ALLHAT ALLHAT Antihypertensive Trial Results by Baseline Diabetic & Fasting Glucose Status.

ALLHAT ALLHAT Antihypertensive Trial Results by Baseline Diabetic & Fasting Glucose Status

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

Health and Human Services National Heart, Lung, and Blood Institute
U.S. Department of Health and Human Services National Institutes of Health National Heart, Lung, and Blood Institute ALLHAT Major Outcomes in High Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs Diuretic The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Treatment and complications among the million Americans with hypertension are estimated to cost the nation $37 billion annually, with antihypertensive drug costs alone accounting for an estimated $15.5 billion/year. There is conclusive evidence that antihypertensive drug therapy can substantially reduce the risk of hypertension-related morbidity and mortality. However, the optimal choice for initial pharmacotherapy of hypertension is uncertain. Earlier clinical trials documented the benefit of lowering blood pressure (BP) using primarily thiazide diuretics or beta-blockers. After these studies, several newer classes of antihypertensive agents, i.e. angiotensin-converting-enzyme inhibitors (ACEIs), calcium channel blockers (CCBs), alpha-adrenergic blockers, and more recently angiotensin receptor blockers (ARBs) became available. Over the past decade, major placebo-controlled trials have documented that ACEIs and CCBs reduce cardiovascular events in hypertensive individuals. However, their relative value compared with older, less expensive agents remains unclear. There has been considerable uncertainty regarding effects of some classes of antihypertensive drugs on risk of coronary heart disease (CHD). The relative benefit of various agents in high-risk subgroups such as older, diabetic, and Black hypertensive persons also needed to be established. The ALLHAT Collaborative Research Group Sponsored by the National Heart, Lung, and Blood Institute (NHLBI) JAMA 2002;288:

Introduction and Background
ALLHAT Introduction and Background 15,297 ALLHAT participants had diabetes (by history) at baseline. This represents 36% of the study cohort. Clearly makes ALLHAT the largest antihypertensive drug comparison trial in hypertensive diabetic patients.

Randomized Design of ALLHAT BP Trial
High-risk hypertensive patients Consent / Randomize Amlodipine Lisinopril Doxazosin Chlorthalidone Follow for CHD and other outcomes until death or end of study (up to 8 yr; mean 4.9 yrs).

Participants with DM in AHT Drug Trials
ALLHAT 15,297 ASCOT 5,145 VALUE 4,891 HOPE 3,577 (43.6% hypertensive) CONVINCE 3,266 HOT 1,501 LIFE 1,195 UKPDS 1,148 SHEP 583 Syst-Eur 492 ABCD 470 ANBP-2 426

Results Based On Diabetes by History Only JAMA 2002;288:2981-2997

Biochemical Results – Fasting Glucose – mg/dL
ALLHAT Biochemical Results – Fasting Glucose – mg/dL Chlorthalidone Amlodipine Lisinopril Total Baseline 123.5 123.1 122.9 4 Years 126.3 123.7 121.5* Among baseline nondiabetics with baseline FG <126 mg/dL 93.1 93.0 93.3 104.4 103.1 100.5* Diabetes Incidence (follow-up fasting glucose  126 mg/dL) 11.6% 9.8%* 8.1%* The respective mean fasting serum glucose levels at baseline were 123.5, 123.1, and mg/dL (6.9, 6.8 and 6.8 mmol/L); at 4 years, the respective mean levels were 126.3, 123.7, and mg/dL (7.0, 6.9, and 6.7 mmol/L). The comparison of the lisinopril and chlorthalidone groups was statistically significant at p<.05. Among individuals classified as nondiabetic at baseline, with baseline fasting serum glucose less than 126 mg/dl (7.0 mmol/L), incidence of diabetes (fasting serum glucose 126 mg/dl) at four years was 11.6%, 9.8%, and 8.1%, respectively. Both comparisons with the chlorthalidone group were statistically significant at p<.05. *p<.05 compared to chlorthalidone JAMA 2002;288:

ALLHAT Diabetes Incidence - 4 Years (follow-up FBS  126 mg/dL for those <126 mg/dL at baseline) * * * p<.05 compared to chlorthalidone JAMA 2002;288:

