Hypertension and diabetic nephropathy

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1 Hypertension and diabetic nephropathy Elisabeth R. Mathiesen Professor, Chief Physician, Dr sci Dep. Of Endocrinology Rigshospitalet, University of Copenhagen Denmark

2 Hypertension Brain Eye Heart Kidney Arteries

3 Severe complications to Diabetes Stroke Blindnes Myocardial infarction Heart failure End Stage Renal Failure Amputation of a limb

4 Complications at diagnose of type 2 diabetes Retinopathy 30% Microalbuminuria 20% Arteriosclerosis 20%

5 Hypertension Eye

6 Retinopathy in Type 1 diabetes Background retinopathy Present in 90 % with 15 years of diabetes Maculopathy Present in 25 % with 25 years of diabetes Proliferative retinopathy Present in 50 % with 25 years of diabetes

7 Diabetic Maculopathy

8 Proliferative Diabetic Retinopathy

9 UKPDS Laser treated retinopathy 1% HbA 1c 37% 10/5 mm Hg 35%

11 Prevention of sight-threatening Retinopathy Strict metabolic control Antihypertensive treatment Blocking of the renin angiotensin system Regular screning for retinopathy Laser therapy when needed

12 Cumulative incidence of proliferative retinopathy in type 1 diabetes Cumulative incid dence (%) (n = 113) (n = 130) (n = 113) (n = 244) Duration of diabetes (years)

13 Hypertension Kidney

14 Progression of Diabetic Renal Disease Albuminuria (µg/min) Overt nephropathy Microalbuminuria Normoalbuminuria 40% 60% 2 Time (Years)

15 Clinical diagnosis of diabetic nephropathy Persistent albuminuria (>300 mg/24 h) Presence of diabetic retinopathy No clinical or laboratory evidence of kidney or the renal tract disease other than diabetic glomerulosclerosis

17 The renin-angiotensin-aldosterone system Angiotensinogen Renin Angiotensin I ACE ACE-I Angiotensin II ARB Angiotensin II receptor Spironolactone Aldosterone Aldosterone receptor

18 Angiotensin II Plays a Central Role in Organ Damage Atherosclerosis* Vasoconstriction Vascular hypertrophy Endothelial dysfunction Stroke Hypertension A II AT 1 receptor LV hypertrophy Fibrosis Remodeling Apoptosis Heart failure MI DEATH GFR Proteinuria Aldosterone release Glomerular sclerosis Renal failure *preclinical data LV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate Adapted from Willenheimer R et al Eur Heart J 1999; 20(14): , Dahlöf B J Hum Hypertens 1995; 9(suppl 5): S37 S44, Daugherty A et al J Clin Invest 2000; 105(11): , Fyhrquist F et al J Hum Hypertens 1995; 9(suppl 5): S19 S24, Booz GW, Baker KM Heart Fail Rev 1998; 3: , Beers MH, Berkow R, eds. The Merck Manual of Diagnosis and Therapy. 17th ed. Whitehouse Station, NJ: Merck Research Laboratories 1999: , Anderson S Exp Nephrol 1996; 4(suppl 1): 34 40, Fogo AB Am J Kidney Dis 2000; 35(2):

19 Effect of ACE inhibition on diabetic nephropathy in patients with Type 1 diabetes 40 Captopril Progression to death, dialysis or transplant (%) Placebo p= Follow-up (years) Lewis EJ et al. N Engl J Med. 1993

21 Impact of blood pressure and HbA 1c on decline in GFR in diabetic nephropathy n=301 Decline in GFR (ml/min/ye ear) > 102 < MABP (mm Hg)

22 Antihypertensive treatment in patients with diabetes and kidney involvement ACE- inhibition or AII receptor blocker Diuretics Betablockers Calcium antagonists Others including renin blockers

23 Effective long-term antihypertensive treatment in diabetic nephropathy Reduces albuminuria Reduces the rate of decline in kidney function Postpones end stage renal disease Improves survival

24 Survival in diabetic patients with ESRD in haemodialysis and peritoneal dialysis 1,0 0,9 0,8 Dialysis Modality and Diabetic Patient Survival Age years Proportion Surv viving 0,7 0,6 0,5 0,4 HD PD 0,3 0,2 0, Survival Time (Years) DNS register

25 Survival after kidney transplantation in patients with diabetes 1,0 Patient Survival, Cadaver Grafts, DM vs Non-DM, ,9 0,8 Non-diabetic Diabetic Survival Rate 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0, Years

