33% HRT (women)26%23%22%* *p<.05 compared with chlorthalidone

12. 12 Diabetes Incidence – Logistic Regressions ALLHAT OR for Incident Fasting Glucose ≥126 mg/dL (Adjusted for age, gender, race, smoking, BMI, and fasting glucose, SBP, and DBP at baseline a ) BL to 2Y2Y to 4Y4Y to 6Y ACE / diur (randomized)0.55 b 0.820.86 CCB / diur (randomized)0.73 b 0.740.96 K<3.2 on K suppl c -- (small numbers) 0.99528.01 K<3.2 not on K suppl c 0.630.641.54 Atenolol a 1.021.091.23 Statin a 1.080.870.81 a Drug use at the beginning of the interval b p<0.05 c BL to 2Y - BL K, supplements at 1 yr; 2Y to 4Y – Any K<3.2 up to 2Y, supplements at 2Y; 4Y to 6Y – any K<3.2 up to 4Y, supplements at 4Y

13. 13 Effect of Change in Fasting Glucose on ALLHAT Endpoints* (Cox Regressions Beginning at 2 Years) ΔFG to 2 Yr (per 10 mg/dl) – HR (95% CI) CHD1.02 (0.97 – 1.06) Stroke1.00 (0.92 – 1.08) CCVD1.00 (0.97 – 1.04) Heart failure1.02 (0.96 – 1.08) ESRD1.06 (0.94 – 1.19) Total mortality1.01 (0.97 – 1.05) * In patients without diabetes at baseline. Adjusted for age, treatment group, race, gender, smoking, baseline FG, baseline BMI, 2-year serum potassium, 2-year atenolol atenolol & statin treatment. ALLHAT

14. 14 Effect of Change in Fasting Glucose on ALLHAT Endpoints* (Cox Regressions Beginning at 2 Years) ΔFG to 2 Yr (per 10 mg/dl) – HR (95% CI) P compared with chlorthalidone CHDTotal1.02 (0.97 – 1.06)0.44 Chlorthalidone1.00 (0.94 – 1.07)0.94 Amlodipine0.99 (0.89 – 1.10)0.87 Lisinopril1.09 (1.01 – 1.18)0.03 CCVDTotal1.00 (0.97 – 1.04)0.84 Chlorthalidone0.99 (0.94 – 1.03)0.56 Amlodipine1.00 (0.94 – 1.07)0.95 Lisinopril1.06 (1.00 – 1.12)0.04 * In patients without diabetes at baseline. Adjusted for age, treatment group, race, gender, smoking, baseline FG, baseline BMI, 2-year serum potassium, 2-year atenolol atenolol & statin treatment. ALLHAT

15. 15 Effect of Incident Diabetes on ALLHAT Endpoints* (Cox Regressions Beginning at 2 Years) Incident Diabetes / No Diabetes HR (95% CI) CHD1.64 (1.15 – 2.33) Stroke1.61 (0.92 – 2.84) CCVD1.04 (0.80 – 1.35) Heart failure1.37 (0.84 – 2.24) ESRD2.86 (0.97 – 8.39) Total mortality1.31 (0.95 – 1.81) * In patients without diabetes at baseline. Adjusted for age, treatment group, race, gender, smoking, baseline FG, baseline BMI, 2-year BP, 2-year serum potassium, 2-year atenolol & statin treatment. ALLHAT

16. 16 Effect of Incident Diabetes on CHD & Heart Failure by Treatment Group* (Cox Regressions Beginning at 2 Years) Incident Diabetes / No Diabetes HR (95% CI), pP for interaction CHDTotal1.64 (1.15 – 2.33), 0.0060.21 Chlorthalidone1.46 (0.88 – 2.42), 0.14 Amlodipine1.71 (0.87 – 3.34), 0.12 Lisinopril2.23 (1.07 – 4.62), 0.03 Heart FailureTotal1.37 (0.84 – 2.24), 0.210.36 Chlorthalidone0.96 (0.46 – 2.00), 0.91 Amlodipine1.29 (0.53 – 3.10), 0.58 Lisinopril3.66 (1.30 – 10.32), 0.01 * In patients without diabetes at baseline. Adjusted for age, treatment group, race, gender, smoking, baseline FG, baseline BMI, 2-year BP, 2-year serum potassium, 2-year atenolol & statin treatment. ALLHAT