Diabetics & Nondiabetics (History) Amlodipine/Chlorthalidone
ALLHAT Diabetics & Nondiabetics (History) Amlodipine/Chlorthalidone Relative Risk and 95% Confidence Intervals Diabetics Nondiabetics CHD 0.99 (0.87, 1.13) Mortality 0.96 (0.87, 1.07) Stroke 0.90 (0.75, 1.08) Heart Failure 1.42 (1.23, 1.64) Combined CVD 1.06 (0.98, 1.15) ESRD 1.30 (0.98, 1.73) Favors Favors Amlodipine Chlorthal 0.50 1 2 0.97 (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) 0.50 1 2 There are no significant treatment effect differences between diabetic and nondiabetic participants for the amlodipine / chlorthalidone comparisons. Favors Favors Amlodipine Chlorthal JAMA 2002;288:

Diabetics & Nondiabetics (History) Lisinopril/Chlorthalidone
ALLHAT Diabetics & Nondiabetics (History) Lisinopril/Chlorthalidone Relative Risk and 95% Confidence Intervals Diabetics Nondiabetics CHD 1.00 (0.87, 1.14) Mortality 1.02 (0.91, 1.13) Stroke 1.07 (0.90, 1.28) Heart Failure 1.22 (1.05, 1.42) Combined CVD 1.08 (1.00, 1.17) ESRD 1.17 (0.87, 1.57) 0.99 (0.88, 1.11) 1.00 (0.91, 1.09) 1.23 (1.05, 1.44) 1.20 (1.04, 1.38) 1.12 (1.04, 1.19) 1.05 (0.74, 1.48) 0.50 1 2 Favors Favors Lisinopril Chlorthal 0.50 1 2 There are no significant treatment effect differences between diabetic and nondiabetic participants for the lisinopril / chlorthalidone comparisons. Favors Favors Lisinopril Chlorthal JAMA 2002;288:

Results Based On Diabetes by History and Baseline Glucose Measurements Arch Intern Med. 2005;165:

Diabetes by History & Baseline Fasting Glucose
ALLHAT Diabetes by History & Baseline Fasting Glucose History of Diabetes* No History of Diabetes FG <110 mg/dL Diabetic Nondiabetic NFG <110 mg/dL FG mg/dL Impaired fasting glucose (IFG) FG 126 mg/dL Other/missing Excluded FG = Fasting glucose NFG = Nonfasting glucose *Medical record evidence in the past 2 years: Fasting glucose >140 mg/dl, non-fasting glucose >200 mg/dl, and/or on insulin or oral hypoglycemic agents For these analyses, participants were classified as to baseline diabetes status using their history information as well as their baseline glucose from the central laboratory.

Diabetes by History & Baseline Fasting Glucose*
ALLHAT Diabetes by History & Baseline Fasting Glucose* History of Diabetes** No History of Diabetes FG <110 mg/dL 13,456 NFG <110 mg/dL 3,556 FG mg/dL 12,063 1,399 FG 126 mg/dL 1,038 Other/missing 1,845 FG = Fasting glucose NFG = Nonfasting glucose *Randomized to chlorthalidone, amlodipine, or lisinopril **Medical record evidence in the past 2 years: Fasting glucose >140 mg/dl, non-fasting glucose >200 mg/dl, and/or on insulin or oral hypoglycemic agents

Diabetes by History and Baseline Fasting Glucose by Treatment Group
ALLHAT Diabetes by History and Baseline Fasting Glucose by Treatment Group Chlorthalidone Amlodipine Lisinopril Diabetic 5,994 41.6% 3,597 42.0% 3,510 41.1% IFG 628 4.4% 364 4.3% 407 4.8% Nondiabetic 7,791 54.1% 4,594 53.7% 4,627 54.2% Total 14,413 100.0% 8,555 8,544 Missing 842 493 510

