Hypertension and nephropathy in diabetes

1. Hypertension and nephropathy in diabetes R Ajjan Senior Lecturer and Honorary Consultant Diabetes and Endocrinology The LIGHT Laboratories University of Leeds Leeds General Infirmary

2. Case 1 A 27 year old with T1DM for 14 years. • Complications • Background retinopathy • Current treatment • Novomix 30: 28 and 16 units • Recent results • HbA1c 7.8% • U&Es • Na 140 mmol/l, K 3.7 mmol/l, Urea 3.4 mmol/l, Creatinine 77 mmol/l • Lipids • TC 4.9 mmol/l, TG 1.7 mmol/l • ACR 4.1 and 3.9 (N<2.5) checked twice in 2 months

3. Discussion points (Case 1) • Patient has microalbuminuria together with at least one other microvascular complication (discuss treatment ARB/ACEI). • Needs tightening of glycaemic control to prevent further deterioration of microvascular complications (UKPDS) • Increased CV risk; need to consider a statin (JBS)

4. -16 P=0.052 MI Retinopathy Cataract extraction Microvascular endpoint Albuminuria at 12 years Any diabetes related endpoint -21 P=0.015 -24 P=0.046 -25 P=0.009 -34 P=0.00005 -12 P=0.029 0 -10 -20 -30 -40 -50 % Reduction in Risk Lowering HbA1C Reduces Risk of Complications In intensively-treated patients, HbA1C was 0.9% lower compared with conventionally treated patients UK Prospective Diabetes Study (UKPDS) Group (33). Lancet 1998; 352 (Sept. 12): 837–853.

5. Miettinen H, et al. Stroke 1996; 27:2033–2039.

6. Microalbuminuria and CV outcome(DM and non-DM individuals) • MA is associated with CAC • MA is associated with carotid and femoral artery stenosis • MA is associated with LVH/LV dysfunction and ECG abnormalities • MA and MI • a marker of silent MI (DM and non-DM) • related to MI size • a predictor of 1 yr mortality post MI • MA is a predictor of ischemic stroke Liu, J Am Coll Cardiol 2003, 41:2022 Earle, Diabetologia 1996, 39:854 Diercks, Eur Heart J 2000, 21;1922 Berton J Hypertens 1998, 16:515 Spoelstra-de Man, Diab Care 2001, 24:2097 Beamer, Arch Neurol 1999, 56: 699 Kramer, Hypertension 2005, 46:38

7. CV mortality in relation to MA&ECG(>7000 subjects) Aged 28-75 Diercks, J Am Coll Cardiol 2002, 40:1401

8. Case 2 • 18 year old male with T1DM for 2 years. • No known complications • Results • BP 160/90 • HbA1c 8.1% • Na 136, K 4.1, Creatinine 95, Urea 7.5 • Chol 6.7, TG 5.6 • Urine ACR 495 (N <2.5) • Urine MC&S negative

9. Learning points (Case 2) • Severe microalbuminuria in the absence of other microvascular disease is unlikely to be diabetes-related and needs to be fully investigated (this patient had glomerulonephritis with nephrotic syndrome) • Raised TC should be discussed (? Secondary to nephrotic syndrome)

10. Prevention of DM nephropathy Yearly screen using ACR. Rule out microalbuminuria secondary to other causes. • Exercise. • Poor glycemic control. • Poorly controlled Hypertension. • UTI. • Pregnancy. • Fever. • Haematuria. • CCF. If positive, repeat twice (in 3 months). If 2 of 3 positive, initiate treatment.

