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Diabetic Nephropathy in T2DM: Blood Pressure and Cholesterol Targets Nemanja Stojanović Consultant Endocrinologist Queens Hospital, Romford.

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Presentation on theme: "Diabetic Nephropathy in T2DM: Blood Pressure and Cholesterol Targets Nemanja Stojanović Consultant Endocrinologist Queens Hospital, Romford."— Presentation transcript:

1 Diabetic Nephropathy in T2DM: Blood Pressure and Cholesterol Targets Nemanja Stojanović Consultant Endocrinologist Queens 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:

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:

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

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 Microalbuminuria and 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: ; 2004

15 Preventing Microalbuminuria in T2DM TrandolaprilTrandolapril + Verapamil Verapamil Placebo N= Microalb- uminuria 6%5.7%11.9%10% BP over baseline mmHg 151/87 150/87152/87 NEJM 351: ; 2004

16 Irbesartan in T2DM Nephropathy 1715 pts- duration 2.6 years Irbesartan 300mg OD vs Amlodipine OD vs Placebo Proteinuria 900mg/day Cr umol/l umol/l Target BP 135/85 mmHg Primary composite outcome: ESRF, doubling of Cr & Death: any cause NEJM 2001; 345:

17 Irbesartan in T2DM Nephropathy IrbesartanAmlodipinePlacebo N 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:

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 NEJM :

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:

20 Telmisartan vs Enalapril Patients with early diabetic nephropathy 250 subject over 5 years Similar decrements in GFR in both groups: ml/min/1.73m2 of body surface area Cr, AER no difference N Engl J Med 2004; 351:

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:

24 CARDS 63% 30% 6% 1% The Lancet 2004; 364:

25 Primary Endpoints Acute coronary heart disease event (incl. MI, silent MI, unstable angina, death, CPR) Coronary revascularisation procedures Stroke The Lancet 2004; 364:

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:

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

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:

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

30 Equivalent Doses Dose LDL Reduction % Atorvastatin Simvastatin Pravastatin 4034 Rosuvastatin Fluvastatin Ezetamibe (12-21c) + max dose decreases the LDL by additional 20%

31 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 Fluvastatin2C9 isozyme systems (75%) Ezetamibe 70 % faeces unchanged; conjugation with glucuronide

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:

33 Ahead of the Press

34 ADVANCE 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; /NEJMoa

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; /NEJMoa

36 ADVANCE Intensive RxConventional Rx n Study End A1c 6.5%7.3% Gliclazide MR 90% (30-120mg OD) NA Insulin40.5%24.1% Weight> 0.7kg Prim outcome18.1%20% N Engl J Med 2008; /NEJMoa

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; /NEJMoa

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 Death rates begin to separate after 1 year….. N Engl J Med 2008; /NEJMoa

39 ACCORD Intensive (%)Conventional(%) n Hypoglycaemia 538 (10.5)179 (3.5) Weight gain> 10kg 1399 (27.8)713 (14.1) CVD Death135 (2.6)94 (1.8) Non fatal MI186 (3.6)235 (4.6) Non fatal CVA67 (1.3)61 (1.2) Any Death257 (5)203 (4) N Engl J Med 2008; /NEJMoa

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


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