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Diabetic Nephropathy in T2DM: Blood Pressure and Cholesterol Targets Nemanja Stojanović Consultant Endocrinologist Queen’s Hospital, Romford We will talk about • • • • • Kidney in Diabetes Drug related renal injury in T2DM Preventing DM Nephropathy Cholesterol/ BP/ Glucose Treatment Guidelines/ Conclusion Nephropathy • 35-50% with Type 1 after 20 years of disease • 10- ? 20% Type 2 patients on diagnosis Nephropathy: aetiology • • • • • • • HbA1c >7–8% Genetic factors Hypertension Inflammation Altered vascular permeability Hyperlipidaemia Excessive protein intake Determinants of Glomerular Proteinuria • Mean transcapillary hydraulic-pressure difference • Glomerular surface area • Size selectivity of the glomerular filter • Charge selectivity Microalbuminuria • Normoalbuminuria <30 mg/day • Microalbuminuria 30–300 mg/day • Clinical or macroalbuminuria >300 mg/day- POINT OF NO RETURN • ACR Nephropathy: Patient Should Know… • Optimal glycaemic control will prevent it or delay it • Annual urine test: only way to detect it • Importance of BP monitoring • Hypertension: predisposes and aggravates nephropathy Microalbuminuria: Type 2 DM • 10% have it at diagnosis • 80% CVS mortality over 10 years • Associated with insulin resistance sy • 2 positive samples required for the diagnosis STENO-2 Study • 160 patients with T2DM and microalbuminuria • 80 treated according to the national guidelines + 80 active treatment • Active group reviewed 3 monthly • Duration: 7.8 years NEJM 2003; 348: 383- 93 STENO-2 Study • • • • • Intensive glycaemic control A1c < 7.5 or 6.5% Systolic Bp < 140 or 130 mmHg Diastolic BP < 85 or 80 mm Hg Cholesterol < 4.9 or 4.6 mmol/l Triglycerides < 1.7mol/l • Most active treatment patients were on Aspirin NEJM 2003; 348: 383- 93 STENO-2 Endpoints • • • • • • Composite death from CVS causes CVG PTCA Nonfatal CVA Amputation Vascular surgery to correct ischaemia • Microvascular NEJM 2003; 348: 383- 93 STENO-2 • After the end of the study • Prospective follow up for 5.5 years • Both groups now treated to the national targets Preventing Microalbuminuria and Progression of Diabetic Nephropathy: Antihypertensives Preventing Microalbuminuria in T2DM: BENEDICT Study • • • • • 1204 Hypertensive Subjects with T2DM No microalbuminuria Target BP 120/80 HbA1c ~ 5.8± 1.5% Duration of Diabetes< 25 years NEJM 351: 1941-51; 2004 Preventing Microalbuminuria in T2DM Trandolapril Trandolapril Verapamil Placebo + Verapamil N= 301 300 303 300 Microalbuminuria 6% 5.7% 11.9% 10% BP over baseline mmHg 151/87 151/87 150/87 152/87 NEJM 351: 1941-51; 2004 Irbesartan in T2DM Nephropathy • 1715 pts- duration 2.6 years • Irbesartan 300mg OD vs Amlodipine OD vs Placebo • Proteinuria 900mg/day • Cr ♀ 88- 265 umol/l ♂ 107- 265 umol/l • Target BP 135/85 mmHg • Primary composite outcome: ESRF, doubling of Cr & Death: any cause NEJM 2001; 345: 851-61 Irbesartan in T2DM Nephropathy Irbesartan Amlodipine Placebo N 579 567 569 BP achieved 140/ 77 mmHg 141/ 77 mmHg 144/ 82 mmHg •Renal Outcome Irbesartan group 23% better than Amlodipine and 20% than Placebo • CVS mortality: no difference NEJM 2001; 345: 851-61 Losartan and Diabetic Nephropathy • Secondary outcomes - Composite of morbidity and mortality from cardiovascular causes (p=NS) - Proteinuria Losartan: 35% reduction - Progression of renal disease Losartan: 18% reduction NEJM2008 358: 2433-2446 Irbesartan • In patients with microalbuminuria • Renoprotective, prevents albuminuria in hypertensive patients with T2DM • Higher dose was more effective • A higher proportion of patients restored normoalbuminuria Irbesartan 300mg OD group than placebo 34% vs 21% Parving H et al. N Engl J Med 2001;345:870-878 Telmisartan vs Enalapril • Patients with early diabetic nephropathy • 250 subject over 5 years • Similar decrements in GFR in both groups: -17.9 ml/min/1.73m2 of body surface area • Cr, AER no difference N Engl J Med 2004; 351:1952-61 Drugs: Frequent Offenders • • • • • • • • Iodine based contrast Metformin & Contrast NSAIDS & COX-2 Inhibitors ACE ARBs Aminoglycoside antibiotics Amphotericin B Immunosuppressants Lipids ± Diabetes At least One Complication • • • • Hypertension Retinopathy/ Maculopathy/ Previous laser Smoking Micro or macroalbuminuria • LDL < 4.14 mmol/l • Triglycerides< 6.78mmol/l The Lancet 2004; 364: 685 - 696 CARDS Risk Factors 1% 6% 30% 63% 1 2 3 4 The Lancet 2004; 364: 685 - 696 Primary Endpoints • Acute coronary heart disease event (incl. MI, silent MI, unstable angina, death, CPR) • Coronary revascularisation procedures • Stroke The Lancet 2004; 364: 685 - 696 Primary Endpoints: Results No difference between the sexes or risk factor subgroups • Acute coronary heart disease event • Coronary revascularisation procedures • Stroke 36% 31% 48% The Lancet 2004; 364: 685 - 696 CARDS • LDL < 2.6mmol subgroup • 743 patients • 26% reduction in major cardiovascular events The Lancet 2004; 364: 685 - 696 REVERSAL Trial • Endovascular USS • Pravastatin 40mg vs Atorvastatin 80mg OD • Baseline LDL: 3.89mmol/l • End of Study LDL: Pravastatin 2.85mmol/l Atorvastatin 2.05mmol/l • After 18/12 atheroma progressed in pravastatin group but not in Atorvastatin group JAMA. 2004; 291:1071-1080 Drugs on Offer • • • • Simvastatin Atorvastatin Pravastatin Rosuvastatin • • • • • Ezetamibe Niacin Fibrates Omacor Diet Equivalent Doses Atorvastatin+ Simvastatin Pravastatin Rosuvastatin Fluvastatin Ezetamibe + max Dose LDL Reduction % 10 39 20-40 35-41 40 34 5-10 39-45 40-80 25-35 10 16-18 (12-21c) dose decreases the LDL by additional 20% Metabolism Atorvastatin cytochrome P 450 3A4 Simvastatin cytochrome P 450 3A4 Pravastatin 70% faeces, 20 % urine; 7 different sets of enzymes Rosuvastatin 90% unchanged in faeces Fluvastatin 2C9 isozyme systems (75%) Ezetamibe 70 % faeces unchanged; conjugation with glucuronide Effect of reduction of LDL by 1mmol/l by any means on coronary death and non-fatal MI: meta-analysis of 58 trials 0% 5% 10% 15% 20% 25% 30% 35% Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 40% Law MR BMJ 2003, 326: 1423-9 Ahead of the Press ADVANCE • 11140 patients: 5 years • Intensive glycaemic control (A1c 6.5%) vs Conventional (A1c 7.3%) • Intensive group: gliclazide MR 30 to 120 mg daily and other hypoglycamic agents including insulin N Engl J Med 2008;10.1056/NEJMoa0802987 ADVANCE Primary Endpoints • Composite of macro and microvascular events considered jointly and separately • Macro: CVD death, non fatal CVA & MI • Micro:new or worsening nephropathy ; doubling of the serum creatinine; the need for dialysis; death due to renal causes; worsening of retinopathy N Engl J Med 2008;10.1056/NEJMoa0802987 ADVANCE Intensive Rx Conventional Rx n 5571 5569 Study End A1c 6.5% 7.3% 90% (30-120mg OD) NA Insulin 40.5% 24.1% Weight > 0.7kg Prim outcome 18.1% Gliclazide MR 20% N Engl J Med 2008;10.1056/NEJMoa0802987 ADVANCE Conclusion • The main contributor to the 10% relative reduction in the primary outcome found with intensive control as compared with standard control was a 21% relative reduction in the risk of new or worsening nephropathy • More modest but significant reduction in microalbuminura N Engl J Med 2008;10.1056/NEJMoa0802987 ACCORD Trial • 10,251 patients • Intensive glycaemic control and CVS outcomes • Primary outcomes : CVD death, Non fatal CVA & MI • Intensive Treatment: HbA1c< 6% • Conventional Treatment HbA1c 7-7.9 • Death rates begin to separate after 1 year….. N Engl J Med 2008;10.1056/NEJMoa0802743 ACCORD Intensive (%) Conventional(%) n 5128 5123 538 (10.5) 179 (3.5) 1399 (27.8) 713 (14.1) CVD Death 135 (2.6) 94 (1.8) Non fatal MI 186 (3.6) 235 (4.6) Non fatal CVA 67 (1.3) 61 (1.2) Any Death 257 (5) 203 (4) Hypoglycaemia Weight gain> 10kg N Engl J Med 2008;10.1056/NEJMoa0802743 NICE BP < 130/80 ACE/ ARB Cholesterol<4mmol/l LDL< 2mmol/l Aspirin Instead of Conclusion • If I had T2DM and microalbuminuria: - BP 129 (114)/ 79 mmHg LDL < 2mmol/l ACE or ARB Aspirin www.EndoDiabetes.com