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:

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
Trandolapril
Trandolapril + Verapamil
Verapamil
Placebo N=
301
300
303
Microalb-uminuria 6%
5.7%
11.9%
10%
BP over baselinemmHg
151/87
150/87
152/87
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
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:

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 1% 6%
30%
63%
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 %
Coronary revascularisation procedures %
Stroke %
The Lancet 2004; 364:

27. CARDS 743 patients 26% reduction in major cardiovascular events
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 Atorvastatin+ Simvastatin Pravastatin Rosuvastatin
LDL Reduction %
Atorvastatin+ 10 39
Simvastatin
20-40
35-41
Pravastatin 40 34
Rosuvastatin
5-10
39-45
Fluvastatin
40-80
25-35
Ezetamibe
16-18 (12-21c)
+ max dose decreases the LDL by additional 20%

31. Metabolism Atorvastatin Simvastatin Pravastatin Rosuvastatin
cytochrome P 450 3A4
Simvastatin
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

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 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; /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 Rx Conventional Rx n 5571 5569 6.5% 7.3%
Study End A1c
6.5%
7.3%
Gliclazide MR
90% (30-120mg OD) NA
Insulin
40.5%
24.1%
Weight
> 0.7kg
Prim outcome
18.1%
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 7-7.9
Death rates begin to separate after 1 year…..
N Engl J Med 2008; /NEJMoa

39. ACCORD Intensive (%) Conventional(%) 5128 5123 538 (10.5) 179 (3.5)
Hypoglycaemia
538 (10.5)
179 (3.5)
Weight gain> 10kg
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)
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