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The concerns about new onset diabetes With various antihypertensive medications

The concerns about new onset diabetes With various antihypertensive medications Should not be a major determining factor In the choice of initial therapy. Past History Attempts to minimize benefits of therapy with diuretics or diuretics/B-blockers Statement:

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The concerns about new onset diabetes With various antihypertensive medications

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  1. The concerns about new onset diabetes With various antihypertensive medications Should not be a major determining factor In the choice of initial therapy.

  2. Past History Attempts to minimize benefits of therapy with diuretics or diuretics/B-blockers Statement: 1) Reduced strokes and heart failure but minimal effect on CHD events - result of effects on lipids Proven false 2) Poorly tolerated - Proven false 3) Increased ectopy - sudden death - Proven false 4) Use did not result in regression of LVH - Proven false

  3. The Present Statement: New onset diabetes (NOD) is increased with diuretics - should reconsider use of these agents as initial therapy Fact: NOD increased by about 1% compared to placebo or CCBs and 1- 3.5% compared to ACE-Is but Fact: Long-term outcome not affected; CVD events reduced to as great or greater extent as other Rx

  4. Incidence of New Onset Diabetes with Various Medications. How significant is it?

  5. Effects of High-Dose Diuretic Therapy Compared To Control or Placebo on Glucose Metabolism Study Yrs Serum Glucose (mg/dL) Hyperglycemia or Diabetes Oslo 5 No difference D/Pl No data EWPHE Increase of 6.6 , D/Pl MRC 3-4 Excess of 6 new cases/1000 pt yrs HAPPY HDFP 5 1.6% (57/3,563) SHEP 1 Difference of 5, D/Pl No diff – new onset diabetes Rx/C MRFIT 6 Excess of 5% (SI) diuretics vs (UC) no diuretics** *Diuretics compared with placebo **Fasting glucose >110 mg/dL Cleve Clin J Med 1993;60:27-37

  6. Incidence of New Onset Diabetes in the 3-8 Year Hypertension Treatment Trials Yrs % New Absolute Trial Duration Onset Diabetes Difference UC or D/B-Bl I. ACE-I compared to conventional Rx ACE-I CAPPP ACE-I/B-Bl/D 6.1 6.5 7.5 1.0 STOP-2 ACE-I/B-Bl/D 6+ 4.7 4.9 0.2 ANBP-2 ACE-I/ 4+ 4.5 6.6 2.1 ALLHAT ACE-I/D 4.9 8.1 11.6 3.5 II. CCB compared to conventional Rx CCB NORDIL CCB/B-Bl/D 4.5 4.3 4.9 0.6 ALLHAT CCB/D 4.9 9.8 11.6 1.8 INVEST CCB/B-Bl 4.0 6.2 7.3 1.1 INSIGHT CCB/D 3.5 5.4 7.0 1.6 STOP-2 CCB/B/Bl/D 6+ 4.8 4.9 0.1

  7. Incidence of New Onset Diabetes in the 3-8 Year Hypertension Treatment Trials Yrs % New Absolute Trial Duration Onset Diabetes Difference • III. ARB vs other RxARBOther Rx • VALUE ARB/CCB 4.2 13.1 16.4 3.3 • LIFE ARB/B-Bl 4.8 6.0 8.0 2.0 • SCOPE ARB/UC 5 4.3 5.3 1.0 • CHARM ARB/other Rx 3+ 6.0 7.4 1.4 • IV. ACE-I vs CCB ACE CCB • ALLHAT ACE-I/CCB 4.9 8.1 9.8 1.7 Approximate overall difference ACE or ARB vs D/B-Bl: 2.0%; ACE/CCB: 2.0%; CCB vs D/B-Bl: 1.5%

  8. Many clinical trial* results demonstrate that: • Fewer cases of new onset diabetes occur if an ACE or an ARB is included in therapy • Diabetic patients, especially those with proteinuria, have a better outcome if an ACE or an ARB is included in therapy *IDNT, RENAAL, LIFE, HOPE, CAPPP, AASK, VALUE, ALLHAT

  9. ALLHAT Total 1.10 Total 1.04 Age < 65 1.05 Age < 65 1.03 Age >= 65 1.13 Age >= 65 1.05 Men 1.08 Men 1.04 Women 1.12 Women 1.04 Black 1.19 Black 1.06 Non-Black 1.06 Non-Black 1.04 Diabetic 1.08 Diabetic 1.06 Non-Diabetic 1.12 Non-Diabetic 1.02 0.50 1 2 0.50 1 2 Lisinopril Better Chlorthalidone Better Amlodipine Better Chlorthalidone Better Combined CVD – Subgroup Comparisons P = .04 for interaction

  10. ALLHAT Conclusions • Among non diabetics, incidence of fasting glucose 126 mg/dL at 4 years was 1.8% higher in chlorthalidone vs amlodipine, and 3.5% higher in chlorthalidone vs lisinopril. • Overall, metabolic differences did not translate into more adverse cardiovascular events, or into higher all-cause mortality, with chlorthalidone.

