Prevention And Treatment of Diabetic Nephropathy. MOH Clinical Practice Guidelines 3/2006 Dr Stephen Chew Tec Huan

Prevention And Treatment of Diabetic Nephropathy MOH Clinical Practice Guidelines 3/2006 Dr Stephen Chew Tec Huan

Prevention Tight glucose control reduces the development of diabetic nephropathy

Progression Of Complications In Type 1 Diabetics With Intensive And Conventional Treatment (DCCT) - Primary Prevention Complications Conventional Therapy Intensive Therapy Risk Reduction Rate/100 patient-year % (95% CI) Urinary Alb (mg/24hr) >40 3.4 2.2 34 (2-56) >300 0.3 0.2 44 (-124-86) Clinical Nephropathy at 5 years 9.8 3.1 69 (24-87) The Diabetes Control And Complications Trial Research Group, NEJM 1993

Progression Of Complications In Type 1 Diabetics With Intensive And Conventional Treatment (DCCT) -Secondary Prevention Complications Conventional Therapy Intensive Therapy Risk Reduction Rate/100 patient-year % (95% CI) Urinary Alb (mg/24hr) >40 5.7 3.6 43 (21-58) >300 1.4 0.6 56 (18-76) Clinical Nephropathy at 5 years 16.1 7.0 57 (29-73) The Diabetes Control And Complications Trial Research Group, NEJM 1993

UKPDS Prospective randomized trial in type II diabetics Selected newly diagnosed Type II DM with little or no prexisting renal complications Compared the effect of intensive therapy and conventional therapy on development of complications.

UKPDS Patients on the intensive therapy arm were treated with a sulphonylurea, or if needed insulin was added, to keep fasting blood glucose <7mmo/l Conventional therapy was started with diet, and a sulphonylurea added to keep fasting blood glucose <15mmol/l. Patients followed up 10 years

Effect of Intensive Therapy And Conventional Therapy On Renal End Points At Nine Years In Type 2 DM with Normoalbuminuria Intensive (FG <7) Conventional (FG<15) p RR for intensive (99% CI) Microalbuminuria 19.2 25.4 <0.001 0.76 (0.62-0.91) Proteinuria 4.4 6.5 0.02 0.67 (0.42-1.07) Doubling of serum creatinine 0.91 3.52 <0.01 0.26 (0.07-0.91) UK Prospective Diabetes Study Group, Lancet 1998

Prevention Blood pressure control reduces the development of microvascular disease in diabetics

Tight BP control reduces microvascular events Tight : 144/82 mm Hg achieved Less: 154/72 mmhg achieved ight blood pressure control and risk of macrovascular and icrovascular complications in type 2 diabetes: UKPDS 38. K Prospective Diabetes Study Group UK Prospective Diabetes Study Group, BMJ 1998;317:703-713

Tight BP control reduces microvascular events ight blood pressure control and risk of macrovascular and icrovascular complications in type 2 diabetes: UKPDS 38. K Prospective Diabetes Study Group UK Prospective Diabetes Study Group, BMJ 1998;317:703-713

Tight Blood Pressure Control Confers CV Benefits in Diabetic Patients The benefits of lowering BP in the UKPDS were greater than those achieved through glycemic control 0 Stroke Any DM endpoint DM death Microvascular complications Reduction in Risk (%) -10-20 -30-40 -50 DM=diabetes mellitus FPG=fasting plasma glucose *P<0.05. * * Tight glucose control (FPG < 107 mg/dl) * Tight BP control (150/85 mmhg) * UKPDS 35. BMJ. 2000;321:405-412; UKPDS 38. BMJ. 1998;317:703-713.