ALLHAT Baseline Characteristics – Diabetic, IFG, and Nondiabetic Participants* Age Diabetic IFG Nondiabetic N 13,101 1,399 17,012 Age – mean 66.6** 67.0 67.1 Women (%) 49.3** 37.7** 45.4 Black (%) 38.8** 29.5 32.1 SBP – mean 146.5** 146.5 146.0 DBP – mean 82.9** 84.6 84.8 Current smokers (%) 13.4** 23.5** 27.7 ASCVD (%) 35.8** 62.6 61.7 Points for this slide: 9,061 participants were assigned to doxazosin and are not included in these analyses. Of these, 3220 were diabetics. ALLHAT randomized a total of 15,283 diabetics. Current smoking, ASCVD, and diabetes were all included in the criteria for “high risk” hypertensives. Participants not identified as “high risk” based on diabetes had to meet at least one other “high risk” criterion (e.g., current smoking or ASCVD) to quality for ALLHAT. Thus, those two factors have greater prevalence in the nondiabetic subgroup in ALLHAT. *Randomized to chlorthalidone, amlodipine, or lisinopril ** p<.05 compared to nondiabetic participants

ALLHAT Blood Pressure at 5 Years - Diabetic, Impaired Fasting Glucose, and Nondiabetic Participants Chlor Amlod Lisin SBP - Diabetic 135.0 (15.6) 136.3 (15.9)* 137.9 (19.0)* mean (sd) Impaired FG 133.0 (16.1) 134.1 (13.2) 133.5 (15.2) Nondiabetic 133.4 (14.9) 133.5 (14.1) 134.8 (17.3)* DBP - 74.4 (9.7) 73.6 (10.1)* 74.6 (11.1) 74.0 (9.8) 74.4 (9.5) 75.1 (11.2) 76.2 (9.8) 75.3 (9.6)* 76.1 (10.4) * p<0.05 compared with chlorthalidone

ALLHAT CHD in Participants with a History of Diabetes Mellitus or with FG 126+ at Baseline .2 HR (95% CI) p value A/C 0.97 ( ) 0.64 L/C 0.97 ( ) 0.59 .16 Chlorthalidone Amlodipine Lisinopril .12 Cumulative CHD Event Rate .08 .04 1 2 3 4 5 6 7 Years to CHD Event

ALLHAT CHD in Participants With Impaired Fasting Glucose
(No History of Diabetes) .2 HR (95% CI) p value A/C 1.73 ( ) 0.02 L/C 1.16 ( ) 0.56 .16 Chlorthalidone Amlodipine Lisinopril .12 Cumulative CHD Event Rate .08 Within the IFG stratum, the primary outcome was significantly more common in those assigned to amlodipine compared with chlorthalidone, with the difference emerging after approximately 2 years of follow-up. .04 1 2 3 4 5 6 7 Years to CHD Event

CHD in Normoglycemic Participants (No History of Diabetes)
ALLHAT CHD in Normoglycemic Participants (No History of Diabetes) .2 HR (95% CI) p value A/C 0.94 ( ) 0.36 L/C 1.02 ( ) 0.79 .16 .12 Cumulative CHD Event Rate Chlorthalidone Amlodipine Lisinopril .08 .04 1 2 3 4 5 6 7 Years to CHD Event

Diabetes-Treatment Interactions - CHD
ALLHAT Diabetes-Treatment Interactions - CHD Comparison & p for interaction Subgroup RR A/C 0.01 Diab 0.97 (0.86 – 1.10) IFG 1.73 (1.10 – 2.72) Normo 0.94 (0.82 – 1.07)

ALLHAT Outcomes in the Blood Pressure Component of ALLHAT
DIABETIC GROUP 0.50 1 2 0.50 1 2 Amlodipine / Chlorthalidone Lisinopril / Chlorthalidone CHD ( ) All cause mortality ( ) Combined CHD ( ) Stroke ( ) Heart Failure ( ) Combined CVD ( ) ESRD ( ) 0.97 ( ) 0.99 ( ) 1.03 ( ) 1.06 ( ) 1.15 ( ) 1.07 ( ) 1.09 ( ) Favors Favors Amlodipine Chlorthalidone Favors Favors Lisinopril Chlorthalidone

