Question 116#

An obese man presents as he is concerned about his risk of developing cardiovascular disease.

Which one of the following sets of results would suggest a diagnosis of the metabolic syndrome using the Scottish Intercollegiate Guidelines Network (SIGN) criteria?

A. Waist circumference = 98 cm; fasting glucose = 7.2 mmol/l; HDL = 1.2 mmol/l

Correct Answer D: Whilst all the results contain at least one factor consistent with the metabolic syndrome only option D contains three of the criteria and would hence support a diagnosis. 

Metabolic syndrome:
Unfortunately there are a number of competing definitions of the metabolic syndrome around at the present time. It is thought that the key pathophysiological factor is insulin resistance.

SIGN recommend using criteria similar to those from the American Heart Association. The similarity of the International Diabetes Federation criteria should be noted. For a diagnosis of metabolic syndrome at least 3 of the following should be identified:

• Elevated waist circumference: men > 102 cm, women > 88 cm
• Elevated triglycerides: > 1.7 mmol/L
• Reduced HDL: < 1.03 mmol/L in males and < 1.29 mmol/L in females
• Raised blood pressure: > 130/85 mmHg, or active treatment of hypertension
• Raised fasting plasma glucose > 5.6 mmol/L, or previously diagnosed type 2 diabetes

The International Diabetes Federation produced a consensus set of diagnostic criteria in 2005, which are now widely in use. These require the presence of central obesity (defined as waist circumference > 94cm for Europid men and > 80cm for Europid women, with ethnicity specific values for other groups) plus any two of the following four factors:

• Raised triglycerides level: > 1.7 mmol/L, or specific treatment for this lipid abnormality
• Reduced HDL cholesterol: < 1.03 mmol/L in males and < 1.29 mmol/L in females, or specific treatment for this lipid abnormality
• Raised blood pressure: > 130/85 mm Hg, or active treatment of hypertension
• Raised fasting plasma glucose > 5.6 mmol/L, or previously diagnosed type 2 diabetes

In 1999 the World Health Organization produced diagnostic criteria which required the presence of diabetes mellitus, impaired glucose tolerance, impaired fasting glucose or insulin resistance, AND two of the following:

• Blood pressure: > 140/90 mmHg
• Dyslipidaemia: triglycerides: > 1.695 mmol/L and/or high-density lipoprotein cholesterol (HDL-C) < 0.9 mmol/L (male), < 1.0 mmol/L (female)
• Central obesity: waist:hip ratio > 0.90 (male), > 0.85 (female), and/or body mass index > 30 kg/m2
• Microalbuminuria: urinary albumin excretion ratio > 20 mg/min or albumin:creatinine ratio > 30 mg/g

Other associated features include:

• Raised uric acid levels
• Non-alcoholic fatty liver disease
• Polycystic ovarian syndrome 

Question 117#

Each one of the following is associated with Pendred's syndrome, except: 

A. Goitre

Correct Answer B: 

Pendred's syndrome:
Autosomal recessive disorder of defective iodine uptake.

Features:

• Sensorineural deafness
• Goitre
• Euthyroid or mild hypothyroidism

Question 118#

A 62-year-old man is investigated for hypertension and proximal myopathy. On examination he is noted to have abdominal striae.

Which one of the following is most associated with ectopic ACTH secretion?

A. Carcinoid tumour

Correct Answer B: Small cell lung cancer accounts 50-75% of case of ectopic ACTH.

Adrenal carcinoma and cardiac myxoma are causes of ACTH independent Cushing's syndrome.

Cushing's syndrome: causes:

ACTH dependent causes:

• Cushing's disease (80%): pituitary tumour secreting ACTH producing adrenal hyperplasia
• Ectopic ACTH production (5-10%): e.g. small cell lung cancer

ACTH independent causes:

• Iatrogenic: steroids
• Adrenal adenoma (5-10%)
• Adrenal carcinoma (rare)
• Carney complex: syndrome including cardiac myxoma
• Micronodular adrenal dysplasia (very rare)

Pseudo-Cushing's:

• Mimics Cushing's
• Often due to alcohol excess or severe depression
• Causes false positive dexamethasone suppression test or 24 hr urinary free cortisol
• Insulin stress test may be used to differentiate 

Question 119#

Which one of the following combinations of treatments should be avoided in patients with type 2 diabetes mellitus?

