Hypertension and diabetic nephropathy Elisabeth R. Mathiesen Professor, Chief Physician, Dr sci Dep. Of Endocrinology Rigshospitalet, University of Copenhagen Denmark
Hypertension Brain Eye Heart Kidney Arteries
Severe complications to Diabetes Stroke Blindnes Myocardial infarction Heart failure End Stage Renal Failure Amputation of a limb
Complications at diagnose of type 2 diabetes Retinopathy 30% Microalbuminuria 20% Arteriosclerosis 20%
Hypertension Eye
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
Diabetic Maculopathy
Proliferative Diabetic Retinopathy
UKPDS Laser treated retinopathy 1% HbA 1c 37% 10/5 mm Hg 35%
Prevention of sight-threatening Retinopathy Strict metabolic control Antihypertensive treatment Blocking of the renin angiotensin system Regular screning for retinopathy Laser therapy when needed
Cumulative incidence of proliferative retinopathy in type 1 diabetes Cumulative incid dence (%) 60 40 20 0 1965 1969 (n = 113) 1970 1974 (n = 130) 1975 1979 (n = 113) 1979 1984 (n = 244) 0 10 20 30 40 Duration of diabetes (years)
Hypertension Kidney
Progression of Diabetic Renal Disease Albuminuria (µg/min) 2000 200 20 Overt nephropathy Microalbuminuria Normoalbuminuria 40% 60% 2 Time (Years)
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
The renin-angiotensin-aldosterone system Angiotensinogen Renin Angiotensin I ACE ACE-I Angiotensin II ARB Angiotensin II receptor Spironolactone Aldosterone Aldosterone receptor
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): 997 1008, Dahlöf B J Hum Hypertens 1995; 9(suppl 5): S37 S44, Daugherty A et al J Clin Invest 2000; 105(11): 1605 1612, Fyhrquist F et al J Hum Hypertens 1995; 9(suppl 5): S19 S24, Booz GW, Baker KM Heart Fail Rev 1998; 3: 125 130, Beers MH, Berkow R, eds. The Merck Manual of Diagnosis and Therapy. 17th ed. Whitehouse Station, NJ: Merck Research Laboratories 1999: 1682 1704, Anderson S Exp Nephrol 1996; 4(suppl 1): 34 40, Fogo AB Am J Kidney Dis 2000; 35(2):179 188
Effect of ACE inhibition on diabetic nephropathy in patients with Type 1 diabetes 40 Captopril Progression to death, dialysis or transplant (%) Placebo 30 20 p=0.006 10 0 0 1 2 3 4 Follow-up (years) Lewis EJ et al. N Engl J Med. 1993
Impact of blood pressure and HbA 1c on decline in GFR in diabetic nephropathy n=301 Decline in GFR (ml/min/ye ear) 8 6 4 2 0 6.1 4.9 1.5 > 102 < 102 3.7 MABP (mm Hg)
Antihypertensive treatment in patients with diabetes and kidney involvement ACE- inhibition or AII receptor blocker Diuretics Betablockers Calcium antagonists Others including renin blockers
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
Survival in diabetic patients with ESRD in haemodialysis and peritoneal dialysis 1,0 0,9 0,8 Dialysis Modality and Diabetic Patient Survival Age 20-70 years 1990-97 Proportion Surv viving 0,7 0,6 0,5 0,4 HD PD 0,3 0,2 0,1 0 1 2 3 4 5 6 Survival Time (Years) DNS register
Survival after kidney transplantation in patients with diabetes 1,0 Patient Survival, Cadaver Grafts, DM vs Non-DM, 1990-99 0,9 0,8 Non-diabetic Diabetic Survival Rate 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0,0 0 1 2 3 4 5 6 7 8 9 10 Years
Diabetic nephropathy - costs Dialysis 75,000 $/year Transplantation 15,000 $/year
Microalbuminuria - Act now or pay later Albuminuria (µg/min) 2000 200 20 Overt nephropathy Microalbuminuria Normoalbuminuria 40% 60% 2 Time (Years)
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
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
Microalbuminuria Higher prevalence of retinopathy, neuropathy and foot ulcers Enhanced cardiovascular morbidity Enhanced all-cause mortality, especially cardiovascular Predict development of diabetic nephropathy
Proteinuria Is an Independent Risk Factor for Mortality in Type 2 Diabetes Surv vival (all-cause mortality) 1.0 0.9 0.8 0.7 0.6 Normoalbuminuria (n=191) Microalbuminuria (n=86) Macroalbuminuria (n=51) 0.5 0 1 2 3 4 5 6 Years P<0.01 normo vs. micro- and macroalbuminuria P<0.05 micro vs. macroalbuminuria Gall, MA et al. Diabetes 1995;44:1303
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
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
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 (%) 14 12 10 8 6 4 2 0 log-rank p=0.039 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Years of follow-up
Steno-2 Post Trial: Mortality Percentage of patients dying (%) 70 60 50 40 30 20 10 Numbers at risk Conventional Intensive 0 HR=0.54 (0.32-0.89), P=0.015 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Years of follow-up 80 80 80 78 77 75 69 72 63 65 51 62 43 57 30 39
Steno-2 Post Trial: Mortality 80 Number of mortalities 70 60 50 40 24 patients died in the intensive group compared to 40 patients in the conventional group HR = 0.54 (0.32-0.89), P=0.015 30 20 10 0 Intensive Conventional 100 Percentage of mortalities 90 80 70 60 50 40 30 20 10 0 Intensive Conventional 30% of patients died in the intensive group compared to 50% of patients in the conventional group Absolute risk reduction = 20%
Steno-2: Major papers Lancet 1999; 353: 617-22 New Engl J Med 2003; 348: 383-93
Cumulative incidence of diabetic nephropathy in type 1 diabetes Cumulative incid dence (%) 50 40 30 20 10 0 0 10 20 30 40 Duration of diabetes (years) 1965 1969 (n = 113) 1970 1974 (n = 130) 1975 1979 (n = 113) 1979 1984 (n = 244)
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
Hypertension in diabetes Brain Eye Heart Kidney Arteries
Threashold for initiating antihypertensive treatment 160/95 when I was young 140/90 Many years 130/80- Recent international guidelines
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 15 10 5 0 90 85 80 Target Diastolic Blood Pressure (mmhg) Hansson, Lancet 1998;351:1755
Goal for antihypertensive treatment 140/90 Many years 130/80 - Recent guidelines 120 systolic not superior (2010)
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
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
Conclusion: Early antihypertenisve treatment prevents diabetic complications Stroke Blindnes Myocardial infarction Heart failure End Stage Renal Failure Amputation of a limb