Hypertension and nephropathy in diabetes

R AjjanSenior Lecturer and Honorary Consultant

Diabetes and Endocrinology

The LIGHT Laboratories

University of Leeds

Leeds General Infirmary

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

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)

UK Prospective Diabetes Study (UKPDS) Group (33). Lancet 1998; 352 (Sept. 12): 837–853.

Lowering HbA1C Reduces Risk of Complications

In intensively-treated patients, HbA1C was 0.9% lower compared with conventionally treated patients

MI

Retinopathy

Cataract extraction

Microvascular endpoint

Albuminuria at 12 years

Any diabetes related endpointP=0.029

P=0.009

P=0.052

P=0.046

P=0.015

P=0.00005

-12-12

-25-25

-16-16

-21-21

-34-34

-24-24

0 -10 -20 -30 -40 -50% Reduction in Risk

Cardiovascular mortality and microalbuminuria

n = 2,431

Su

rviv

al

Time (years)

1.0

0.9

0.8

0.7

0.6

0.5

500.0

< 150 mg/L

150–300 mg/L

> 300 mg/L

Urinary protein:

2 3 4 6 7 81

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

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 strokeLiu, J Am Coll Cardiol 2003, 41:2022Earle, Diabetologia 1996, 39:854Diercks, Eur Heart J 2000, 21;1922Berton J Hypertens 1998, 16:515Spoelstra-de Man, Diab Care 2001, 24:2097Beamer, Arch Neurol 1999, 56: 699Kramer, Hypertension 2005, 46:38

CV mortality in relation to MA&ECG(>7000 subjects)

Diercks, J Am Coll Cardiol 2002, 40:1401Aged 28-75

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

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)

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.

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

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

Secondary causes of HBP

• Endocrine– Pheochromocytoma– Conn’s– Acromegaly– Cushing’s

• Non-endocrine– Renal artery stenosis– Coarctation of the aorta

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

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.

Impact of Blood Pressure Reduction on Mortality in Diabetes

TrialConventional

care

Intensive

care

Risk

reductionP-value

UKPDS 154/87 144/82 32% 0.019

HOT 144/85 140/81 66% 0.016

Turner RC, et al. BMJ. 1998;317:703-713. Hansson L, et al. Lancet. 1998;351:1755–1762.

Mortality endpoints are:UK Prospective Diabetes Study (UKPDS) – “diabetes related deaths”Hypertension Optimal Treatment (HOT) Study – “cardiovascular deaths” in diabetics

Diabetes: Tight Glucose vs Tight BP Control and CV Outcomes in UKPDS

StrokeAny Diabetic

EndpointDM

DeathsMicrovascularComplications

-50

-40

-30

-20

-10

0

% R

ed

ucti

on

In

Rela

tive R

isk

Tight Glucose Control (Goal <6.0 mmol/l or 108 mg/dL)

Tight BP Control (Average 144/82 mmHg)

32%

37%

10%

32%

12%

24%

5%

44%

Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661.

*

*

*

**P <0.05 compared to tight glucose control

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?

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)

Classification of Diabetes (1)

Type I DM Type II DM

Aetiology Autoimmune

(- cell destruction)

Insulin resistance and -cell dysfunction

Peak age 12 years 60 years

Prevalence 0.3% 6% (>10% above 60 years)

Presentation Osmotic symptoms, weight loss (days to weeks), DKA

Patient usually slim

Osmotic symptoms, diabetic complications (months to years).

Patient usually obese

Treatment Diet and insulin Diet, exercise (weight loss), oral hypoglycemics, Insulin later

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.

Classification of Diabetes (2)

Case 6

38 year old lady diagnosed with T1DM for 15 years. Also suffers from a bipolar disorder.

TreatmentLevemir 16 and 12 unitsNovorapid (CHO counting 1:10)Lithium

Complaining of tiredness

ResultsHbA1c 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)

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

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

• BloodsHbA1c 6.6%TC 5.1 (HDL 2.2; LDL 2.9, TG 1.1)U&Es (normal); alb/creatinine ratio (normal)

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.

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!

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)

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.

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)

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?

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)

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

Learning points (case 10)

• Excellent control despite small doses of insulin.

• FH of T2DM

• Need to question the Dx of T1DM

• Patient had MODY

MODY

Hattersley, Endocrinology 2006; 147: 2657

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

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)

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

THANK YOU