GP VTS Programme Diabetes: Hot topics and case histories

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GP VTS ProgrammeDiabetes Hot topics and case
histories

• Dr Masud Haq
• Consultant in Diabetes Endocrinology
• Maidstone Tunbridge Wells NHS Trust

11th Feb 2009
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Diabetes - WHO 2002 criteria

• Symptoms of diabetes plus
• - FPG 7.0 mmol/l
• (fasting for at least 8hrs) OR
• - Random PG 11.1 mmol/l
• In the absence of symptoms
• 2 FPG 7.0 mmol/l OR
• 2 random PG 11.1 mmol/l OR
• 11.1 mmol/l 2hrs post OGTT

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Classification of diabetes

• Type 1 (previously IDDM)
• ?-cell destruction
• Autoimmune or idiopathic

• Type 2 (previously NIDDM)
• Insulin resistance
• Progressive ?-cell failure

Other types Maturity onset diabetes of the young
(MODY) Genetic defects of ?-cell function or
insulin action Disorders of exocrine
pancreas Endocrinopathies Drug induced
(steroids) Gestational diabetes
World Health Organization. Definition, diagnosis
and classification of Diabetes Mellitus and its
complications. Geneva WHO, 1999.
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WHO 2002
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How common is Diabetes in West Kent Primary Care
Trust ?
674,000 residents 23,082 people with diabetes
26,771 by 2010 29,195 if obesity continues to
rise
Acute NHS Trusts
Quality and Outcomes Framework Data (Dept of
Health) 2007 PBS Diabetes Population
Prevalence Model Phase 2 (YHPHO)
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Why is the local population at risk?

• Prevalence of obesity trebled since 1980
• Growth in over 65yrs population by 54 in next
  25yrs

Annual Public Health Report (West Kent PCT)
2007
Cost to NHS considerable

• 10 of all hospital expenditure
• highest single prescribing budget cost (500
  million per yr)

Prescribing for Diabetes in England (NHS
Information Centre) 2007
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Magnitude of Diabetes

• Approx. 2 million people in UK
• Approx. 85 - 90 due to T2DM
• Prevalence of T2DM 6 of all adults
• 5 fold increase in last 40 yrs
• earlier age of onset

Diabetes UK 2007
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Case histories
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Case 1

• 35yr woman
• Type 2 diabetes Rx rosiglitazone and metformin
  (recent HbA1c 10)
• Other Rx - statin
• Background retinopathy and microalbuminuria
• Overweight
• Wants to fall pregnant

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What issues do you need to discuss?

• Glycaemic Control
• Renal function
• Last retinal screen
• Complications
• Drugs
• Weight
• Folate
• Need for contraception

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Confidential enquiry in maternal and childrens
health (CEMACH 2002)

• Women with diabetes have high risk pregnancies,
  their babies
• x5 stillborn
• x3 die in first month
• x2 congenital malformation
• x2 macrosomia
• x5 preterm

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Risks of diabetes in pregnancy

• Congenital malformation
• Miscarriage
• Fetal macrosomia
• Birth trauma
• Stillbirth / neonatal death
• Need for induction / caesarian section

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Pre-conception care

• Benefits of pre-conception glycaemic control
• Avoid unplanned pregnancy
• Use contraception
• Review drugs stop statins, ACE inhibitors,
  ARBs, glitazones, weight loss drugs
• Metformin and insulin are both safe
• Start folate 5mg od until 12 weeks gestation
• Stop smoking
• Please refer to pre-conception diabetes clinic
  for advice

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Case 2

• 45 year old male
• 2 yr history of urinary frequency and 6kg weight
  loss
• 12 months of lethargy
• FH Mother coeliacs disease
• O/E BMI 22
• No ketones

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Case 2 (Continued)

• Commenced on gliclazide
• But converted to insulin therapy within a month.

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Case 2 Question

• What type of diabetes has this patient got ?
• Type 1 diabetes
• Type 2 diabetes
• Something else

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Latent Autoimmune Diabetes of Adulthood (LADA)

• Known as slow-onset type 1
• Slowly progressive form of autoimmune diabetes
• Features of both type 1 and type 2 diabetes
• May account for up 10 of all diabetes patients

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Features of LADA

• Age at diagnosis (gt30 yrs)
• Presentation as for type 2 (non-ketotic) but
  often normal / low body weight
• May be other autoimmune diseases (or family
  history)
• Usually no family history of type 2 diabetes
• Positive pancreatic autoantibodies
• Low C-peptide levels