Screening Screening for albuminuria should begin 5 years after the diagnosis of type 1 diabetes It should be done immediately after the diagnosis of type 2 diabetes. Screening for albuminuria should be done annually

ABNORMAL ALBUMIN EXCRETION Timed (ug/min) 24 hour (mg/day) Alb/Cr (mg/gm) Normal <20 <30 <30 Microalbuminuria 20-200 30-300 30-300 Macroalbuminuria >200 >300 >300 Microalbuminuria needs to be persistent over 6 months

Screening Serum creatinine should be done annually and the GFR estimated Cockcroft Gault equation (Age/weight/cr) MDRD formula (Age, creatinine)

Renal insufficiency in the absence of albuminuria and retinopathy among adults with type 2 diabetes mellitus 3 rd NHNES; > 40 yrs, T2 DM; Survey 13% of type 2 DM with CRI (MDRD) DR 28% Microalbuminuria 45% Macroalbuminuria 19% 30% of CRI with neither DR nor albuminuria Kramer HJ et al; JAMA 2003; 289; 3273-77

Detection of Microalbuminuria

Impact of Blood Pressure Reduction on Mortality in Diabetes Trial Conventional care Intensive care Risk reduction P-value UKPDS 154/87 144/82 32% 0.019 HOT 144/85 140/81 66% 0.016 Mortality endpoints are: UK Prospective Diabetes Study (UKPDS) diabetes related deaths Hypertension Optimal Treatment (HOT) Study cardiovascular deaths in diabetics Turner RC, et al. BMJ. 1998;317:703-713. Hansson L, et al. Lancet. 1998;351:1755 1762.

Drug choices in the non-albuminuric hypertensive diabetic patient Blood pressure control reduces cardiovascular events Initial drug choices include Angotensin converting enzyme inhibitors Angiotensin receptor blockers Beta blockers Diuretics Calcium channel blockers

ABCD: Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes. 470 hypertensive diabetics DBP> 90 2 x 2; nislodipine vs enalapril; Intensive versus moderate 5 year follow up Intensive BP 132/78 vs Mod 138/76 Results GFR decline no difference Normo to Micro: 25% vs 18 % (p 0.20 ns) Micro to Macro: 16 % vs 25% (p 0.28 ns) Estacio RO et al; Diabetes Care 2000; 23; Suppl 2 B 54-64

Blood Pressure Target The blood pressure target in all diabetics should be less than 130/80 Diabetics with proteinuria in excess of 1 gram should attempt to achieve values of less than 125/75 mm Hg

COURSE OF GFR, ALBUMINURIA, MEAN ARTERIAL BLOOD PRESSURE IN 9 IDDM PATIENTS TREATED WITH ANTIHYPERTENSIVES 125 MAP (mmhg) 95 105 GFR (ml/min/1.73m2) 45 1250 Albuminuria (ug/min) 250 0 9 years Parving HH et al; Am J Kidney Dis. 1993 Jul;22(1):188-95

GFR (ml/min/year) Meta Analysis: Lower Mean BP Results in Slower Rates of Decline in GFR in Diabetics and Non-Diabetics MAP (mmhg) 95 98 101 104 107 110 113 116 119 0-2 -4-6 -8-10 -12-14 130/85 140/90 r = 0.69; P < 0.05 Untreated HTN Parving HH, et al. Br Med J. 1989. Moschio G, et al. N Engl J Med. 1996. Viberti GC, et al. JAMA. 1993. Bakris GL, et al. Kidney Int. 1996. Klahr S, et al. N Eng J. Med 1994. Bakris GL. Hypertension. 1997. Hebert L, et al. Kidney Int. 1994. The GISEN Group. Lancet. 1997. Lebovitz H, et al. Kidney Int. 1994. Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661. Reprinted by permission, Harcourt Inc. Slide Source HypertensionOnline www.hypertensiononline.org

Mean glomerular filtration rate (GFR) decline and achieved follow-up blood pressure in study B* GFR 13-24; n = 255 Peterson, J. C. et. al. Ann Intern Med 1995;123:754-762

Mean glomerular filtration rate (GFR) decline and achieved follow-up blood pressure in study A* GFR 22-55ml/min; n = 585 Peterson, J. C. et. al. Ann Intern Med 1995;123:754-762

Combination Therapy Needed to Achieve Target SBP Goals Trial/SBP Achieved UKPDS (144 mm Hg) RENAAL(141 mm Hg) ALLHAT (138 mm Hg) IDNT HOT (138 mm Hg) (138 mm Hg) INVEST (133 mm Hg) ABCD MDRD AASK (132 mm Hg) (132 mm Hg) (128 mm Hg) 1 2 3 4 Number of BP Medications Bakris GL et al. Am J Kidney Dis. 2000;36:646-661.

