1 ALLHAT Antihypertensive Trial Results by Baseline Diabetic Status January 28, 2004.

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1 ALLHAT Antihypertensive Trial Results by Baseline Diabetic Status January 28, 2004

2 Introduction and Background Clinical trials have reported reduction in CV events with diuretics, CCBs, ACE inhibitors,  -blockers, and ARBs. Clinical trials have reported reduction in CV events with diuretics, CCBs, ACE inhibitors,  -blockers, and ARBs. Concerns have been raised regarding effects of some classes in diabetes. Concerns have been raised regarding effects of some classes in diabetes. JNC7 guidelines indicate all these classes are acceptable. JNC7 guidelines indicate all these classes are acceptable. ALLHAT

3 History of Diabetes at Baseline Medical record evidence in the past 2 years (1 or more of the following):Medical record evidence in the past 2 years (1 or more of the following): –Fasting glucose >140 mg/dl –Non-fasting glucose >200 mg/dl –On insulin or oral hypoglycemic agents

4 Baseline Characteristics Diabetic and Nondiabetic Participants* AgeDiabeticNondiabetic N12,06321,294 Age – mean Women (%) Black (%) SBP – mean DBP – mean Current smokers (%) ASCVD (%) *Randomized to chlorthalidone, amlodipine, or lisinopril.

5 BP Results by Treatment Group and Baseline Diabetic Status Diabetic-ChlorDiabetic–AmlodDiabetic–Lisin Nondiab–ChlorNondiab–AmlodNondiab–Lisin BL6M1Y3Y5Y D–C D–A D-L ND-C ND-A ND-L BL6M1Y3Y5Y D–C D–A D-L ND-C ND-A ND-L

6 Blood Pressure at 5 Years by Baseline Diabetic Status ChlorAmlodLisin SBP -Diabetic135.1 (15.7)136.3 (16.1)138.1 (19.2)* mean (sd)Nondiabetic133.3 (14.9)133.8 (14.1)134.7 (17.1)* DBP – mean (sd) Diabetic74.4 (9.8)73.5 (10.2)*74.5 (11.1) Nondiabetic76.0 (9.8)75.2 (9.6)*75.9 (10.5) SBP/DBP difference compared with chlorthalidone Diabetic / -0.9*+3.0* / +0.1 Nondiabetic+0.5 / -0.8*+1.3* / -0.1 * p<0.05 compared with chlorthalidone The SBP difference between lisinopril and chlorthalidone was larger in diabetic (+3.0 mm Hg) than for nondiabetic participants (1.3 mm Hg) (p=0.04).

7 Biochemical Measures at 4 Years in Participants with Diabetes ChlorAmlodLisin Chol - mg/dL Mean N * 1574 Fasting Glucose – mg/dl Mean % 126+ N % % % 855 Potassium – mmol/L Mean N * * 1528 * p<0.05 compared with chlorthalidone

8 Biochemical Measures at 4 Years in Participants without Diabetes ChlorAmlodLisin Chol - mg/dL Mean N * * 3137 Fasting Glucose – mg/dl Mean % 126+ N % * 12.8%* * 11.1%* 1876 Potassium – mmol/L Mean N * * 3088 * p<0.05 compared with chlorthalidone

9 Potassium Supplementation at 4 Years in Participants with and without Diabetes at Baseline ChlorAmlodLisin Diabetic participants N3,9312,1972,227 On K suppl – n (%) 545 (13.9%) 163 (6.9%)* 122 (5.5%)* Nondiabetic participants N7,2414,3074,227 On K suppl – n (%) 1,170 (16.2%) 319 (7.4%)* 212 (5.0%)*

10 Cumulative CHD Event Rate Years to CHD Event CHD by Antihypertensive Treatment Group In Participants With Diabetes at Baseline HR (95% CI)p value A/C0.99 ( )0.93 L/C1.00 ( )0.97 Chlorthalidone Amlodipine Lisinopril

11 Cumulative CHD Event Rate Years to CHD Event CHD by Antihypertensive Treatment Group In Participants Without Diabetes at Baseline HR (95% CI)p value A/C0.97 ( )0.56 L/C0.99 ( )0.85 Chlorthalidone Amlodipine Lisinopril

12 Cumulative Mortality Rate Years to Death All-Cause Mortality by Antihypertensive Treatment Group In Participants With Diabetes at Baseline HR (95% CI)p value A/C0.96 ( )0.48 L/C1.02 ( )0.77 Chlorthalidone Amlodipine Lisinopril

13 Cumulative Mortality Rate Years to Death All-Cause Mortality by Antihypertensive Treatment Group In Participants Without Diabetes at Baseline HR (95% CI)p value A/C0.95 ( )0.26 L/C1.00 ( )1.00 Chlorthalidone Amlodipine Lisinopril

14 Cumulative Stroke Rate Years to Stroke Stroke by Antihypertensive Treatment Group In Participants With Diabetes at Baseline HR (95% CI)p value A/C0.90 ( )0.26 L/C1.07 ( )0.45 Chlorthalidone Amlodipine Lisinopril

