1. 1 Presenter Disclosure Information FINANCIAL DISCLOSURE: DSMB’s: Merck, Takeda Barry R. Davis, MD, PhD Clinical Outcomes in Participants with Dysmetabolic Syndrome in ALLHAT UNLABELED / UNAPPROVED USES DISCLOSURE: None

2. 2 Clinical Outcomes in Participants with Dysmetabolic Syndrome in ALLHAT Barry R. Davis, MD, PhD & Henry R. Black, MD for the ALLHAT Collaborative Research Group Presented at the American Heart Association Meeting November 8, 2004 ALLHAT

3. 3 Randomized Design of ALLHAT High-risk hypertensive patients Consent / Randomize (42,418) Amlodipine Chlorthalidone Doxazosin Lisinopril Eligible for lipid- lowering Not eligible for lipid-lowering Consent / Randomize (10,355) Pravastatin Usual care Follow for CHD and other outcomes until death or end of study (up to 8 yr). ALLHAT

4. 4 Dysmetabolic Syndrome ALLHAT reported overall superiority of thiazide-type treatment for first-step therapy of hypertension ALLHAT reported overall superiority of thiazide-type treatment for first-step therapy of hypertension Patients with dysmetabolic syndrome (DS) are at especially high risk for many hypertensive complications Patients with dysmetabolic syndrome (DS) are at especially high risk for many hypertensive complications Post hoc analyses from ALLHAT regarding treatment of hypertension in patients with and without DS are of interest Post hoc analyses from ALLHAT regarding treatment of hypertension in patients with and without DS are of interest Definitions of DS vary (WHO, ATP III, etc.) Definitions of DS vary (WHO, ATP III, etc.) ALLHAT

5. 5 Dysmetabolic Syndrome (DS) Any 3 or more of the following items: Glycemic disorder –History of diabetes –Baseline glucose BMI ≥30 Fasting triglycerides 150+ HDL cholesterol <40 in men, <50 in women High BP (“yes” for all ALLHAT participants) DS missing: # yes <3 and # yes + # missing ≥ 3 ALLHAT

6. 6 Glycemic Disorder ALLHAT Fasting GlucoseNonfasting glucose Missing glucose <100≥100<100100-199≥200 Hx of diabetes Yes No hx of diabetes NoYesNoMissingYesMissing

7. 7 Definitions of Dysmetabolic Syndrome ALLHATATP IIIWHOAACE Insulin resistance (any of following): Fasting glucose≥100≥110IFG110 - 126 Nonfasting glucose ≥200 History of diabetesYes OGTTNAIGT 2-hr post-glucose>140 Obesity (any of following): Abdominal obesityWC: >40” M, >35” F W/H: >.9M >.85W BMI≥30>30≥25 ALLHAT ATP III – National Cholesterol Education Program’s Adult Treatment Panel III Report WHO – World Health Organization AACE – American Association of Clinical Endocrinologists IFG = Impaired fasting glucose IGT = Impaired glucose tolerance WC = Waist circumference W/H = Waist / hip ratio

8. 8 Definitions of Dysmetabolic Syndrome (continued) ALLHAT ALLHATATP IIIWHOAACE Lipids (any of following): Fasting TRIGs≥150 HDL<40 M <50 F <35M <39F<40 M <50 F Blood pressure: ↑BPYes≥130/ ≥85≥140/ ≥90≥130/ ≥85 AHT medicationsYes Other: UA* Exr ≥20 or A/C** ≥30 Many + * UA = Urinary albumin excretion rate ** A/C = Albumin:creatinine ratio + Family history of type 2 diabetes, hypertension or CVD; polycystic ovary syndrome; sedentary lifestyle; advancing age; ethnic groups having high risk for type 2 diabetes or CVD

9. 9 Dysmetabolic Syndrome – Classification & Missing Values DSNo DSMissingTotal Chlor8,31554.5%5,15533.8%1,78511.7%15,255 Amlod4,91554.3%3,03033.5%1,10312.2%9,048 Lisin4,95354.7%2,99533.1%1,10612.2%9,054 Total18,18354.5%11,18033.5%3,99412.0%33,357 ALLHAT