Drug choices in early nephropathy The initial therapy of choice should include and ACE inhibitor or an ARB

Drug Choices in Type 1 diabetics with overt nephropathy In the presence of overt nephropathy in type 1 diabetes, there is evidence that an ACE inhbitor can retard the progression of otherwise progressive renal disease

ACE-I Is More Renoprotective Than Conventional Therapy in Type 1 Diabetes % with doubling of baseline creatinine 100 75 50 25 0 Baseline creatinine >1.5 mg/dl & overt proteinuria Placebo n=202 P<.001 Captopril n=207 0 1 2 3 4 Placebo BP achieved 129-136/80-84; Captopril BP achieved 128/134/77-82 Years of follow-up 50% ollaborative Study Group Trial Lewis EJ, et al. N Engl J Med. 1993;329(20):1456-1462.

Drug choices in type 2 diabetics with overt nephropathy In type 2 diabetes with overt nephropathy, either an ACE inhibitor or an ARB may be used to retard the progression of renal disease.

Long-Term Benefits of ACE Inhibition in Normotensive Type 2 Diabetics With Microalbuminuria Proteinuria (mg/24 h) 460 420 380 340 300 260 220 180 140 100 60 Placebo (n=45) * ** *** *** Enalapril Percentage of initial value 100/creatinine 110 105 100 95 90 85 80 Enalapril (n=49) * * Placebo 20 0 1 2 3 4 5 Years *p<0.05; **p<0.01; p<0.02; ***p<0.005 75 0 1 2 3 4 5 Years Ravid et al. Ann Intern med. 1993; 118(8):577-581

ARBs Can Reduce Diabetic Renal Disease Progression 30 RENAAL 30 IDNT Doubling of serum creatinine concentration (% of patients) 25 20 15 10 5 p = 0.006 rr 25% 25 20 15 10 5 p = 0.003 rr 20% p < 0.001 rr 23% 0 Losartan Placebo 0 Irbesartan Amlodipine Placebo n = 1513; 3.45 years n = 1715; 2.6 years Brenner et al. N Engl J Med 2001;345:861 869; Lewis et al. N Engl J Med 2001;345:851 860

IRMA II Irbesartan vs Placebo Primary Endpoint at 2 Years Total # of Progression to Nephropathy Patients n % Unadjusted Risk Reduction P Value Adjusted* Risk Reduction P Value 300 mg Irbesartan 194 10 5.2 70% <0.001 68% <0.001 150 mg Irbesartan 195 19 9.7 39% 0.08 44% 0.05 Placebo 201 30 14.9 - - - - For irbesartan vs placebo (the significance level for the primary endpoint was 0.025) *Hazard ratios were adjusted for baseline level of microalbuminuria and blood pressure achieved during the study Parving HH, et al. N Engl J Med. 2001;345(12):870-878.

IRMA II Change in Urinary Albumin Excretion* 20 10 % change in urinary albumin excretion 0-10 -20-30 -40-50 Placebo 150 mg of irbesartan 300 mg of irbesartan 0 3 6 12 18 22 24 Months of Follow-up *P<0.001 for difference between both irbesartan groups and placebo Parving HH, et al. N Engl J Med. 2001;345(12):870-878.

Incidence of Diabetic Nephropathy (%) 20 15 10 5 0 Placebo (n) Irbesartan 150 mg (n) Irbesartan 300 mg IRMA II Incidence of Progression to Diabetic Nephropathy 0 3 6 12 18 22 24 201 201 164 154 139 195 195 167 161 148 194 P<0.001 for difference between 300 mg irbesartan group and placebo Placebo Months of Follow-up 150 mg of irbesartan 300 mg of irbesartan 129 142 194 180 172 159 150 49 14.9% 36 45 9.7% 5.2% Parving HH, et al. N Engl J Med. 2001;345(12):870-878.