IMPAIRED FASTING GROUP Amlodipine / Chlorthalidone Lisinopril / Chlorthalidone CHD ( ) All cause mortality ( ) Combined CHD ( ) Stroke ( ) Heart Failure ( ) Combined CVD ( ) ESRD ( ) 1.16 ( ) 1.07 ( ) 1.12 ( ) 0.91 ( ) 1.20 ( ) 1.09 ( ) 1.50 ( ) 0.17 0.25 0.33 0.50 1 2 3 0.33 0.50 1 2 3 4 5 Favors Favors Amlodipine Chlorthalidone Favors Favors Lisinopril Chlorthalidone

NORMOGLYCEMIC Amlodipine / Chlorthalidone Lisinopril / Chlorthalidone 0.50 1 2 1.02 ( ) 1.02 ( ) 1.05 ( ) 1.31 ( ) 1.19 ( ) 1.13 ( ) 0.99 ( ) CHD ( ) All cause mortality ( ) Combined CHD ( ) Stroke ( ) Heart Failure ( ) Combined CVD ( ) ESRD ( ) 0.50 1 2 Favors Favors Amlodipine Chlorthalidone Favors Favors Lisinopril Chlorthalidone

Diabetes-Treatment Interactions - CCHD
ALLHAT Diabetes-Treatment Interactions - CCHD Comparison & p for interaction Subgroup RR (95% CI) A/C 0.03 Diab 1.02 (0.93 – 1.12) IFG 1.37 (1.00 – 1.87) Normo 0.95 (0.86 – 1.05) Given the large number of treatment comparisons that were examined, this interaction should be interpreted with caution.

Race-Diabetes-Treatment Interactions
ALLHAT Race-Diabetes-Treatment Interactions Comparison & p for interaction Subgroup RR CHD - L/C 0.04 Total Diab 0.97 Total IFG 1.16 Black IFG 4.35 Nonblack IFG 0.77 Total Nondiab 1.02 Total Mortality - 0.95 A/C 0.05 0.93 1.25 0.92 There was a significant difference in the primary outcome for the comparison of lisinopril with chlorthalidone therapy across the 3 glycemic strata in black compared with non-black participants (P=.04forinteraction).Specifically,among participants with IFG, the RR was 4.35 for black and 0.68 for nonblack participants. There was also a significant difference in total mortality for the comparison of amlodipine with chlorthalidone across the 3 glycemic strata in black compared with nonblack participants (P=.05 for interaction). Specifically, among participants with IFG, the RR was 1.25 for black and 0.92 for nonblack participants. Given the large number of treatment comparisons that were examined, these marginally-significant three-way interactions should be interpreted with caution.

ALLHAT Results by Baseline Diabetic Status – Summary
Treatment group comparison results for CVD and ESRD events were similar in diabetic and nondiabetic participants. Compared with chlorthalidone arm – Higher risk of HF with amlodipine Higher risk of stroke, HF, and combined CVD with lisinopril

ALLHAT Results by Baseline Diabetic Status – Summary (cont)
Results for CVD and ESRD events were also similar in small group of participants with IFG, except for possible excess CHD with amlodipine Post-hoc sub-group May merit further study

ALLHAT Results by Baseline Diabetic Status – Implications
For minimizing CVD/renal risk in medium term, thiazide-like diuretics preferred, except: ALLHAT did not address proteinuric nephropathy. Do differences in glycemia translate into long-term advantage for CVD/renal events? Not for CVD death, based on SHEP extended follow-up analyses; post-trial ALLHAT FU continues. Ongoing trials testing glycemia-reduction→CVD NOTE: There is a separate slide set based on the SHEP-X analyses.

The conclusions presented for the ALLHAT diabetes subgroups are entirely consistent with the overall conclusions for the entire study cohort.

