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 Microalbuminuriaand 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

Verapamil Placebo

N= 301 300 303 300

Microalb-uminuria

6% 5.7% 11.9% 10%

BP over baselinemmHg

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

CARDSRisk Factors

1

2

34

63%30%

6%

1%

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 36%

• Coronary revascularisation procedures 31%• Stroke

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

Dose LDL Reduction %

Atorvastatin+ 10 39

Simvastatin 20-40 35-41

Pravastatin 40 34

Rosuvastatin 5-10 39-45

Fluvastatin 40-80 25-35

Ezetamibe 10 16-18 (12-21c)

+ + max dose decreases the LDL by additional 20%max 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 trials0%

5%

10%

15%

20%

25%

30%

35%

40%

Year 1 Year 2 Year 3 Year 4 Year 5 Year 6

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

ADVANCEIntensive Rx Conventional Rx

n 5571 5569

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;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

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;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