  11. Risk of Hyperglycemia with Use of Antihypertensive Drugs Thiazide Central antiadrenergic agents Peripheral antiadrenergic agents ACE inhibitors B-Blockers Calcium channel blockers Vasodilators >1 Agent without thiazide >1 Agent with thiazide 0.51 1.5 2 2.5 3 Decreased Risk Increased Risk Adjusted ORs and 95%CI

  12. In a large prospective survey, it was concluded that “subjects with hypertension who were taking thiazide diuretics were not at greater risk for the subsequent development of diabetes than were subjects with hypertension who were not receiving any antihypertensive therapy. However, subjects with hypertension who were taking B-blockers had a 28% higher risk of subsequent diabetes.” Gress, et al. NEJM 2000;342:905-12

  13. Conclusions: “Concern about the risk of diabetes should not discourage physicians from prescribing thiazide diuretics to nondiabetic adults who have hypertension. The use of B-blockers appears to increase the risk of diabetes, but this adverse effect must be weighed against the proven benefits of B-blockers in reducing the risk of cardiovascular events.” Gress, et al. NEJM 2000;342:905-12

  14. Results of Tight Blood Pressure Control Compared with Less-Tight BP Control in the UKPDS Study Risk Reduction (%) Any diabetes related end- point Diabetes related death Stroke Micro vascular endpoints Retinopathy progression Deterior- ation of vision Heart failure BMJ 1998;317:703-713

  15. The ALPINE Study (392 patients) • Candesartan + felodipine (71%) compared to HCTZ + • Atenolol (84%) (mean dose 68 mg/day, 50% on 100 mg/day) • Baseline BMI - 28 kg/m2 • SBP more in HCTZ group • 12 mos. - no difference in cholesterol or LDL levels • Significant difference in HDL and triglycerides • 8 new diabetics in HCTZ vs 1 in C groups • Metabolic syndrome - 18 HCTZ vs 5 C The Antihypertensive Treatment and Lipid Profile in the North of Sweden Efficacy Evaluation J Hypertens 2003;21:1563-74

  16. Prognostic Significance of New Diabetes • in Treated Hypertensive Subjects* • 795 untreated hypertensives - follow-up - median 6.0 Years • New onset diabetes (NOD) - 5.8% • Plasma glucose and diuretic Rx at follow-up visit (but not B-blockers) • were predictive of NOD • Relative risk of CV event 2.92 NOD • 3.57 patients with pre Rx diabetes • Baseline: non diabetic patients who developed diabetes: • SBP and DBP higher • more LVH • glucose levels higher • 1 FG 42% vs 6% who did not develop NOD *Verdecchia, Hypertens 2004;43:963-968 (observational cohort study)

  17. Cardiovascular Events inTreated Hypertensive Subjects 4.70 3.90 Rate of events (per 100 patient years) .97 Verdecchia, Hypertens 2004;43:963-968

  18. “It is important to remark that the occurrence of new diabetes was an independent predictor of cardiovascular risk, whereas the use of diuretics, albeit predictive of new diabetes, did not show any independent relation with subsequent cardiovascular events.” Verdecchia, Hypertens 2004;43:963-968

  19. Morbidity and Mortality in Diabetic and Nondiabetic Subjects in the Systolic Hypertension in the Elderly Program Reduction in risk (%) in treated compared with placebo groups Fatal or nonfatal MI, SCD, CABG, or angioplasty All-cause mortality Nonfatal and fatal MI Therapy: low-dose diuretic with B-blocker added if necessary; n = 4736; subjects >60 years of age Curb KD. et al. JAMA 1996;276:1886-1892

  20. 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) From Kostis, et al

  21. Results-6 CV death (%) SHEP-X 14.3 Year Follow-up PLACEBO ACTIVE From Kostis et al

  22. 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. From Kostis, et al

  23. “Intensive control of blood pressure reduces cardiovascular morbidity and mortality in diabetic patients regardless of whether low- dose diuretics, B-blockers, angiotensin- converting enzyme inhibitors, or calcium antagonists are used as first-line treatment.” Grossman, Messerli…Arch Intern Med 2000;?60;2447-2452