17. 17 Effect of Incident Diabetes on Combined CVD & ESRD by Treatment Group* (Cox Regressions Beginning at 2 Years) Incident Diabetes / No Diabetes HR (95% CI), pP for interaction Combined CVDTotal1.04 (0.80 – 1.35), 0.770.36 Chlorthalidone0.96 (0.66 – 1.37), 0.80 Amlodipine1.14 (0.69 – 1.90), 0.61 Lisinopril1.31 (0.76 – 2.26), 0.33 ESRDTotal2.86 (0.97 – 8.39), 0.060.49 Chlorthalidone3.05 (0.82 – 11.33), 0.10 Amlodipine(Did not converge) Lisinopril3.80 (0.39 – 36.83), 0.25 * In patients without diabetes at baseline. Adjusted for age, treatment group, race, gender, smoking, baseline FG, baseline BMI, 2-year BP, 2-year serum potassium, 2-year atenolol & statin treatment. ALLHAT

18. 18 Effect of Incident Diabetes on Total Mortality by Treatment Group* (Cox Regressions Beginning at 2 Years) Incident Diabetes / No Diabetes HR (95% CI), pP for interaction Total1.31 (0.95 – 1.81), 0.100.19 Chlorthalidone1.05 (0.66 – 1.67), 0.83 Amlodipine1.92 (1.07 – 3.44), 0.03 Lisinopril1.31 (0.64 – 2.70), 0.46 * In patients without diabetes at baseline. Adjusted for age, treatment group, race, gender, smoking, baseline FG, baseline BMI, 2-year BP, 2- year serum potassium, 2-year atenolol & statin treatment. ALLHAT

19. 10/11/2006 19 Incident Diabetes in ALLHAT – Summary FG increased in all 3 treatment groups –Differences between treatment groups were small –For incident DM to 2 years, mean increase was 52 mg/dl Follow-up FG and incident diabetes were highest in chlorthalidone, lowest in lisinopril –Chlorthalidone has detrimental effect on FG? –Lisinopril / amlodipine have neutral / protective effect on FG? ALLHAT

20. 10/11/2006 20 Effect of  FG & Incident Diabetes on Outcomes – Summary No significant overall effect of change in FG on any of the study endpoints in the combined treatment groups or the chlorthalidone group separately Incident DM increased risk of CHD –Statistically significant for total group & lisinopril –In chlorthalidone group, increase in risk was smallest and not significant ALLHAT

21. 10/11/2006 21 Discussion of ALLHAT Findings Lisinopril group:  FG associated with  risk of CCHD and CCVD; incident DM associated with  risk of CHD –Lisinopril generally prevents  FG Amlodipine group: Incident DM associated with  risk of total mortality –Amlodipine does not generally raise glucose levels →Participants with  FG in these groups may have been very insulin resistant and at high risk for CV events

22. 10/11/2006 22 Discussion of ALLHAT Findings Low potassium did not significant increase the odds of developing DM –Use of K supplements doubled from year 2 to year 5 –Treatment differences in FG and DM decreased at years 4 and 6 –Sustained low K+ not captured in dataset – prescription of K+ supplement may indicate this, and tends to be associated with DM Recent review – “thiazide-induced hyperglycemia should be anticipated and prevented by measures to preserve normokalemia and total body K+”. (Zillich et al. Hypertension. 2006;48:219-224.)