EXTRA SLIDES

ALLHAT All-Cause Mortality in Participants with a History of Diabetes Mellitus or FG 126+ mg/dL at Baseline Cumulative Mortality Rate Years to Death 1 2 3 4 5 6 7 .04 .08 .12 .16 .2 .24 .28 0.69 0.99 ( ) L/C 0.33 0.95 ( ) A/C p value HR (95% CI) Chlorthalidone Amlodipine Lisinopril

ALLHAT All-Cause Mortality in Participants with Impaired Fasting Glucose (No History of Diabetes) .28 HR (95% CI) p value A/C 0.93 ( ) 0.71 L/C 1.07 ( ) 0.70 .24 .2 .16 Chlorthalidone Amlodipine Lisinopril Cumulative Mortality Rate .12 .08 .04 1 2 3 4 5 6 7 Years to Death

ALLHAT All-Cause Mortality in Normoglycemic Participants
(No History of Diabetes) Cumulative Mortality Rate .04 .08 .12 .16 .2 .24 .28 0.69 1.02 (0.92 - 1.13) L/C 0.33 0.95 (0.86 1.05) A/C p value HR (95% CI) Chlorthalidone Amlodipine Lisinopril 1 2 3 4 5 6 7 Years to Death

Combined CHD in Participants with a History of Diabetes Mellitus or
ALLHAT Combined CHD in Participants with a History of Diabetes Mellitus or FG 126+ mg/dL at Baseline .3 HR (95% CI) p value A/C 1.02 ( ) 0.64 L/C 1.03 ( ) 0.56 .2 Chlorthalidone Amlodipine Lisinopril Cumulative Combined CHD Event Rate .1 1 2 3 4 5 6 7 Years to Combined CHD Event

ALLHAT Combined CHD in Participants with Impaired Fasting Glucose
(No History of Diabetes) .3 HR (95% CI) p value A/C 1.37 ( ) 0.05 L/C 1.12 ( ) 0.47 .2 Chlorthalidone Amlodipine Lisinopril Cumulative Combined CHD Event Rate .1 1 2 3 4 5 6 7 Years to Combined CHD Event

in Normoglycemic Participants (No History of Diabetes)
ALLHAT Combined CHD in Normoglycemic Participants (No History of Diabetes) .3 HR (95% CI) p value A/C 0.95 ( ) 0.33 L/C 1.05 ( ) 0.28 .2 Chlorthalidone Amlodipine Lisinopril Cumulative Combined CHD Event Rate .1 1 2 3 4 5 6 7 Years to Combined CHD Event

ALLHAT Stroke in Participants with a History of Diabetes Mellitus or with FG 126+ mg/dL at Baseline Cumulative Stroke Rate Years to Stroke 1 2 3 4 5 6 7 .04 .08 .12 0.50 1.06 ( ) L/C 0.20 0.89 ( ) A/C p value HR (95% CI) Chlorthalidone Amlodipine Lisinopril

ALLHAT Stroke in Participants with Impaired Fasting Glucose
(No History of Diabetes) .12 HR (95% CI) p value A/C 0.68 ( ) 0.23 L/C 0.91 ( ) 0.75 .08 Chlorthalidone Amlodipine Lisinopril Cumulative Stroke Rate .04 1 2 3 4 5 6 7 Years to Stroke

Stroke in Normoglycemic Participants (No History of Diabetes)
ALLHAT Stroke in Normoglycemic Participants (No History of Diabetes) .12 HR (95% CI) p value A/C 1.03 ( ) 0.77 L/C 1.31 ( ) 0.003 .08 Chlorthalidone Amlodipine Lisinopril Cumulative Stroke Rate .04 1 2 3 4 5 6 7 Years to Stroke

ALLHAT Stroke by Race by Baseline Diabetic Status – Amlodipine / Chlorthalidone HR (95% CI) p value Diabetic Black 0.96 (0.73 – 1.26) 0.77 Non-Black 0.83 (0.66 – 1.07) 0.15 IFG 0.74 (0.28 – 1.97) 0.55 0.61 (0.26 – 1.45) 0.26 Nondiabetic 0.95 (0.68 – 1.34) 0.79 1.07 (0.85 – 1.35) 0.57

ALLHAT Stroke by Race by Baseline Diabetic Status – Lisinopril / Chlorthalidone HR (95% CI) p value Diabetic Black 1.36 (1.06 – 1.75) 0.02 Non-Black 0.85 (0.67 – 1.09) 0.20 IFG 1.35 (0.58 – 3.11) 0.49 0.68 (0.31 – 1.50) 0.34 Nondiabetic 1.54 (1.15 – 2.08) 0.004 1.19 (0.95 – 1.50) 0.13