15 Cumulative Stroke Rate Years to Stroke Stroke by Antihypertensive Treatment Group In Participants Without Diabetes at Baseline HR (95% CI)p value A/C0.96 ( )0.63 L/C1.23 ( )0.01 Chlorthalidone Amlodipine Lisinopril

16 Cumulative HF Rate Years to HF Heart Failure by Antihypertensive Treatment Group In Participants With Diabetes at Baseline HR (95% CI)p value A/C1.42 ( )<0.001 L/C1.22 ( )0.009 Chlorthalidone Amlodipine Lisinopril

17 Cumulative HF Rate Years to HF Heart Failure by Antihypertensive Treatment Group In Participants Without Diabetes at Baseline HR (95% CI)p value A/C1.33 ( )<0.001 L/C1.20 ( )0.01 Chlorthalidone Amlodipine Lisinopril

18 Cumulative Combined CVD Event Rate Years to Combined CVD Event Combined CVD by Antihypertensive Treatment Group In Participants With Diabetes at Baseline HR (95% CI)p value A/C1.06 ( )0.12 L/C1.08 ( )0.05 Chlorthalidone Amlodipine Lisinopril

19 Cumulative Combined CVD Event Rate Years to Combined CVD Event Combined CVD by Antihypertensive Treatment Group In Participants Without Diabetes at Baseline HR (95% CI)p value A/C1.02 ( )0.51 L/C1.12 ( )0.001 Chlorthalidone Amlodipine Lisinopril

20 End Stage Renal Disease by Antihypertensive Treatment Group In Participants With Diabetes at Baseline HR (95% CI)p value A/C1.30 (0.98, 1.73)0.07 L/C1.17 (0.87, 1.57) Cumulative ESRD Rate Years to ESRD

21 End Stage Renal Disease by Antihypertensive Treatment Group In Participants Without Diabetes at Baseline HR (95% CI)p value A/C0.86 (0.60, 1.25)0.43 L/C1.05 (0.73, 1.48)0.78 Chlorthalidone Amlodipine Lisinopril Cumulative ESRD Rate Years to ESRD

22 Diabetics & Nondiabetics Amlodipine/Chlorthalidone Relative Risk and 95% Confidence Intervals CHD0.99 (0.87, 1.13) Mortality0.96 (0.87, 1.07) Stroke0.90 (0.75, 1.08) Heart Failure1.42 (1.23, 1.64) Combined CVD1.06 (0.98, 1.15) ESRD1.30 (0.98, 1.73) Favors Amlodipine Chlorthal (0.86,1.09) 0.95 (0.87, 1.04) 0.96 (0.81, 1.14) 1.33 (1.16, 1.52) 1.02 (0.96, 1.09) 0.86 (0.60, 1.25) Favors Amlodipine Chlorthal DiabeticsNondiabetics There is no difference in treatment group effect by baseline history of diabetes.

23 Favors Lisinopril Chlorthal CHD1.00 (0.87, 1.14) Mortality1.02 (0.91, 1.13) Stroke1.07 (0.90, 1.28) Heart Failure1.22 (1.05, 1.42) Combined CVD1.08 (1.00, 1.17) ESRD1.17 (0.87, 1.57) Diabetics & Nondiabetics Lisinopril/Chlorthalidone Relative Risk and 95% Confidence Intervals DiabeticsNondiabetics (0.88, 1.11) 1.00 (0.91, 1.09) 1.23 (1.05, 1.44) 1.20 (1.04, 1.38) 1.12 (1.05, 1.19) 1.05 (0.74, 1.48) Favors Lisinopril Chlorthal There is no difference in treatment group effect by baseline history of diabetes.

24 ESRD Events and Estimated GFR by Baseline Diabetes Status ChlorAmlodLisin Participants with a History of Diabetes ESRD events 6-yr/100 (se) RR (p) 2.6 (0.3)3.6 (0.4) 1.30 (p=0.07) 3.2 (0.4) 1.17 (p=0.31) Est 4-yr GFR Mean (N)70.0 (2796)75.8* (1620)70.7 (1530) Participants without a History of Diabetes ESRD events 6-yr/100 (se) RR (p) 1.2 (0.2)1.0 (0.2) 0.86 (p=0.43) 1.2 (0.9) 1.05 (p=0.78) Est 4-yr GFR Mean (N)70.1 (5520)74.7* (3304)70.7 (3091) * p<0.05 compared with chlorthalidone

25 ALLHAT Results by Baseline Diabetic Status - Conclusions Treatment group comparison results were similar in diabetic and nondiabetic participants For both diabetic and nondiabetic participants, there were significant advantages for the diuretic arm –Compared with the ACEI and CCB arms, there was less HF –Compared with the ACEI arm, there was less stroke and less combined CVD

26 ALLHAT 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 both diabetic and nondiabetic participants.

27 Additional Slides

28 BP Results – Amlodipine vs Chlorthalidone and Baseline Diabetic Status Diabetic-ChlorDiabetic–Amlod Nondiabetic–ChlorNondiabetic–Amlod BL6M1Y3Y5Y D – C D – A ND – C ND – A BL6M1Y3Y5Y D – C D – A ND – C ND – A