11. Case 3 • A 31 year old T1DM patient for 5 years. He is complaining of episodes of palpitation and sweating. Also, dizziness on standing. • Treatment • Novorapid 12 units tds • Lantus 24 units od • Results • Weight 70, BMI 24 • BP L: 195/105; S 170/95 • HbA1c: 7.1% • U&Es • Na 134 mmol/L, K 4.3 mmol/L, U 4.3 mmol/L, Creatinine 82 mmol/L • Lipids • TC 3.9, TG 2.1

12. Learning points (Case 3) • Severe hypertension in a young patient, particularly in the presence of symptoms, should be fully investigated. • This patient had a pheochromocytoma

13. Secondary causes of HBP • Endocrine • Pheochromocytoma • Conn’s • Acromegaly • Cushing’s • Non-endocrine • Renal artery stenosis • Coarctation of the aorta

14. Case 4 • 57 year old T1DM for more than 30 years. • Complications • Microalbuminuria • Hypertension • Hyperlipidaemia • Treatment • Glargine and novorapid • Ramipril 10 mg • BFZ 2.5 mg • Atorvastatin 10mg • Aspirin 75 mg • Results • Weight 65 (BMI 24), HbA1c 7.3%, BP 155/86 • Na 137, K 4.9, Urea 6.1, Creatinine 102 • TC 4.9, LDL 2.9, TG 1.3

15. Learning points (Case 4) • Recognise that HBP is the most important point to focus on (discuss antihypertensive treatment options). • Due to multiple risk factors, a more aggressive approach with lipid lowering agents is probably warranted.

17. Impact of Blood Pressure Reduction on Mortality in Diabetes Mortality endpoints are: UK Prospective Diabetes Study (UKPDS) – “diabetes related deaths” Hypertension Optimal Treatment (HOT) Study – “cardiovascular deaths” in diabetics Turner RC, et al. BMJ. 1998;317:703-713. Hansson L, et al. Lancet. 1998;351:1755–1762.

18. Diabetes: Tight Glucose vs Tight BP Control and CV Outcomes in UKPDS DM Deaths Microvascular Complications Stroke Any Diabetic Endpoint 0 5% 10% -10 12% -20 24% % Reduction In Relative Risk * 32% 32% -30 * 37% * *P <0.05 compared to tight glucose control -40 44% Tight Glucose Control (Goal <6.0 mmol/l or 108 mg/dL) Tight BP Control (Average 144/82 mmHg) * -50 Bakris GL, et al. Am J Kidney Dis.2000;36(3):646-661.

21. Case 5 • 47 year old with insulin treated T2DM and 12 months history of erectile dysfunction • Results • HbA1c 7.3% • U&Es N • Chol 5.8 mmol/l, TG 2.3 mmol/l • ALT 160, AP 397, Bili 31 • Testosterone 5 (low), FSH 1.1 (low), LH 0.8 (low) • Prolactin 233 • Would you give a statin? What would you do?

22. Learning points (case 5) • Discuss erectile dysfunction in DM • Recognise high lipids. • Recognise abnormal LFTs (? Statins CI): discuss when to investigate abnormal LFTs in DM patients. • Unifying diagnosis (haemachromatosis)

23. Classification of Diabetes (1)

24. Classification of Diabetes (2) • Latent autoimmune diabetes in adults (LADA); Type I. • Maturity onset DM of the young (MODY); Type II. • Gestational diabetes. • Secondary: pancreatic destruction (pancreatitis, cystic fibrosis), Acromegaly, Cushing’s syndrome, Haemochromatosis.

25. Case 6 38 year old lady diagnosed with T1DM for 15 years. Also suffers from a bipolar disorder. Treatment Levemir 16 and 12 units Novorapid (CHO counting 1:10) Lithium Complaining of tiredness Results HbA1c 7.8% FBC Hb 11.1, MCV 100, WBC 4.6, Plat 221. U&Es Na 138 mmol/l, K 4.3 mmol/l, Cr 87 mmol/l, Urea 5.1 mmol/l. Lipids TC 6.8 mmol/l, TG 1.6 mmol/l (4.8 and 1.4 respectively, 8 months ago)

26. Learning points (case 6) • A big change in TC over 8 months is suspicious (need to think about secondary hypercholesterolaemia) • Notice raised MCV • Dx hypothyroidism

27. Case 7 • 27 year old lady with T1DM for 12 years • No documented complications, no FH • On qds insulin; feels her diabetes is well controlled • Bloods HbA1c 6.6% TC 5.1 (HDL 2.2; LDL 2.9, TG 1.1) U&Es (normal); alb/creatinine ratio (normal)

28. Learning points (case 7) • A woman in a child bearing age. • Minor rise in TC • No other complications/good DM control. • The immediate risk is negligible and therefore medical treatment is probably not advised.

