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The Management of Hypertension in Diabetes

The Management of Hypertension in Diabetes. James T. Lane, MD Professor The Harold Hamm Chair in Clinical Diabetes Research The Harold Hamm  Diabetes Center. Overview. Epidemiology Renin-angiotensin-aldosterone system in hypertension and diabetes Target organ protection

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The Management of Hypertension in Diabetes

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  1. The Management of Hypertension in Diabetes James T. Lane, MD Professor The Harold Hamm Chair in Clinical Diabetes Research The Harold Hamm  Diabetes Center

  2. Overview • Epidemiology • Renin-angiotensin-aldosterone system in hypertension and diabetes • Target organ protection • Microvascular complications • Macrovascular complications • Clinical Trials • What is the current goal for blood pressure control in diabetes and how do you get there?

  3. Epidemiology • 12% of Americans have hypertension and diabetes • 75% of people with diabetes have hypertension • Obesity is an independent predictor of hypertension; 40% of patients with hypertension have a BMI > 30 kg/m2 • Microvascular and macrovascular complications are more common in patients with diabetes who also have hypertension

  4. Effects of Angiotensin II • Pressor effect • Proinflammatory • Oxidative stress • Salt retention • Insulin resistance • Through PI3 kinase and downstream Akt pathway • Reduction in NO production within endothelium • Increases vasoconstriction • Increases TGF-b production and hepatic fibrosis

  5. Adipokine production • IL-I • TNF-a • Plaminogen activator inhibitor-1 • IL-6 • Free fatty acids • Leptin (increases sympathetic activity) • Angiotensinogen

  6. Other Effects of Obesity on Metabolism • Monocyte infiltration • Ectopic fat distribution • Skeletal muscle • Liver • b-cells • Increased fatty acid production associated with cardiac insulin resistance and fibrosis • Decreased adiponectin

  7. Additional Factors Favoring Hypertension in Diabetes • Increased sympathetic tone • Endothelial dysfunction associated with hyperglycemia and AGEs, increased free radicals, and altered response to NO • Hyperglycemia stimulates intrarenal production of angiotensin II with increased salt and water retention at the proximal tubule • Genetic factors

  8. Contemporary View of the Renin-Angiotensin System (Pro)Renin Receptor Angiotensinogen Fibrosis Hypertrophy Renin Ang I Ang[1-10] ACE2 Ang[1-9] ACE NEP ACE NEP Vasodilation Natriuresis Antiarrhythmic Antiproliferative AT1R Mas receptor Vasoconstriction Antinatriuresis Aldosterone release ACE2 Ang II Ang[1-8] Ang[1-7] Vasodilation Natriuresis Antiproliferative AT2R ACE Aminopeptidase A Ang III Ang[2-8] Inactive Metabolites Aminopeptidase N AT4R Ang IV Ang[3-8] Fibrosis Inflammation ACE = Angiotensin Converting Enzyme NEP = Neutral Endopeptidase

  9. Inhibition of RAAS and Prevention of Diabetes Complciations: Nephropathy • In 1993, Lewis et al. published the first large study of the use of ACE inhibitors in patients with type 1 diabetes with nephropathy (Lewis et al. NEJM 329:1456, 1993 • Decreased proteinuria • Decreased time to dialysis • ACE inhibitors and ARBs have demonstrated improvement in renal function when used in patients with type 1 or type 2 diabetes with hypertension or microalbuminuria • ACE inhibitors and ARBs have also been associated with decreased albuminuria • Renal protection has not been shown for patients without hypertension or micoralbuminuria • Microabluminuria has also been shown to be a marker of increased cardiovascular disease

  10. Blood Pressure and Progression of Diabetic Kidney Disease National Kidney Foundation, Am J Kid Dis 39 (Suppl 1): S1-S321

  11. Cardiovascular Death Risk and Proteinuria In Diabetes National Kidney Foundation, Am J Kid Dis 39 (Suppl 1): S1-S321

  12. Microalbuminuria and Cardiovascular Morbidity in Type 2 Diabetes National Kidney Foundation, Am J Kid Dis 39 (Suppl 1): S1-S321

  13. Systolic BP Goal and Renal Progression Flynn and Bakris. Curr Hypertens Rep 2011

  14. Inhibition of RAAS and Prevention of Diabetes Complications: Retinopathy • Not as well studied as nephropathy • Benefits harder to study and suggest that therapy needs to begin earlier • Evidence for RAAS in the retina • Diabetic Retinopathy Candesartan Trials Programme with primary and secondary prevention component • Benefit on prevention but not progression • Lancet 372f:1394, 2008

  15. Enalapril/Losartan Effect on Retinopathy Mauer et al. N Engl J Med 361: 40, 2009

  16. Inhibition of RAAS and Cardiovascular Disease in Diabetes • Trials for prevention of CV endpoint required larger patient populations than those used to study nephropathy • These have subsequently shown that CV endpoints are improved with ACE inhibitors and ARBs