23. SHEP-X Total Mortality (%) 14.3 yrs Follow up * p< 0.05 vs no diabetes SHEP-X: Systolic Hypertension in the Elderly Program extended follow-up. Kostis, et al. Am J Cardiol. 2005;95:29-35

24. SHEP-X Cardiovascular Death (%) 14.3 yrs Follow up * p< 0.05 vs no diabetes SHEP-X: Systolic Hypertension in the Elderly Program extended follow-up. Kostis, et al. Am J Cardiol. 2005;95:29-35

25. 25 New diabetes and CVD risk: Verdecchia 2004 795 treated HTs, median FU 6 yrs. Diuretic rx (low-mod dose HCTZ or CLTD) independently predictive of new diabetes. Adjusted* RR (95% CI) of CVD-renal event (n=63) --BL DM, 3.57 (1.65, 7.73) --New DM, 2.92 (1.33, 6.41) Results for specific regimens not given, & only 11% on diuretic/β blocker alone. Verdecchia et al. Hypertension 2004;43:963-69. *age, 24h SBP, LVH.

26. 10/11/2006 26 Evidence from Previous Studies 15-y follow-up of 686 middle-age hypertensive adults treated with diuretic –Diabetes at baseline significantly associated with CHD--RR 2.1 (1.1, 4.1) –Incident diabetes was not significantly related with CHD—RR 1.5 (0.4, 6.0). Samuelsson O, et al. Brit Med J 1996; 313:660-63.

27. 10/11/2006 27 Evidence from Previous Studies Cessation of long-term use of thiazide diuretics is associated with prompt improvement in FG levels –Suggests that diuretics lead to elevated glucose levels by mechanisms different from those associated with DM Murphy MB, et al. Lancet 1982:2(8311):1293-95.

28. 10/11/2006 28 Evidence from Previous Studies Meta-analysis of ACE inhibitors & ARBs –Both decrease the risk of DM –Neither reduces the odds of mortality, CV events, or cerebrovascular events vs control therapy e.g., thiazides and beta blockers Gillespie EL, et al. Diabetes Care 2005; 28:2261-66.

29. 10/11/2006 29 Strengths ALLHAT much larger than other studies –  statistical power Use of central biochemical laboratory Variety of practice environments

30. 10/11/2006 30 Limitations Misclassification of incident diabetes and not identifying impaired glucose tolerance could have diluted findings –FU measures in ½ of cohort were non-fasting, and not used –Data on diabetes medication use not collected Conclusions cannot be extrapolated beyond about 5 years Other measures of glucose metabolism (e.g., HbA1c, insulin levels) may have been helpful

31. 10/11/2006 31 Conclusions Treatment of hypertension with chlorthalidone was associated with small initial increase in FG & increased risk of DM compared with amlodipine & lisinopril. Differences in FG diminished over 5 years. No corresponding increase in risk of stroke, combined CVD, total mortality or ESRD over the period of follow-up.  risk of CHD associated with  DM not clearly identified in chlorthalidone arm

32. 10/11/2006 32 Perspectives on Incident Diabetes Assuming CCB is metabolically neutral, 85% (9.3% vs 11.0%) of DM at 4 years on chlorthalidone was not due to chlorthalidone Lifestyle intervention remains paramount

33. 10/11/2006 33 Conclusion Neither amlodipine- nor lisinopril-based treatment led to superior outcomes for any CVD endpoint. Both were inferior for prevention of heart failure While clinicians need to be aware of, and monitor patients for hyperglycemia, the totality of the evidence still supports the use of thiazide diuretics as preferred agents for prevention of cardiovascular disease in hypertensive patients. The relatively small detrimental metabolic effects of thiazide-type diuretic should not affect their preferred use in the management of hypertension.