A. Metformin + insulin + exenatide

Correct Answer A: Exenatide should only be used in combination with metformin, a sulfonylurea or both.

Diabetes mellitus: management of type 2:
NICE updated its guidance on the management of type 2 diabetes mellitus (T2DM) in 2009. Key points are listed below:

Dietary advice:

• Encourage high fibre, low glycaemic index sources of carbohydrates
• Include low-fat dairy products and oily fish
• Control the intake of foods containing saturated fats and trans fatty acids
• Limited substitution of sucrose-containing foods for other carbohydrates is allowable, but care should be taken to avoid excess energy intake
• Discourage use of foods marketed specifically at people with diabetes
• Initial target weight loss in an overweight person is 5-10%

HbA1c:

• The general target for patients is 48 mmol/mol (DCCT = 6.5%). HbA1c levels below 48 mmol/mol (DCCT = 6.5%) should not be pursued
• However, individual targets should be agreed with patients to encourage motivation
• HbA1c should be checked every 2-6 months until stable, then 6 monthly

Blood pressure:

• Target is < 140/80 mmHg (or < 130/80 mmHg if end-organ damage is present)
• ACE inhibitors are first-line

The NICE treatment algorithm has become much more complicated following the introduction of new therapies for type 2 diabetes. We suggest reviewing this using the link provided. Below is a very selected group of points from the algorithm:

• NICE still suggest a trial of lifestyle interventions first*
• Usually metformin is first-line, followed by a sulfonylurea if the HbA1c remains > 48 mmol/mol (DCCT = 6.5%)
• If the patient is at risk from hypoglycaemia (or the consequences of) then a DPP-4 inhibitor or thiazolidinedione should be considered rather than a sulfonylurea
• Meglitinides (insulin secretagogues) should be considered for patients with an erratic lifestyle
• If HbA1c > 58 mmol/mol (DCCT = 7.5%) then consider human insulin
• Metformin treatment should be continued after starting insulin
• Exenatide should be used only when insulin would otherwise be started, obesity is a problem (BMI > 35 kg/m^2) and the need for high dose insulin is likely. Continue only if beneficial response occurs and is maintained (> 1.0 percentage point HbA1c reduction and weight loss > 3% at 6 months)

Starting insulin:

• Usually commenced if HbA1c > HbA1c > 58 mmol/mol (DCCT = 7.5%)
• NICE recommend starting with human NPH insulin (isophane, intermediate acting) taken at bedtime or twice daily according to need

Other risk factor modification:

• Current NICE guidelines suggest giving aspirin to all patients > 50 years and to younger patients with other significant risk factors. However, recent evidence does not support this approach. The 2010 SIGN guidelines do not advocate the use of aspirin for primary prevention in diabetics
• The management of blood lipids in T2DM has changed slightly. Previously all patients with T2DM > 40- years-old were prescribed statins. Now patients > 40-years-old who have no obvious cardiovascular risk (e.g. Non-smoker, not obese, normotensive etc) and have a cardiovascular risk < 20%/10 years do not need to be given a statin. We suggest reviewing the NICE T2DM guidelines for further information
• If serum cholesterol target not reach consider increasing simvastatin to 80mg on
• If target still not reached consider using a more effective statin (e.g. Atorvastatin) or adding ezetimibe
• Target total cholesterol is < 4.0 mmol/l
• If serum triglyceride levels are > 4.5 mmol/l prescribe fenofibrate

*many local protocols now recommend starting metformin upon diagnosis.

Question 120#

A 55-year-old accountant with type 2 diabetes mellitus comes for review. When he was diagnosed 12 months ago he was started on metformin and the dose was titrated up. His IFCC-HbA1c one year ago was 75 mmol/mol (DCCT-HbA1c 9%) and is now 69 mmol/mol (8.5%). His body mass index is 33 kg/m².