10. 10 Baseline Characteristics - Participants* With and Without DS DSNo DS N 18,18311,180 Age – mean 66.168.0 ** Women (%) 49.842.0 ** Black (%) 28.434.6 ** SBP – mean 146.1146.6 ** DBP – mean 83.884.4 ** Current smokers (%) 17.827.4 ** ASCVD (%) 46.558.4 ** *Randomized to chlorthalidone, amlodipine, or lisinopril. ** p<.05 ALLHAT

11. 11 Baseline Characteristics - Participants* With and Without DS DSNo DS N 18,18311,180 Fasting gluc - mean (sd)135.2 (61.3)102.6 (41.5) ** History of diabetes %31.76.3 ** BMI – mean (sd)32.0 (6.2)26.5 (4.4) ** Fasting trig - mean (sd)205.1 (148.4)122.1 (84.6) ** HDL chol – mean (sd) 42.3 (12.2)53.9 (15.5) ** *Randomized to chlorthalidone, amlodipine, or lisinopril. ** p<.05 ALLHAT

12. 12 Blood Pressure at 5 Years by Baseline DS Status ChlorAmlodLisin SBP mean (sd) DS134 (15)135 (15)136 (18)* No DS133 (15)134 (15)136 (18)* DBP mean (sd) DS75 (10)74 (10)*75 (10) No DS76 (10)75 (10)*76 (11) SBP/DBP difference compared with chlorthalidone DS---+0.6 / +0.2*+1.9* / 0.0 No DS---+0.9 / -1.0*+2.1* / 0.0 * p<0.05 compared with chlorthalidone ALLHAT

13. 13 Biochemical Measures at 4 Years in Participants with Dysmetabolic Syndrome ChlorAmlodLisin TChol mg/dL Mean N 196.3 4,736 195.6 2,752 194.7 2,629 Fasting Glucose mg/dL Mean % 126+ N 137.5 43.1 2,809 134.7 41.8 1,674 131.1* 37.6* 1,523 Potassium mmol/L Mean N 4.1 4572 4.4* 2658 4.6* 2523 * p<0.05 compared with chlorthalidone ALLHAT

14. 14 Biochemical Measures at 4 Years in Participants without Dysmetabolic Syndrome ChlorAmlodLisin TChol mg/dL Mean N 197.4 2,924 194.6* 1,765 194.9* 1,606 Fasting Glucose mg/dL Mean % 126+ N 108.6 16.7 1,793 106.6 13.1* 1,057 107.7 16.4 989 Potassium mmol/L Mean N 4.1 2,849 4.4* 1,720 4.5* 1,570 * p<0.05 compared with chlorthalidone ALLHAT

15. 15 CHD by Treatment Group In Participants With DS at Baseline Chlorthalidone Amlodipine Lisinopril ALLHAT 0 2 4 6 08 10 12 14 Cumulative CHD Event Rate, % 0123456 Years to CHD HR (95% CI)p value A/C 0.95 (0.84 – 1.07)0.37 L/C 1.01 (0.90 – 1.13)0.86

16. 16 CHD by Treatment Group In Participants Without DS at Baseline Chlorthalidone Amlodipine Lisinopril ALLHAT 0 2 4 6 8 10 12 14 Cumulative CHD Event Rate, % 0123456 Years to CHD HR (95% CI)p value A/C 1.05 (0.90 – 1.22)0.53 L/C 1.02 (0.88 – 1.20)0.78

17. 17 CHD All-cause mortality Stroke Heart Failure Combined CVD ESRD Favors Chlorthalidone Favors Amlodipine Favors Chlorthalidone With Dysmetabolic Syndrome Without Dysmetabolic Syndrome Favors Amlodipine 0.5012 0.81 (0.51 - 1.26) 1.05 (0.96 - 1.15) 1.45 (1.20 - 1.75) 1.04 (0.83 - 1.29) 0.93 (0.83 - 1.04) 1.05 (0.90 - 1.22) 0.5012 1.27 (0.96 - 1.68) 1.05 (0.98 - 1.12) 1.32 (1.15 - 1.51) 0.87 (0.74 - 1.04) 0.97 (0.88 - 1.06) 0.95 (0.84 - 1.07) Amlodipine/Chlorthalidone Relative Risk and 95% Confidence Intervals ALLHAT