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MODY

• Rare hereditary form diabetes mellitus (autosomal
  dominant)
• Onset of diabetes before 25 years of age
• Non-ketotic non-insulin dependent at
  presentation
• Negative pancreatic autoantibodies
• Diagnosis-
• Mild hyperglycaemia is often detected at routine
  screening
• Fasting glucose is elevated
• Oral glucose tolerance test is less elevated than
  expected

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Genetics of MODY
MODY 2 Glucokinase (14)
MODY X (11)
Transcription factors (75)
MODY 1 HNF4? (3)
MODY 3 HNF1? (69)
MODY 4 IPF-1 (lt1)
MODY 5 HNF1 ? (3)
MODY 6 NeuroD1 (lt1)
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Not all diabetes is type 1 or type 2

• MODY patients have strong family history
• MODY 2 needs no treatment has no long-term
  complications
• MODY 3 is v. sensitive to sulphonylureas can ?
  diabetic complications

• LADA patients may have other autoimmune diseases
• Pancreatic autoantibody positive
• Likely to need insulin
• Risk of diabetic complications

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Case 3

• 50 year old female
• Type 2 diabetes (diagnosed age 35)
• Osteoarthritis, hyperlipidaemia, obstructive
  sleep apnoea
• DH Gliclazide 160 mg bd
• Metformin 1 g tds
• Atorvastatin 40 mg od
• Ramipril 10mg od

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Case 3 (Continued)

• BMI 45
• BP 160/80
• No complications
• HbA1c 13.1
• eGFR normal

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Case 3 Questions

• 1. What key issues need to be addressed ?
• 2. What is the next move to help
• a) diabetes ?
• 3. Any other therapeutic strategies ?

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Case 3 Key Issues

• Lifestyle diet, weight, exercise
• Drug compliance
• BP
• Hyperlipidaemia

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Case 3 options

• Low dose aspirin
• anti-obesity agents ?
• Exenatide ?
• Insulin ?
• Obesity surgery ?

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• What are Incretin Hormones?

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The Incretin Effect is Reduced in Subjects with
Type 2 Diabetes
The Incretin Effect accounts for 60 of total
Insulin release following a meal
Time (min)
Nauck MA, et al. Diabetologia
1986294652. P .05
compared with respective value after oral load.
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GLP-1 effects in humansUnderstanding the
natural role of incretins
GLP-1 secreted upon the ingestion of food
5.Brain promotes satiety and reduces appetite4,5
2.a-cell suppresses postprandialglucagon
secretion1
3.Liver reduces hepatic glucose output2
1.?-cellenhances glucose-dependent insulin
secretion in the pancreas1
4.Stomach slows the rate of gastric emptying3
Adapted from 1Nauck MA, et al. Diabetologia
199336741744 2Larsson H, et al. Acta Physiol
Scand 1997160413422 3Nauck MA, et al.
Diabetologia 19963915461553 4Flint A, et al.
J Clin Invest 1998101515520 5Zander et al.
Lancet 2002359824830.
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Exenatide (byetta)

• 1st GLP 1 analogue
• Twice daily sc injection
• Initial 5mcgs bd then 10 mcgs bd maintenance dose
• European licence late 2006
• Long acting once weekly preparation in pipeline

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Benefits

• Sustained weight loss (can be substantial)
• HbA1c reduction (1-2 or more)
• Beneficial effect on lipids and BP
• Possible benefit on LV function ??

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Side effects

• GI
• - nausea vomiting most freq problems
• - also diarrhoea, very rarely pancreatitis
• Hypoglycaemia
• - rare and only if concurrent sulphonylureas
• Antibodies
• - but not assoc. with any effect on outcome or
  adverse events

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Oral incretin mimetics - gliptins
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Sitagliptin (Januvia) use in T2DM

• License combination therapy with
• either metformin or sulphonylurea or glitazone
• add on to metformin plus sulphonylurea
• - Tablet form
• - Weight neutral
• - Modest reductions in HbA1C
• - Expensive
• Pembury Diab Centre-
• limited use to pts with previous hypoglycaemia
  and/or allergic reaction to sulphonylureas

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Gliptins

• Side-effects-
• GI effects nausea, vomiting
• Nasopharyngitis, skin rash
• Safety-
• Animal studies using non-selective DPP-IV
  inhibitors skin and neurological toxicity
• Selective DPP-IV inhibitors (eg., sitagliptin)
  long-term effects ?? unknown

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Case 4

• 75 year old female
• Type 2 diabetes
• Hypertension hyperlipidaemia
• DH Gliclazide 80 mg bd
• Metformin 1 g bd
• Perindopril 4 mg od
• Amlodipine 5 mg od
• Simvastatin 40 mg od
• Aspirin 75 mg od

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Case 4

• BMI 34
• BP 154/84
• Retinopathy (previous laser therapy)
• Mild peripheral neuropathy

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Case 4 (Results)
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Case 4 Questions

• What would you do with metformin?
• Stop it?
• Continue on same dose? yes
• Increase dose?
• Decrease dose?
• Something else?