  17. UKPDS: Tight Blood Control and Risk of Macrovascular and Microvascular Complications in Type 2 Diabetes • 1148 patients randomized to right control or less tight control • Tight control defined as < 150/85 mm Hg • Less tight control defined as < 180/105 mm Hg • Half of tight control to ACE inhibitors (captopril) and half to beta blockers (atenolol) • Mean follow-up of 8.4 years • Part of larger UKPDS with follow-up every 3-4 months

  18. UKPDS: Results • Mean blood pressure during follow-up • Tight control: 144/82 mm Hg • Less tight control: 154/87 mm Hg • 1/3 patients in tight control group required 3 or more medications • 24% decrease in diabetes-related endpoints • 32% decrease in deaths related to diabetes • 37% decrease in microvascular endpoints • Mostly related to reduced risk of laser treatment • 44% decrease in strokes BMJ 317: 703, 1998

  19. UKPDS: Efficacy of Captopril vs Atenolol on Risk Reduction for • Of 758 patients allocated to tight control, 400 were on captopril and 358 on atenolol • The agents were equally effective in lowering blood pressure • Similar effects on reducing macrovascular events and microvascular complications BMJ 317:713, 1998

  20. HOT: Hypertension Optimal Treatment • 18,790 patients from 26 countries, age 50 -80, and diatolic blood pressure between 100-115 mm Hg were recruited • Patients were randomized to 3 groups based on diastolic pressure goal (< 90, < 85, and < 80 mm Hg) • Primary endpoint was composite macrovascular outcome of non-fatal MI, non-fatal stroke, or CV death • Major finding was that patients with diabetes had a 51% reduction in primary endpoint (target < 80 vs target < 90 mm Hg, p = 0.005) • No increase in side effects. Question J-curve DBP < 60 Hansson et al. Lancet 351:1755, 1998

  21. ABCD Trial: Appropriate Blood Pressure Control in Diabetes • Compared intensive versus vs moderate blood pressure control on the incidence and progression of complications in type 2 diabetes • 470 patients with entry diastolic blood pressure > 90 mm Hg followed for 5.3 years • Moderate pressure: 80 – 89 mm Hg • Intensive pressure: <75 mm Hg • Compared effect of CCB vs ACE inhibitor • Endpoints: Change in creatinine clearance as primary and development of microvascualr complications and CV disease as secondary

  22. ABCD: Results • BP attained for last 4 years • 132/78 mm Hg for intensive • 138/86 mm Hg for moderate • There was no difference in creatinine clearance between moderate and intensive • No difference between groups in those that progressed from normo to microalbuminuria or micro- to macroalbuminuria • Intensive therapy had a loer overall incidence of death, 5.5 vs 10.7%, p = 0.037 • No difference in progression of retinopathy or neuropathy • No difference in results based on CCB or ACE inhibitor Estacio et al. Diabetes Care 23, Suppl 2: 854, 2000

  23. ONTARGET • Purpose: compare telmisartan (ARB) with ramipril (ACEI), as well as combination of telmisartan plus ramiprilvsramipril alone, as treatment for prevention of vascular events in patients with CVD and patients with diabetes and known microvascular complications, but no CHF • Noninferiority trial • Primary endpoint a composite of death from CV causes, MI, stroke, or hospitalization for CHF

  24. ONTARGET:Results • 25,620 patients randomized • Telmisartan was equivalent to ramipril in patients with vascular disease or high-risk diabetes • The combination of telmisartan plus ramipril vs ramipril alone was no better, but there were more adverse events associated with the combination N Engl J Med 358:1547, 2008

  25. HOPE Trial • Objective: to evaluate the effect of ramipril (ACEI) on the prevention of a CV composite endpoint of death from CV causes, MI, or stroke • Secondary outcomes included death from any cause, need for revascularization, hospitalization for unstable angina, heart failure, and the development of diabetes

  26. HOPE: Results- 1 • 9297 patients randomized to ramiprilvs placebo • 8162 had cardiovascular disease • 4355 had hypertension • 3577 had diabetes • Ramipril-treated patients reached primary endpoint at rate lower than placebo (14.0 vs 17.8%, p < 0.001) • Ramipril reduced rate of death from any CV cause (6.1 vs 8.1%, p < 0.001)

  27. Hope: Results -2 • Ramipril decreased rate of MI (9.9 vs 12.3%, p < 0.001) • Ramipril decreased stroke (3.4 vs 4.9%, p < 0.001) • Ramiprildecresed death from any cause (10.4 vs 12.2%, p = 0.005) • In addition, revascularization, rate of heart failure, rate of cardiac arrest and complications related to diabetes were all decreased by ramipril • There was also a decrease in the rate of new diagnosis of diabetes N Engl J Med 342:145, 2000