18. 18 CHD All-cause mortality Stroke Heart Failure Combined CVD ESRD Favors Chlorthalidone Favors Lisinopril Favors Chlorthalidone Favors Lisinopril 0.5012 1.22 (0.92 - 1.63) 1.14 (1.06 - 1.21) 1.28 (1.12 - 1.47) 1.09 (0.93 - 1.28) 1.01 (0.93 - 1.12) 1.01 (0.90 - 1.13) 0.5012 0.76 (0.48 - 1.21) 1.07 (0.98 - 1.17) 1.02 (0.83 - 1.25) 1.20 (0.97 - 1.48) 1.02 (0.91 - 1.14) 1.02 (0.88 - 1.20) ALLHAT Lisinopril/Chlorthalidone Relative Risk and 95% Confidence Intervals With Dysmetabolic Syndrome Without Dysmetabolic Syndrome

19. 19 Results by Baseline Dysmetabolic Syndrome - Conclusions Treatment group comparison results were similar in participants with and without DS at baseline (i.e., there were no significant interactions) For both DS and non-DS participants, neither the CCB nor ACEI arms were superior to the diuretic arm –For HF, diuretic was superior to CCB Results were similar with DS definition similar to ATP III ALLHAT

20. 20 Results - Overall Because of the superiority of thiazide-type diuretics in preventing one or more major forms of CVD and their lower cost, they should be the drugs of choice for first- step antihypertensive drug therapy in patients with and without dysmetabolic syndrome. ALLHAT

21. 21 Additional Slides (Not presented at AHA) ALLHAT

22. 22 BP Results by Treatment Group and Baseline DS DS-ChlorDS–AmlodDS–Lisin No DS–ChlorNo DS–AmlodNo DS–Lisin ALLHAT

23. 23 DS-ChlorDS–Amlod No DS–ChlorNo DS–Amlod ALLHAT BP Results by Treatment Group and Baseline DS Amlodipine vs Chlorthalidone

24. 24 ALLHAT BP Results by Treatment Group and Baseline DS Lisinopril vs Chlorthalidone DS-ChlorDS–Lisin No DS–ChlorNo DS–Lisin

25. 25 Outcomes in Participants with DS – Amlodipine Compared With Chlorthalidone 6-Year Rates per 100 (se) # Events RR (95% CI) p ChlorAmlAml/Chl CHD11.5 (0.4) 771 10.9 (0.5) 434 0.95 (0.84 – 1.07) 0.37 Mortality15.6 (0.5) 1,126 15.1 (0.6) 644 0.97 (0.88 – 1.06) 0.49 Stroke5.7 (0.3) 386 5.2 (0.4) 201 0.87 (0.74 – 1.04) 0.12 Heart Failure8.0 (0.4) 526 10.5 (0.5) 403 1.32 (1.15 – 1.51) <0.001 Combined CVD 20.6 (0.5) 1,447 21.2 (0.7) 863 1.05 (0.98 – 1.12) 0.15 ESRD1.8 (0.2) 135 2.4 (0.3) 97 1.27 (0.96 – 1.68) 0.09 ALLHAT

26. 26 Outcomes in Participants with DS – Lisinopril Compared with Chlorthalidone 6-Year Rates per 100 (se) # Events RR (95% CI) p ChlorLisinLisin/Chl CHD11.5 (0.4) 771 11.4 (0.5) 457 1.01 (0.90 – 1.13) 0.86 Mortality15.6 (0.5) 1,126 15.7 (0.6) 678 1.01 (0.93 – 1.12) 0.70 Stroke5.7 (0.3) 386 6.1 (0.4) 248 1.09 (0.93 – 1.28) 0.27 Heart Failure8.0 (0.4) 526 9.7 (0.5) 395 1.28 (1.12 – 1.47) <0.001 Combined CVD 20.6 (0.5) 1,447 21.4 (0.7) 883 1.14 (1.06 – 1.21) <0.001 ESRD1.8 (0.2) 135 2.3 (0.3) 92 1.22 (0.92 – 1.63) 0.16 ALLHAT