  24. Effect of DM on Mortality SHEP-X 13.4 Year Follow-up From Kostis et al

  25. Hypertension Detection and Follow-Up Program Results in Diabetic Subjects* Nondiabetics Diabetics 5-yr all-cause 17% lower No difference mortality in SC group between SC and RC groups Patients with DBPs 90-104 22.2% lower 20.5% lower in mm Hg (466 in SC group SC group** patients) * 1079 patients with history of diabetes or fasting blood sugar > 140 mg/dL ** Although the relative decrease in mortality was similar in the diabetic subjects, the baseline absolute risk was greater in diabetic subjects and absolute benefits were greater in those individuals.

  26. “Plasma glucose levels at entry and diuretic treatment on follow-up were independent predictors of new diabetes” but" while the occurrence of new diabetes was an independent predictor of cardiovascular risk, the use of diuretics, albeit predictive of new diabetes, did not show any independent relation with the subsequent cardiovascular events.” Verdecchia, Hypertens 2004;43:963-968

  27. ALLHAT AHT Age 65+ Amlodipine/Chlorthalidone Relative Risk and 95% Confidence Intervals 0.50 1 2 Favors Amlodipine Favors Chlorthalidone 05/15/03

  28. ALLHAT AHT Age 65+ Lisinopril/Chlorthalidone Relative Risk and 95% Confidence Intervals 0.50 1 2 Favors Lisinopril Favors Chlorthalidone 05/15/03

  29. AHT Age 75+ ALLHAT Amlodipine/Chlorthalidone Relative Risk and 95% Confidence Intervals 0.50 1 2 Favors Amlodipine Favors Chlorthalidone 05/11/03

  30. AHT Age 75+ ALLHAT Lisinopril/Chlorthalidone Relative Risk and 95% Confidence Intervals 0.50 1 2 Favors Lisinopril Favors Chlorthalidone 05/11/03

  31. Systolic Hypertension in the Elderly Program: Influence of Diabetes on Cardiovascular Event Rates 7-Yr Incidence of CV Events (%)

  32. Cardiovascular Events in Diabetics in the Hypertension Optimal Treatment Study CV Events/1000 Patient-Years Major CV Events Myocardial Infarctions CV Mortality CV events were reduced to a greater degree in diabetics who achieved the lowest levels of diastolic blood pressure Hansson L, et al. Lancet 1998;351:1755-1762

  33. Cumulative 5-Year Rates (1000 Patient Years) of Cardiovascular Events in the Systolic Hypertension in the Elderly program Active Active Therapy Placebo Therapy Placebo Major CHD events 9.2 16 6.9 7.6 Nonfatal MI or fatal CHD 7.7 13.1 5.1 5.7 Nonfatal and fatal strokes 9.7 14.4 4.4 7.5 Major cerebrovascular disease events 21.4 31.5 13.3 10.4 Placebo-treated diabetic patients had about 2-3 times the risk of a cardiovascular event as placebo-treated nondiabetics

  34. Systolic Hypertension in the Elderly Trial* Results in Diabetics • Blood pressure changes - difference between therapy • and placebo: -9/-4 mm Hg • In the placebo subjects, the rate of events in diabetics was • twice that in nondiabetics. Rate of events became equal in • treated diabetics compared with nondiabetics • Therapy compared with placebo: • - Reduction of 63% in CV events • - Reduction of 69% in strokes • - Reduction of 70% in CV mortality Absolute benefit was 36 compared with 8 CV events/100 patient years that were prevented in diabetics and nondiabetics, respectively.

  35. Significant Differences in Outcomes in the Clinical Trials Heart Failure: Other Rx Compared to Diuretics/B-Blockers LA Nifedipine 2x INSIGHT Amlodipine 1.4x ALLHAT Verapamil (high risk) 1.3x CONVINCE

  36. Results of Different Levels of Blood Pressure Control in Hypertensive Patients with Type 2 Diabetes: B-Blocker compared with ACE Inhibitor-Based Treatment Program • Better control of blood pressure compared with less aggressive treatment in 8.4-year follow-up of 1148 subjects (achieved blood pressure of 144/82 mm Hg compared with 154/87 mm Hg) • Reduced risk of: • Stroke (44%) • Fatal strokes (58%) • Death related to diabetes (32%) • Heart failure (56%) • Fatal and nonfatal coronary heart disease events (21%) (trend but not significant) • No difference in outcome between a captopril-based and an atenolol- • based treatment program UKPDS . BMJ 1998;317:703-713

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