ALLHAT Heart Failure in Participants with a History of Diabetes Mellitus or with FG 126+ mg/dL at Baseline .2 HR (95% CI) p value A/C 1.39 (1.22–1.59) <0.001 L/C 1.15 ( ) 0.06 .16 Chlorthalidone Amlodipine Lisinopril .12 Cumulative HF Rate .08 .04 1 2 3 4 5 6 7 Years to HF

ALLHAT Heart Failure in Participants with Impaired Fasting Glucose
(No History of Diabetes) .2 HR (95% CI) p value A/C 1.66 ( ) 0.06 L/C 1.20 ( ) 0.52 .16 Chlorthalidone Amlodipine Lisinopril .12 Cumulative HF Rate .08 .04 1 2 3 4 5 6 7 Years to HF

Heart Failure in Normoglycemic Participants (No History of Diabetes)
ALLHAT Heart Failure in Normoglycemic Participants (No History of Diabetes) .2 HR (95% CI) p value A/C 1.30 ( ) 0.001 L/C 1.19 ( ) 0.03 .16 Chlorthalidone Amlodipine Lisinopril .12 Cumulative CHF Rate .08 .04 1 2 3 4 5 6 7 Years to CHF

ALLHAT Combined CVD in Participants with a History of Diabetes Mellitus or with FG 126+ mg/dL at Baseline .45 HR (95% CI) p value A/C 1.06 ( ) 0.13 L/C 1.07 ( ) 0.08 .3 Cumulative Combined CVD Event Rate Chlorthalidone Amlodipine Lisinopril .15 1 2 3 4 5 6 7 Years to Combined CVD Event

ALLHAT Combined CVD in Participants with Impaired Fasting Glucose
(No History of Diabetes) .45 HR (95% CI) p value A/C 1.13 ( ) 0.34 L/C 1.09 ( ) 0.48 .3 Cumulative Combined CVD Event Rate Chlorthalidone Amlodipine Lisinopril .15 1 2 3 4 5 6 7 Years to Combined CVD Event

Combined CVD in Normoglycemic Participants (No History of Diabetes)
ALLHAT Combined CVD in Normoglycemic Participants (No History of Diabetes) .45 HR (95% CI) p value A/C 1.02 ( ) 0.57 L/C 1.13 ( ) 0.001 .3 Chlorthalidone Amlodipine Lisinopril Cumulative Combined CVD Event Rate .15 1 2 3 4 5 6 7 Years to Combined CVD Event

ALLHAT ESRD in Participants with a History of Diabetes Mellitus or with FG 126+ mg/dL at Baseline Cumulative ESRD Rate Years to ESRD 1 2 3 4 5 6 7 .01 .02 .03 .04 0.55 1.09 ( ) L/C 0.08 1.27 ( ) A/C p value HR (95% CI) Chlorthalidone Amlodipine Lisinopril

ALLHAT ESRD in Participants with Impaired Fasting Glucose
(No History of Diabetes) .04 HR (95% CI) p value A/C 0.52 ( ) 0.43 L/C 1.50 ( ) 0.48 .03 Chlorthalidone Amlodipine Lisinopril Cumulative ESRD Rate .02 .01 1 2 3 4 5 6 7 Years to ESRD

ESRD in Normoglycemic Participants (No History of Diabetes)
ALLHAT ESRD in Normoglycemic Participants (No History of Diabetes) .04 HR (95% CI) p value A/C 0.85 ( ) 0.46 L/C 0.99 ( ) 1.00 .03 Chlorthalidone Amlodipine Lisinopril Cumulative ESRD Rate .02 .01 1 2 3 4 5 6 7 Years to ESRD

ALLHAT ALLHAT Antihypertensive Trial Results by Baseline Diabetic & Fasting Glucose Status.

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ALLHAT ALLHAT Antihypertensive Trial Results by Baseline Diabetic & Fasting Glucose Status.

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