27. 27 Outcomes in Participants without DS – Amlodipine Compared with Chlorthalidone 6-Year Rates per 100 (se) RR (95% CI) p ChlorAmlAml/Chl CHD10.4 (0.5) 429 10.9 (0.7) 269 1.05 (0.90 – 1.22) 0.53 Mortality17.6 (0.6) 795 17.0 (0.8) 441 0.93 (0.83 – 1.04) 0.23 Stroke5.0 (0.4) 208 5.1 (0.5) 129 1.04 (0.83 – 1.29) 0.73 Heart Failure6.8 (0.5) 258 8.6 (0.6) 215 1.45 (1.20 – 1.75) <0.001 Combined CVD 17.6 (0.7) 732 17.3 (0.8) 448 1.05 (0.96 – 1.15) 0.28 ESRD1.5 (0.2) 26 1.1 (0.2) 17 0.81 (0.51 – 1.26) 0.35 ALLHAT

28. 28 Outcomes in Participants without DS – Lisinopril Compared with Chlorthalidone 6-Year Rates per 100 (se) RR (95% CI) p ChlorLisinLisin/Chl CHD10.4 (0.5) 429 10.4 (0.7) 256 1.02 (0.88 – 1.20) 0.78 Mortality17.6 (0.6) 795 18.3 (0.8) 476 1.02 (0.91-1.14) 0.72 Stroke5.0 (0.4) 208 5.8 (0.5) 145 1.20 (0.97 – 1.48) 0.09 Heart Failure 6.8 (0.5) 258 6.6 (0.6) 153 1.02 (0.83 – 1.25) 0.84 Combined CVD 17.6 (0.7) 732 18.2 (0.9) 455 1.07 (0.98 – 1.17) 0.15 ESRD1.5 (0.2) 26 1.0 (0.2) 16 0.76 (0.48 – 1.21) 0.26 ALLHAT

29. 29 All-Cause Mortality by Treatment Group In Participants With DS at Baseline Chlorthalidone Amlodipine Lisinopril ALLHAT 0 4 8 12 16 20 Cumulative Death Event Rate, % 0123456 Years to Death HR (95% CI)p value A/C 0.97 (0.88 – 1.06)0.49 L/C 1.01 (0.93 – 1.12)0.70

30. 30 All-Cause Mortality by Treatment Group In Participants Without DS at Baseline Chlorthalidone Amlodipine Lisinopril ALLHAT 0 4 8 12 16 20 Cumulative Death Event Rate, % 0123456 Years to Death HR (95% CI)p value A/C 0.93 (0.83 – 1.04)0.23 L/C 1.02 (0.91-1.14)0.72

31. 31 Stroke by Treatment Group In Participants With DS at Baseline Chlorthalidone Amlodipine Lisinopril ALLHAT 0 1 2 3 4 5 6 7 Cumulative Stroke Event Rate, % 0123456 Years to Stroke HR (95% CI)p value A/C 0.87 (0.74 – 1.04)0.12 L/C 1.09 (0.93 – 1.28)0.27

32. 32 Stroke by Treatment Group In Participants Without DS at Baseline Chlorthalidone Amlodipine Lisinopril ALLHAT 0 1 2 3 4 5 6 7 Cumulative Stroke Event Rate, % 0123456 Years to Stroke HR (95% CI)p value A/C 1.04 (0.83 – 1.29)0.73 L/C 1.20 (0.97 – 1.48)0.09

33. 33 Heart Failure by Treatment Group In Participants With DS at Baseline Chlorthalidone Amlodipine Lisinopril ALLHAT 0 2 4 6 8 10 12 Cumulative HF Event Rate, % 0123456 Years to HF OR (95% CI)p value A/C 1.32 (1.15 – 1.51)<0.001 L/C 1.28 (1.12 – 1.47)<0.001