26 Diabetic nephropathy - costs Dialysis 75,000 $/year Transplantation 15,000 $/year

27 Microalbuminuria - Act now or pay later Albuminuria (µg/min) Overt nephropathy Microalbuminuria Normoalbuminuria 40% 60% 2 Time (Years)

28 Strict metabolic control Microalbuminuria Act now or pay later Antihypertensive treatment Blockade of the renin angiotensin system ACE inhibition Angiotensin II receptor blocking Renin blockers

29 Should all Type 1 diabetic microalbuminuric patients receive ACE inhibitors? - a meta regression analysis (n=698) 62 % reduction in progression to nephropathy 3 times in regression to normoalbuminuria 50 % reduction in UAE at 2 years Preservation of GFR Chaturvedi, Ann Intern Med, 2001

30 Microalbuminuria Higher prevalence of retinopathy, neuropathy and foot ulcers Enhanced cardiovascular morbidity Enhanced all-cause mortality, especially cardiovascular Predict development of diabetic nephropathy

31 Proteinuria Is an Independent Risk Factor for Mortality in Type 2 Diabetes Surv vival (all-cause mortality) Normoalbuminuria (n=191) Microalbuminuria (n=86) Macroalbuminuria (n=51) Years P<0.01 normo vs. micro- and macroalbuminuria P<0.05 micro vs. macroalbuminuria Gall, MA et al. Diabetes 1995;44:1303

32 IRMA 2 Summary 70 % reduction in the risk of progression from microalbuminuria to overt nephropathy with irbesartan 300 mg once daily Observed relative risk reduction was dose dependent Benefits of irbesartan were in addition to blood pressure reduction alone Irbesartan was safe and well tolerated in this population

33 The Steno Type 2 study 160 Type 2 diabetic patients with microalbuminuria Pharmacological Tx - hyperglycaemia - hypertension - dyslipidaemia - microalbuminuria Behavior modification - exercise - diet - smoking Gæde et al, Lancet, 1999 nephropathy Odds ratio of progression retinopathy autonomic neuropathy 0 0,5 1 1,5 2 Favours intensive therapy peripheral neuropathy Favours standard therapy

34 End-stage renal failure requiring dialysis 6 patients in the original conventionally treated group versus 1 patient in the intensively treated group progressed to end-stage renal disease requiring dialysis Propability for dialysis s treatment (%) log-rank p= Years of follow-up

35 Steno-2 Post Trial: Mortality Percentage of patients dying (%) Numbers at risk Conventional Intensive 0 HR=0.54 ( ), P= Years of follow-up

36 Steno-2 Post Trial: Mortality 80 Number of mortalities patients died in the intensive group compared to 40 patients in the conventional group HR = 0.54 ( ), P= Intensive Conventional 100 Percentage of mortalities Intensive Conventional 30% of patients died in the intensive group compared to 50% of patients in the conventional group Absolute risk reduction = 20%

37 Steno-2: Major papers Lancet 1999; 353: New Engl J Med 2003; 348:

38 Cumulative incidence of diabetic nephropathy in type 1 diabetes Cumulative incid dence (%) Duration of diabetes (years) (n = 113) (n = 130) (n = 113) (n = 244)

39 Cost of care- The Helsinki Study Figure 4. Mean excess costs of health care of people with diabetes (USD/person/year) with and without complications by the type of diabetes. Tero Kangas

40 Hypertension in diabetes Brain Eye Heart Kidney Arteries

41 Threashold for initiating antihypertensive treatment 160/95 when I was young 140/90 Many years 130/80- Recent international guidelines

42 HOT Study: Significant Benefit From Intensive Treatment in the Diabetic Subgroup 25 p=0.005 for trend 20 Major cardiovascular events/1,000 patient-years Target Diastolic Blood Pressure (mmhg) Hansson, Lancet 1998;351:1755

43 Goal for antihypertensive treatment 140/90 Many years 130/80 - Recent guidelines 120 systolic not superior (2010)

44 Type of antihypertensiva Diet with low-salt intake Blocking the renin angiotensin system ACE- inhibitors Angiotensin receptor blockers Renin antagonist Diuretics Thiazides Loop diuretics Aldosteron inhibitors Calcium antagonist Betablocker Others

45 Number of antihypertensiva 2-4 different types of drugs are often nessesary Start with blockers of the renin angiotensin system or the cheapest drug available. Consider start with combination of blockers of the renin angiotensin system and diuretics one tablet BP > 145/90 Microalbuminuria

46 Conclusion: Early antihypertenisve treatment prevents diabetic complications Stroke Blindnes Myocardial infarction Heart failure End Stage Renal Failure Amputation of a limb

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