What is the most appropriate next step in management?

A. Add exenatide

Correct Answer C: His HbA1c is still significantly above target so some change to the medication is indicated. The NICE type 2 diabetes mellitus guidelines would advocate the use of a sulfonylurea in this situation. This may seem slightly counter intuitive as it may increase the weight of a patient who is already obese. Why not use exenatide? However the average weight gain for a patient taking a sulfonylurea is 2 kg. It is likely the view of NICE that this modest weight gain does not offset the increased cost, need to involve secondary care and current lack of data surrounding cardiovascular endpoints of exenatide.

Diabetes mellitus: management of type 2:

NICE updated its guidance on the management of type 2 diabetes mellitus (T2DM) in 2009. Key points are listed below: 

Dietary advice:

• Encourage high fibre, low glycaemic index sources of carbohydrates
• Include low-fat dairy products and oily fish
• Control the intake of foods containing saturated fats and trans fatty acids
• Limited substitution of sucrose-containing foods for other carbohydrates is allowable, but care should be taken to avoid excess energy intake
• Discourage use of foods marketed specifically at people with diabetes
• Initial target weight loss in an overweight person is 5-10%

HbA1c:

• The general target for patients is 48 mmol/mol (DCCT = 6.5%). HbA1c levels below 48 mmol/mol (DCCT = 6.5%) should not be pursued
• However, individual targets should be agreed with patients to encourage motivation
• HbA1c should be checked every 2-6 months until stable, then 6 monthly

Blood pressure:

• Target is < 140/80 mmHg (or < 130/80 mmHg if end-organ damage is present)
• ACE inhibitors are first-line 

The NICE treatment algorithm has become much more complicated following the introduction of new therapies for type 2 diabetes. We suggest reviewing this using the link provided. Below is a very selected group of points from the algorithm:

• NICE still suggest a trial of lifestyle interventions first*
• Usually metformin is first-line, followed by a sulfonylurea if the HbA1c remains > 48 mmol/mol (DCCT = 6.5%)
• If the patient is at risk from hypoglycaemia (or the consequences of) then a DPP-4 inhibitor or thiazolidinedione should be considered rather than a sulfonylurea
• Meglitinides (insulin secretagogues) should be considered for patients with an erratic lifestyle xif HbA1c > 58 mmol/mol (DCCT = 7.5%) then consider human insulin
• Metformin treatment should be continued after starting insulin
• Exenatide should be used only when insulin would otherwise be started, obesity is a problem (BMI > 35 kg/m^2) and the need for high dose insulin is likely. Continue only if beneficial response occurs and is maintained (> 1.0 percentage point HbA1c reduction and weight loss > 3% at 6 months)

Starting insulin:

• Usually commenced if HbA1c > HbA1c > 58 mmol/mol (DCCT = 7.5%)
• NICE recommend starting with human NPH insulin (isophane, intermediate acting) taken at bedtime or twice daily according to need

Other risk factor modification:

• Current NICE guidelines suggest giving aspirin to all patients > 50 years and to younger patients with other significant risk factors. However, recent evidence does not support this approach. The 2010 SIGN guidelines do not advocate the use of aspirin for primary prevention in diabetics
• The management of blood lipids in T2DM has changed slightly. Previously all patients with T2DM > 40- years-old were prescribed statins. Now patients > 40-years-old who have no obvious cardiovascular risk (e.g. Non-smoker, not obese, normotensive etc) and have a cardiovascular risk < 20%/10 years do not need to be given a statin. We suggest reviewing the NICE T2DM guidelines for further information
• If serum cholesterol target not reach consider increasing simvastatin to 80mg on
• If target still not reached consider using a more effective statin (e.g. Atorvastatin) or adding ezetimibe
• Target total cholesterol is < 4.0 mmol/l
• If serum triglyceride levels are > 4.5 mmol/l prescribe fenofibrate

*many local protocols now recommend starting metformin upon diagnosis.