34. 34 Heart Failure by Treatment Group In Participants Without DS at Baseline Chlorthalidone Amlodipine Lisinopril ALLHAT 0 2 4 6 8 10 12 Cumulative HF Event Rate, % 0123456 Years to HF OR (95% CI)p value A/C 1.45 (1.20 – 1.75)<0.001 L/C 1.02 (0.83 – 1.25)0.84

35. 35 Combined CVD by Treatment Group In Participants With DS at Baseline Chlorthalidone Amlodipine Lisinopril ALLHAT 0 5 10 15 20 25 30 35 Cumulative CCVD Event Rate, % 0123456 Years to CCVD HR (95% CI)p value A/C 1.05 (0.98 – 1.12)0.15 L/C 1.14 (1.06 – 1.21)<0.001

36. 36 Combined CVD by Treatment Group In Participants Without DS at Baseline Chlorthalidone Amlodipine Lisinopril ALLHAT 0 5 10 15 20 25 30 35 Cumulative CCVD Event Rate, % 0123456 Years to CCVD HR (95% CI)p value A/C 1.05 (0.96 – 1.15)0.28 L/C 1.07 (0.98 – 1.17)0.15

37. 37 End Stage Renal Disease by Treatment Group In Participants With DS at Baseline Chlorthalidone Amlodipine Lisinopril ALLHAT 0 1 2 3 Cumulative ESRD Event Rate, % 0123456 Years to ESRD HR (95% CI)p value A/C 1.27 (0.96 – 1.68)0.09 L/C 1.22 (0.92 – 1.63)0.16

38. 38 End Stage Renal Disease by Treatment Group In Participants Without DS at Baseline Chlorthalidone Amlodipine Lisinopril ALLHAT 0 1 2 3 Cumulative ESRD Event Rate, % 0123456 Years to ESRD HR (95% CI)p value A/C 0.81 (0.51 – 1.26)0.35 L/C 0.76 (0.48 – 1.21)0.26

39. 39 CHD All-cause mortality Stroke Heart Failure Combined CVD ESRD Favors Amlodipine 0.5012 1.27 (0.96 - 1.68) 1.05 (0.98 - 1.12) 1.32 (1.15 - 1.51) 0.87 (0.74 - 1.04) 0.97 (0.88 - 1.06) 0.95 (0.84 - 1.07) Favors Chlorthalidone ALLHAT Amlodipine/Chlorthalidone Relative Risk and 95% Confidence Intervals Outcomes in Participants With Dysmetabolic Syndrome-

40. 40 CHD All-cause mortality Stroke Heart Failure Combined CVD ESRD Favors Amlodipine 0.5012 0.81 (0.51 - 1.26) 1.05 (0.96 - 1.15) 1.45 (1.20 - 1.75) 1.04 (0.83 - 1.29) 0.93 (0.83 - 1.04) 1.05 (0.90 - 1.22) Favors Chlorthalidone ALLHAT Amlodipine/Chlorthalidone Relative Risk and 95% Confidence Intervals Outcomes in Participants Without Dysmetabolic Syndrome

41. 41 ESRD Combined CVD Heart Failure Stroke All-cause mortality CHD Favors Lisinopril 0.5012 1.22 (0.92 - 1.63) 1.14 (1.06 - 1.21) 1.28 (1.12 - 1.47) 1.09 (0.93 - 1.28) 1.01 (0.93 - 1.12) 1.01 (0.90 - 1.13) Favors Chlorthalidone ALLHAT Lisinopril/Chlorthalidone Relative Risk and 95% Confidence Intervals Outcomes in Participants With Dysmetabolic Syndrome

42. 42 CHD All-cause mortality Stroke Heart Failure Combined CVD ESRD Favors Lisinopril 0.5012 0.76 (0.48 - 1.21) 1.07 (0.98 - 1.17) 1.02 (0.83 - 1.25) 1.20 (0.97 - 1.48) 1.02 (0.91 - 1.14) 1.02 (0.88 - 1.20) Favors Chlorthalidone ALLHAT Outcomes in Participants Without Dysmetabolic Syndrome Lisinopril/Chlorthalidone Relative Risk and 95% Confidence Intervals