29. JBS guidelines • TC <4.0 and LDL<2.0 or 25% reduction in TC and 30% reduction in LDL. • TG<1.7 and HDL>1.0 are preferred (but not targets) • For audit purposes TC<5 and LDL<3!

30. Who should be given statins (JBS) • All diabetics above the age of 40 (T1DM and T2DM) • Individuals between 18-39 who have diabetes and: • Significant retinopathy • Nephropathy • HbA1c>9.0% • HBP requiring treatment • TC>6.0 • FH of IHD • Presence of the metabolic syndrome (central obesity, TG, HDL)

31. Case 8 May 2004 • Weight 63 • TC 5.2, LDL 3.6, TG 2.6 • HbA1c 8.4 • Na 137, K 4.2, Cr 61, U 4.1 November 2004 • Weight 52 • TC 4.0, LDL 2.8, TG 1.4 • HbA1c 6.1 • Na 137, K 3.9, Cr 52, U 3.2 • Calcium 1.94 28 year old lady with T1DM. Found to have raised cholesterol and was given dietary advice. Complaining of tiredness, frequent hypos and pins & needles in the hands.

32. Learning points (case 8) • Weight loss and hypos in T1DM should be investigated. • DD • Poor control • Coeliac disease (Dx in this case): note low calcium • Addison’s • Hyperthyroidism • General causes of weight loss (including malignancy)

33. Case 9 • 37 year old male T1DM for 15 years, HBP for 6 years. • Current Tx • Lantus and Novorapid • Ramipril 10 mg od (for 6 years) • Feeling very tired and having frequent hypos. • Results • W 58 kg • BP 90/55 • Na 135, K 5.7, Creatinine 64, Urea 3.1 • What would you do?

34. Learning points (case 9) • Weight loss and hypos in T1DM should be investigated. • DD • Poor control • Coeliac disease • Addison’s (Dx in this case) • Hyperthyroidism • General causes of weight loss (including malignancy)

35. Case 10 • A 24 year old lady with T1DM for 16 years. • FH includes T2DM diabetes in her father and brother diagnosed at the age of 32 and 22 respectively. • Treatment • Novomix 30: 4 units twice a day • Results • Weight 59 kg, BMI 22 • HbA1c 5.4% • U&Es normal • ACR 1.1 • TC 3.4, TG 1.1

36. Learning points (case 10) • Excellent control despite small doses of insulin. • FH of T2DM • Need to question the Dx of T1DM • Patient had MODY

37. MODY Hattersley, Endocrinology 2006; 147: 2657

38. Case 11 • A 38 year old lady with T1DM for 9 years and hypothyroidism for 7 years. • Complaining of loss of sensation in the feet and problems with her balance, particularly when walking in the dark. • No retinopathy or nephropathy • Treatment • Novomix 30: 42 and 28 units • Simvastatin 40 mg od • L-thyroxine 100 mcg od • Results • HbA1c 6.8% • U&Es normal • Lipids TC 3.8, TG 1.2 • FT4 19 pmol/l, TSH 1.9 mIU/l

39. Learning points (case 11) • Recognise that it is unusual to have diabetic neuropathy in the absence of other micorvascular complications. • This should prompt full investigations. • Patient already has two autoimmune conditions. • Need to rule out PA (dx here)

40. Treatment options to prevent/treat complications in DM • CVD • Good glucose control • Metformin • Glitazones • ACEI • ARB • Statins • ? Fibrates • ? Omega-3 • ? aspirin • Nephropathy • Good glucose control • ACEI • ARB • Neuropathy • Good glucose control • Simple analgesics • Tricyclic antidepressants • Gabapentin • Pregabalin • Retinopathy • Good glucose control • Laser treatment • ?others Diabetes UK: Within the next 5 years, the possible number of drug combinations in T2DM may be > 4500

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