Drug Choices in type 2 diabetics with early nephropathy Both an ARB and ACE inhibitor demonstrate similar benefit in reducing a decline in the GFR

Inclusion criteria 250 patients Inclusion criteria Male or female, 35 80 years Type 2 diabetes (onset >40 years) on diet ± OHA or insulin ACE inhibitor for 3 months (ACE inhibitor tolerant) Mild-to-moderate hypertension (BP 180/95 mmhg) Barnett et al. N Engl J Med 2004;351:1952 1961. Normal gross renal morphology 12 months

Outcomes Primary endpoint Change in GFR after 5 years Secondary endpoints Changes in GFR after 1, 2, 3 and 4 years Changes in UAER and serum creatinine after 1, 2, 3, 4 and 5 years Incidence of clinical events Barnett et al. N Engl J Med 2004;351:1952 1961. (end-stage renal disease, myocardial infarction,

Barnett et al. N Engl J Med 2004;351:1952 1961. ARB vs ACE inhibitors in type 2 diabetes and incipient nephropathy Total GFR p = NS Change in GFR Telmisartan Enalapril 0 ml/min/1.73m 2 100 90 80 70 60 50 40 30 20 10 0 Telmisartan Enalapril ml/min/1.73m 2-5 -10-15 -20-25 -17.9 p = NS -14.8 Baseline After 5 years *All patients, LOCF; 250 patients; 5 years follow up p = NS, telmisartan vs enalapril

Drug choices in type 2 diabetics with overt nephropathy In type 2 diabetes with overt nephropathy, either an ACE inhibitor or an ARB may be used to retard the progression of renal disease.

Problems of use of ACE inhibitors Hyperkalaemia Acute renal failure with underlying bilateral renal artery stenosis

SBP (mmhg) 170 155 140 Impact of ACE-I I on BP and GFR: Acute and Chronic Effects * * * GFR ml/min/1.73m 2 90 85 80 75 70 65 * * 125 Baseline 1 Month *P<0.05 compared to baseline 5.6 Yrs Month off ACE-I +Clonidine Bakris GL, Weir MR. Arch Intern Med. 2000;160(5):685-93. American Medical Association 60 Baseline 1 Month 5.6 Yrs Month off ACE-I +Clonidine Slide Source HypertensionOnline www.hypertensiononline.org

Recommended Practices The serum creatinine and potassium should be checked within 4 weeks of initiation of treatment to detect any rise in the serum creatinine of hyperkalaemia

The effect of dietary protein restriction on the progression of diabetic and nondiabetic renal diseases: a meta-analysis. Jan 1996 to Dec 1994 5 studies IDDM; 5 studies non DM CRF End points: Death and reduce GFR decline FU (mths) Study Size OR IDDM 9 to 35 108 0.56 [0.44-0.77] Non DM 18 to 36 1413 0.67 [0.50-0.89] Pedrini MT et al; Ann Intern med 1996; 124: 627-32

Other measures: low protein diet Type 1 diabetics with overt nephropathy should be maintained on a low protein diet of 0.8gram / kg/ day of protein

Clinical Targets Therapy should aim to reduce albuminuria as much as possible, and its is reasonable to aim for a urinary protein levels to less than 1 gram per day or at least 50% of the pre treatment value

Recommended nephrology consultation Decline in renal function Difficulties in hyperkalaemia Atypical features eg haematuria, casts, renal bruits Difficult blood pressure control Heavy proteinuria (in excess of 3 gm/day) Absence of retinopathy

Summary

Prevention Tight glucose control reduces the development of diabetic nephropathy

Prevention Blood pressure control reduces the development of microvascular disease in diabetics

Screening Serum creatinine should be done annually and the GFR estimated Cockcroft Gault equation (Age/weight/cr) MDRD formula (Age, creatinine)

Blood Pressure Target The blood pressure target in all diabetics should be less than 130/80 Diabetics with proteinuria in excess of 1 gram should attempt to achieve values of less than 125/75 mm Hg

Drug choices in type 2 diabetics with overt nephropathy In type 2 diabetes with overt nephropathy, either an ACE inhibitor or an ARB may be used to retard the progression of renal disease.

Other measures: low protein diet Type 1 diabetics with overt nephropathy should be maintained on a low protein diet of 0.8gram / kg/ day of protein