29 BP Results – Lisinopril vs Chlorthalidone and Baseline Diabetic Status Diabetic-ChlorDiabetic–Lisin Nondiabetic–ChlorNondiabetic–Lisin BL6M1Y3Y5Y D – C D – L ND – C ND – L BL6M1Y3Y5Y D – C D – L ND – C ND – L

30 Outcomes in Participants with Diabetes – Amlodipine Compared With Chlorthalidone 6-Year Rates per 100 (se) RR (95% CI) p ChlorAmlAml/Chl CHD13.5 (0.6) (0.8) (0.87, 1.13) 0.93 Mortality19.0 (0.6) (0.8) (0.87, 1.07) 0.48 Stroke7.1 (0.4) (0.5) (0.75, 1.08) 0.26 Heart Failure9.7 (0.5) (0.7) (1.23, 1.64) <0.001 Combined CVD 33.9 (0.8) 1, (1.0) 1, (0.98, 1.15) 0.12 ESRD2.6 (0.3) (0.4) (0.98, 1.73) 0.07

31 Outcomes in Participants with Diabetes – Lisinopril Compared with Chlorthalidone 6-Year Rates per 100 (se) RR (95% CI) p ChlorLisinLisin/Chl CHD13.5 (0.6) (0.7) (0.87, 1.14) 0.97 Mortality19.0 (0.6) (0.8) (0.91, 1.13) 0.77 Stroke7.1 (0.4) ( ) 1.07 (0.90, 1.28) 0.45 Heart Failure9.7 (0.5) (0.7) (1.05, 1.42) Combined CVD 33.9 (0.8) 1, (1.0) (1.00, 1.17) 0.05 ESRD2.6 (0.3) (0.4) (0.87, 1.57) 0.31

32 Outcomes in Participants without Diabetes – Amlodipine Compared with Chlorthalidone 6-Year Rates per 100 (se) RR (95% CI) p ChlorAmlAml/Chl CHD9.8 (0.4) (0.5) (0.86, 1.09) 0.56 Mortality15.4 (0.4) 1, (0.6) (0.87, 1.04) 0.26 Stroke4.5 (0.3) (0.3) (0.81, 1.14) 0.63 Heart Failure6.1 (0.3) (0.4) (1.16, 1.52) <0.001 Combined CVD 28.0 (0.6) 2, (0.7) 1, (0.96, 1.09) 0.51 ESRD1.2 (0.2) (0.2) (0.60, 1.25) 0.43

33 Outcomes in Participants without Diabetes – Lisinopril Compared with Chlorthalidone 6-Year Rates per 100 (se) RR (95% CI) p ChlorLisinLisin/Chl CHD9.8 (0.4) (0.5) (0.88, 1.11) 0.85 Mortality15.4 (0.4) 1, (0.6) (0.91, 1.09) 1.00 Stroke4.5 (0.3) (0.4) (1.05, 1.44) 0.01 Heart Failure 6.1 (0.3) (0.4) (1.04, 1.38) 0.01 Combined CVD 28.0 (0.6) 2, (0.7) 1, (1.05, 1.19) ESRD1.2 (0.2) (0.9) (0.74, 1.48) 0.78

34 Diabetics Amlodipine/Chlorthalidone Relative Risk and 95% Confidence Intervals CHD0.99 (0.87, 1.13) All-cause mortality0.96 (0.87, 1.07) Stroke0.90 (0.75, 1.08) Heart Failure1.42 (1.23, 1.64) Combined CVD1.06 (0.98, 1.15) ESRD1.30 (0.98, 1.73) Favors Amlodipine Favors Chlorthalidone

35 Diabetics Lisinopril/Chlorthalidone Relative Risk and 95% Confidence Intervals CHD1.00 (0.87, 1.14) All-cause mortality1.02 (0.91, 1.13) Stroke1.07 (0.90, 1.28) Heart Failure1.22 (1.05, 1.42) Combined CVD1.08 (1.00, 1.17) ESRD1.17 (0.87, 1.57) Favors Lisinopril Favors Chlorthalidone

36 Nondiabetics Amlodipine/Chlorthalidone Relative Risk and 95% Confidence Intervals CHD0.97 (0.86,1.09) All-cause mortality0.95 (0.87, 1.04) Stroke0.96 (0.81, 1.14) Heart Failure1.33 (1.16, 1.52) Combined CVD1.02 (0.96, 1.09) ESRD0.86 (0.60, 1.25) Favors Amlodipine Favors Chlorthalidone

37 Nondiabetics Lisinopril/Chlorthalidone Relative Risk and 95% Confidence Intervals CHD0.99 (0.88, 1.11) All-cause mortality1.00 (0.91, 1.09) Stroke1.23 (1.05, 1.44) Heart Failure1.20 (1.04, 1.38) Combined CVD1.12 (1.05, 1.19) ESRD1.05 (0.74, 1.48) Favors Lisinopril Favors Chlorthalidone