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Case 4 Questions

• What would you do with perindopril?
• Stop it?
• Continue on same dose?
• Increase dose? yes
• Decrease dose?
• Something else?

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Case 4 Questions

• What would be a reasonable BP target ?
• lt 140/80?
• lt 135/80?
• lt 130/80? desirable
• lt 120/70? ideal

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Chronic kidney disease
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Metformin and CKD

• Clinical scenario 1
• Rapidly declining eGFR falling to below 50
  ml/min
• Action
• Stop metformin.
• Investigate cause for marked decline in renal
  function.

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Metformin and CKD

• Clinical scenario 2
• eGFR between 40-50 ml/min over long period of
  time with no change
• Action
• Continue metformin.
• Advise to stop metformin temporarily during
  acute illness, especially assoc. with dehydration.

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Metformin and CKD

• Clinical scenario 3
• Two consecutive eGFR measurements below 40
  ml/min
• Action
• Stop metformin.
• Consider other OHA if necessary (gliclazide is
  safest) or insulin.

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Glitazones concerns raised
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Does NOT appear to be a class effect
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West Kent guidance on the use of glitazones

• For new pts, pioglitazone (PG) is the glitazone
  of choice when indicated
• Rosiglitazone (RG) not recommended for pts with
  IHD or PVD
• Consider stopping treatment if HbA1C has not
  fallen by at least 1 from start despite maximal
  doses
• Avoid glitazone use in pts with heart failure
• Action plan for GPs-
• Option 1 - switch all pts from RG to equivalent
  dose PG
• Option 2 - pts with any history of IHD or PVD
  switch to PG
• Option 3 - pts with active or significant IHD or
  PVD switch to PG

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Lipid management in Diabetes

• 1 prevention
• Statins if 10yr risk gt20
• All type II diabetics with total cholesterol gt
  3.5
• All type I gt 40yrs treated with a statin
• Some higher risk type I and II diabetics aged 18
  - 40

• 2 prevention
• Statins

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Decision to treat
Simvastatin 40 mg
Total cholesterol lt4
Total cholesterol gt4
Simvastatin 80 mg Alternative statin /- Ezetimibe
Monitor
Specialist review
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Hypertension

• Hypertension doubles CV risk in diabetics

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Who to treat
lt130 80
gt130 80
Confirm over 4 8 weeks
130 - 139 80 - 89
gt140 90
Consider lifestyle changes Reassess at 3
months Commence drug treatment if fails to
achieve target
Commence drug therapy
Reassess yearly
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Decision made to treat
ACE i or AIIRB
NB Microlbuminuria or albuminuria
Calcium Channel blocker Thiazide
diuretic ß-blocker
BP difficult to control / renal
insufficiency Consider Renal artery stenosis
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ACEi for all diabetics?

• Micro - HOPE
• Diabetic established CHD or 1 risk factor
• Placebo vs Ramipril
• Significant reduction in
• CV death, stroke, MI
• Development of diabetic nephropathy
• Need for revascularisation

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Aspirin for all diabetics?

• US Physicians health study
• 5 years follow up
• MI reduced from 10 to 4
• HOT trial
• Aspirin reduced MI risk by 36
• Aspirin 75mg od for diabetics gt 40 or younger
  with additional risk factors

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NICE 2008
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Lowering HbA1C reduces the risk of diabetic
complications

• In intensively-treated patients, HbA1c was 7.0
  compared with 7.9 in conventionally-treated
  patients
• This decreased HbA1C (equivalent to an 11
  reduction over 10 years) is associated with a
  reduction in risk for diabetic complications

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Any diabetes-related endpoint
Significant
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Myocardial infarction (MI)
Borderline significance
Retinopathy
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Significant
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Cataract extraction
Borderline significance
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Microvascular endpoint
Significant
Albuminuria at 12 years
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Significant
0
-10
-20
-30
-40
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Reduction in risk ()
UK Prospective Diabetes Study (UKPDS) Group (33).
Lancet 1998 352 837853
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Thankyou