34. 10/11/2006 34 EXTRA SLIDES

35. 10/11/2006 35 ALLHAT Diabetes and Hypertension Links Common antecedents: –Obesity –Insulin resistance Treatment of one may impact the other

36. 10/11/2006 36 Diabetes Incidence - 4 Years - All Participants (<126 mg/dL at baseline) * * * p<.05 compared to chlorthalidone ALLHAT JAMA 2002;288:2981-2997

37. 10/11/2006 37 BP Meds and Glucose in Randomized Clinical Trials – Diuretic vs Placebo, Diuretic vs Beta-blocker Padwal and Laupaci (Diabetes Care 27:247-256) StudySizeTreatmentDiabetes Incidence SHEP4153Chlorthalidone ±atenolol8.6%1.2 (0.9 – 1.5) Placebo7.5% EWPHE840 Triamterine plus HCTZ  methyldopa 7.0%1.5 (0.85 – 2.6) Placebo4.7% HAPPHY6569Thiazides2.3%0.88 (0.65 – 1.19) Beta-blockers2.6%

38. 10/11/2006 38 BP Meds and Glucose in Randomized Clinical Trials – ACEI or ARB vs Placebo Padwal and Laupaci (Diabetes Care 27:247-256) StudySizeTreatmentDiabetes Incidence CHARM5,439Candesartan6.0%0.78 (0.74 – 0.96) Placebo7.0% HOPE5,720Ramipril3.6%0.66 (0.51 – 0.85) Placebo5.4% SCOPE4,342Candesartan4.3%0.81 (0.62 – 1.06) Placebo5.3% Vermes et al 311Enalapril6.0%0.26 (0.13 – 1.53) Placebo22.0%

39. 10/11/2006 39 BP Meds and Glucose in Randomized Clinical Trials – ACEI or ARB vs Diuretic/Beta-blocker Padwal and Laupaci (Diabetes Care 27:247-256) StudySizeTreatmentDiabetes Incidence ALPINE392Candesartan ± felodipine0.5%0.13 (0.02 – 0.99) HCTZ ± atenolol4.1% CAPPP10,413Captopril6.5%0.86 (0.74 – 0.99) BB/thiazides7.2% LIFE7,998Losartan6.0%0.75 (0.63 – 0.88) Atenolol8.0%

40. 10/11/2006 40 BP Meds and Glucose in Randomized Clinical Trials – Diuretic + Beta-blocker vs CCB vs (+) ACEI Padwal and Laupaci (Diabetes Care 27:247-256) StudySizeTreatmentDiabetes Incidence ALLHAT14,816Amlodipine9.8%A/C: 0.80 (0.64 – 0.99) Lisinopril8.1%L/C: 0.70 (0.56 – 0.86) Chlorthalidone11.6% INSIGHT5,019Nifedipine4.3%0.77 (0.62 – 0.96) HCTZ/amiloride5.6% NORDIL10,154Diltiazem4.0%0.87 (0.73 – 1.04) Diuretic/beta-blocker5.0% STOP5,893ACE inhibitorACE/D-BB: 0.96 (0.72 – 1.27) Diuretic/beta-blockerCCB/D-BB: 0.97 (0.73 – 1.29) CCBACE/CCB: 0.96 (0.74 – 1.31)

41. 10/11/2006 41 CAVEAT The criterion for defining DM ( > 125 mg/dl) was chosen not based on CVD risk (a complication not specific to DM). Rather the criterion was based on a microvascular complication specific to DM - retinopathy.

42. 10/11/2006 42 Fasting Glucose at 4 Years in Nondiabetic Participants ALLHAT ChlorAmlodLisin N3,0081,7891,666 Mean (sd)104.3 (28.6)102.4 (26.7)*100.0 (19.4)* % 126+11.09.3*7.8% p<0.05 compared with chlorthalidone

43. 10/11/2006 43 Diuretic Use at 2, 4, and 6 Years ALLHAT Chlor*AmlodLisin 2 years90.8%9.9%10.7% 4 years87.9%14.9%15.7% 6 years87.0%23.6%24.4% *Includes blinded medication or open-label diuretic