  28. HOPE Trial Results N Engl J Med 342:145, 2000

  29. HOPE Trial N Engl J Med 342:145, 2000

  30. Hope Trial N Engl J Med 342:145, 2000

  31. ADVANCE • 215 centers in 20 coun tries with 11,140 patients with type 2 diabetes randomized to fixed combination of perindopril and indapamide or matching placebo, irrespective of initial blood pressure or use of other agents • Primary endpoints were composites of major macro- and microvascular events • Death from CV disease, non-fatal stroke or non-fatal MI • New or worsening renal or diabetic eye disease

  32. ADVANCE Results • 4.3 years of follow-up • Compared to placebo, there was a drop in pressure of 5.6/2.2 mm Hg • There was not a significant decrease in macrovasular (p = 0.16) events or microvascular events (p = 0.16) separately • There was a 9% decrease in combination(p=0.04) • There was a decrease in CV death (p = 0.03) and death from any cause (p = 0.03) Lancet 370:829, 2007

  33. ACCORD • Hypothesis: Targeting normal systolic blood pressure ( <120 mm Hg) in patients with type 2 diabetes and at high risk for cardiovascular events reduces major cardiovascular events • 4733 patients were randomized to intensive therapy (systolic BP < 120 mm Hg) or standard therapy (systolic BP < 140 mm Hg) • Primary compostie outcome was nonfatal MI, nontatalstorke, or death from CV causes • Mean follow-up time was 4.7 years

  34. ACCORD Results • There was no difference between groups, in terms of reaching the primary outcome composite • There was a decrease in rates of stroke and lesser rates of progression of albuminuria • There were more adverse events in the intensive group • This study has been a source of commentaries and discussion about how far to go with BP lowering N Engl J Med 362: 1575, 2010

  35. Combination Therapy • Because multiple agents are needed to control blood pressure with diabetes, consideration should be given for what additional agents might be used • An ideal agent should not increase insulin resistance • Beta blockers should be used post-MI, but they do have the risk of masking hypoglycemia • Thiazide diuretics can be used at low doses • When CCBs are used, dihydropyridine CCBs act differently than non-dihydroprydine CCBs • Dihydropyridine CCBs do not slow nephropathy when microalbuminuria is present • Dihydropuridine CCBs increase insulin resistance

  36. ACCOMPLISH • Hypothesis: Treatment with ACE inhibitor plus dihydropyridine CCB is more effective in reducing the rate of CV events than ACE inhibitor plus thiazide diuretic • Study population made up of 548 centers from 5 nations and included patients with hypertension and at high risk for CV events (not a diabetes-specific population) • This study used a composite CV endpoint as its primary endpoint • No difference blood pressure control • There were fewer patients reaching the primary endpoint with CCB plus ACE inhibitor and fewer fatal and non-fatal Mis • Did not look at renal endpoints Jamerson et al. N Engl J Med 359:2417, 2008

  37. Example of a normal ambulatory blood pressure pattern plotted by the DABL® Program. O'Brien E et al. BMJ 2001;322:1110-1114 ©2001 by British Medical Journal Publishing Group

  38. Systolic and diastolic hypertension without night time dip. O'Brien E et al. BMJ 2001;322:1110-1114

  39. Current ADA Recommendations for Treatment of Blood Pressure • Blood pressure should be measured at every clinic visit • Patients found to have blood pressures > 130/80 mm Hg, and confirmed on a separate day, have hypertension and should be treated • Lifestyle intervention includes weight loss, reduced sodium intake, moderation of alcohol, and increased physical activity • Pharmacologic therapy for patients should include either an ACE inhibitor or an ARB • Also recommended for patients with persistent microalbuminuria or higher levels of albumin excretion American Diabetes Association. Diabetes Care 34 (Suppl 1): S27-S29, 2011

  40. Achieving Antihypertensive Goals National Kidney Foundation, Am J Kid Dis 39 (Suppl 1): S1-S321

  41. Zanchetti et al. J Hypertens 27:923, 2009

  42. Sleight et al. J Hypertens 27:1360, 2009

  43. Conclusions • Hypertension occurs in 75% of patients with type 2 diabetes • Hypertension in patients with type 1 diabetes is also common • Hypertension is a promoter of macro- and microvascular disease • There is evidence to link the RAAS with hypertension in patients with obesity, metabolic syndrome, and patients with type 2 diabetes

  44. Conclusions • Pharmacologic treatment should commence with blood pressure > 130/80 mm Hg documented on more than one occasion • In patients with diabetes, the drug of choice should be a drug that blocks the RAAS • This includes an ACE inhibitor or ARB • Other drugs that block the RAAS are currently being evaluated • It is common to use more than 2 agents in order reach blood pressure goals in patients with type 2 diabetes

  45. Conclusions • There is no data that supports the use of ACE inhibitors or ARBs prior to the development of hypertension (BP > 130/80 mm Hg) or microalbuminuria • Further lowering of blood pressure to values < 120/80 mm Hg is not associated with an improvement in cardiovascular events and is associated with increased side effects

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