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Diabetic Nephropathy in T2DM: Blood Pressure and Cholesterol Targets

Diabetic Nephropathy in T2DM: Blood Pressure and Cholesterol Targets . Nemanja Stojanovi ć 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

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Diabetic Nephropathy in T2DM: Blood Pressure and Cholesterol Targets

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  1. Diabetic Nephropathy in T2DM: Blood Pressure and Cholesterol Targets Nemanja Stojanović Consultant Endocrinologist Queen’s Hospital, Romford

  2. We will talk about • Kidney in Diabetes • Drug related renal injury in T2DM • Preventing DM Nephropathy • Cholesterol/ BP/ Glucose Treatment • Guidelines/ Conclusion

  3. Nephropathy • 35-50% with Type 1 after 20 years of disease • 10- ? 20% Type 2 patients on diagnosis

  4. Nephropathy: aetiology • HbA1c >7–8% • Genetic factors • Hypertension • Inflammation • Altered vascular permeability • Hyperlipidaemia • Excessive protein intake

  5. Determinants of Glomerular Proteinuria • Mean transcapillary hydraulic-pressure difference • Glomerular surface area • Size selectivity of the glomerular filter • Charge selectivity

  6. Microalbuminuria • Normoalbuminuria <30 mg/day • Microalbuminuria 30–300 mg/day • Clinical or macroalbuminuria >300 mg/day- POINT OF NO RETURN • ACR

  7. 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

  8. 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

  9. 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

  10. 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

  11. STENO-2 Endpoints • Composite death from CVS causes • CVG • PTCA • Nonfatal CVA • Amputation • Vascular surgery to correct ischaemia • Microvascular NEJM 2003; 348: 383- 93

  12. STENO-2 • After the end of the study • Prospective follow up for 5.5 years • Both groups now treated to the national targets

  13. Preventing Microalbuminuriaand Progression of Diabetic Nephropathy: Antihypertensives

  14. 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

  15. Preventing Microalbuminuria in T2DM NEJM 351: 1941-51; 2004

  16. 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

  17. Irbesartan in T2DM Nephropathy NEJM 2001; 345: 851-61

  18. 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

  19. 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

  20. 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

  21. Drugs: Frequent Offenders • Iodine based contrast • Metformin & Contrast • NSAIDS & COX-2 Inhibitors • ACE • ARBs • Aminoglycoside antibiotics • Amphotericin B • Immunosuppressants

  22. Lipids ± Diabetes

  23. 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

  24. CARDS 1% 6% 30% 63% The Lancet 2004; 364: 685 - 696

  25. 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

  26. Primary Endpoints: Results No difference between the sexes or risk factor subgroups • Acute coronary heart disease event 36% • Coronary revascularisation procedures 31% • Stroke 48% The Lancet 2004; 364: 685 - 696

  27. CARDS • LDL < 2.6mmol subgroup • 743 patients • 26% reduction in major cardiovascular events The Lancet 2004; 364: 685 - 696

  28. 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

  29. Simvastatin Atorvastatin Pravastatin Rosuvastatin Ezetamibe Niacin Fibrates Omacor Diet Drugs on Offer

  30. Equivalent Doses + max dose decreases the LDL by additional 20%

  31. Metabolism

  32. Effect of reduction of LDL by 1mmol/l by any means on coronary death and non-fatal MI: meta-analysis of 58 trials Law MR BMJ 2003, 326: 1423-9

  33. Ahead of the Press

  34. 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

  35. 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

  36. ADVANCE N Engl J Med 2008;10.1056/NEJMoa0802987

  37. 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

  38. 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

  39. ACCORD N Engl J Med 2008;10.1056/NEJMoa0802743

  40. NICE BP < 130/80 ACE/ ARB Cholesterol<4mmol/l LDL< 2mmol/l Aspirin

  41. Instead of Conclusion • If I had T2DM and microalbuminuria: • BP 129 (114)/ 79 mmHg • LDL < 2mmol/l • ACE or ARB • Aspirin

  42. www.EndoDiabetes.com

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