type 2 diabetes. what is type 2 diabetes? definition of diabetes? who/international diabetes...
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Type 2 Diabetes
What is type 2 diabetes?
Definition of diabetes?WHO/International Diabetes Federation. Definition and diagnosis of diabetes
mellitus and intermediate hyperglycaemia; 2006
• Diabetes– Fasting plasma glucose ≥ 7.0mmol/l (126mg/dl) or– 2h plasma glucose ≥ 11.1mmol/l (200mg/dl)
• Impaired glucose tolerance (IGT)– Fasting plasma glucose < 7.0mmol/l (126mg/dl) and– 2h plasma glucose ≥ 7.8 and < 11.1mmol/l (140mg/dl and 200mg/dl)
• Impaired fasting glucose (IFG)– Fasting plasma glucose 6.1 to 6.9mmol/l (110mg/dl to 125mg/dl) and– 2h plasma glucose < 7.8mmol/l
Change of units for HbA1cDTB 2010; 48: 23-4, MeReC Rapid Review No. 356
Conversion chart for HbA1c values
HbA1c (%) HbA1c (mmol/mol)
4.0 20
4.5 26
5.0 31
5.5 37
6.0 42
6.5 48
7.0 53
7.5 59
8.0 64
8.5 70
9.0 75
9.5 81
10.0 86
Type 1 vs. Type 2 diabetesLambert P, et al. Medicine 2006; 34: 47-51
Nolan JJ, Medicine 2006; 34: 52-6
Features of type 1 diabetes• Onset in childhood / adolescence• Lean body habitus• Acute onset of osmotic
symptoms• Ketosis-prone• High levels of islet autoantibodies• High prevalence of genetic
predisposition
Features of type 2 diabetes• Usually presents in over-30s• Associated with overweight /
obesity• Onset is gradual and diagnosis
often missed (up to 50% cases)• Not associated with ketoacidosis
though ketosis can occur• Family history is often positive
with almost 100% concordance in identical twins
Burden of type 2 diabetesNICE Clinical Guideline 87, May 2009
Royal College of Physicians; 2008
• Type 2 diabetes is a cardiovascular disease: commonly associated with raised BP, disturbance of lipid levels and tendency to develop thrombosis
• Increased cardiovascular risk (macrovascular disease)– Coronary heart disease (MIs, angina)– Peripheral artery disease (leg claudication, gangrene)– Carotid artery disease (strokes, dementia)
• Specific microvascular complications:– Eye damage (blindness)– Kidney damage (sometimes requiring dialysis or transplantation)– Nerve damage (amputation, painful symptoms, erectile dysfunction,
other problems)
Deaths by cause in the general population: Men aged 40-59 years, 1999, UKLaing SP, et al. Diabetic Medicine 1999; 16: 466-471
Office of National Statistics 2000General Register Office 2000
CVD 35%
Cancer 33%
All other causes 15%
Accidents and violence 10%
Respiratory disease 6%
Diabetes 1%
Renal disease 0%
Deaths by cause in people with diabetes: Men aged 40-59 years, 1972/99, UK
CVD 63%
Renal disease 10%
Respiratory disease 6%
Accidents and violence 6%
Cancer 5%
Diabetes 5%
All other causes 5%
What are the management priorities?
Management for type 2 diabetes: AimsNICE Clinical Guideline 87; May 2009
• Adopt a healthy lifestyle (stop smoking, exercise, weight management etc)– Manage symptoms associated with having high blood glucose levels if patients
have them)
• Reduce risk of major life-threatening or disabling complications (heart attacks and stroke)
• Manage diabetic kidney damage, eye damage and nerve damage (foot disease, neuropathic pain, erectile dysfunction etc)
• Targets for all the different aspects of this condition (BP, lipids, blood glucose etc) can be demanding to reach– Agree the priorities for care and targets for each aspect of management on an
individualised patient basis as aggressive therapy of each aspect may not be appropriate for all
Type 2 diabetes management is multifactorial
• Education• Lifestyle
– Dietary advice– Obesity– Weight management
• Smoking• Control BP• Assessing cardiovascular risk• Blood lipids• Aspirin• Control blood glucose
Education
Education – what does NICE say?NICE Clinical Guideline 87; May 2009
• Offer structured education to every person &/or their carer at and around the time of diagnosis, with annual reinforcement and review. Inform patients and their carers that structured education is an integral part of diabetes care
• The necessary lifestyle changes, the complexities of management and the side effects of therapy make self-monitoring and education for people with diabetes central parts of management
• “Patient centred care”
• People with diabetes should have the opportunity to make informed decisions about their care and treatment, in partnership with their healthcare professionals. Good communication is essential
What is the evidence? The DESMOND programmeDavies MJ, et al. BMJ 2008; 336: 491-495.
Gillett M, et al. BMJ 2010; 341: c4093
• Diabetes Education and Self-Management for Ongoing and Newly Diagnosed programme
• Patients taking part were significantly more likely to lose a little weight and stop smoking than those in the control group
• Primary outcomes of the DESMOND programme trial found no statistical differences in HbA1c and no benefits for cholesterol levels and BP
Lifestyle
Dietary adviceNICE Clinical Guideline 87; May 2009
• Provide individualised and ongoing nutritional advice from a healthcare professional with specific expertise and competencies in nutrition
• Healthy balanced eating applicable to general population
• Integrate dietary advice with advice to increase physical activity and lose weight
• Target initial weight loss is 5-10% of body weight is overweight
• Individualised recommendations for carbohydrate and alcohol intake
• Limited substitution for sucrose containing foods and other carbohydrates is allowable but take care to avoid excess energy intake
• Discourage use of foods specifically marketed for people with diabetes
Obesity: exercise and dietNational Audit Office. Tackling obesity in England. 15 February 2001
Avenell A, et al. Health Technol Assess 2004; 8(21): 1-465
• Virtually all obese people develop some associated physical symptoms by the age of 40 years
• The majority require medical intervention for diseases that develop as a result of obesity by the age of 60 years
• National Audit Office suggests that 47% of type 2 diabetes can be attributed to obesity
• As obesity rates increase, so will the prevalence of type 2 diabetes
• Even modest losses in weight can confer significant metabolic and vascular benefits. Losing weight is associated with a reduction in:– Mortality (all-cause, cancer, CVD and diabetes-related)– The risk of developing type 2 diabetes– Hypertension– Cholesterol
Weight managementSIGN 116, Management of diabetes. March 2010
• Obese adults with type 2 diabetes should be offered individualised interventions to encourage weight loss (including lifestyle, pharmacological or surgical interventions) in order to improve metabolic control– A single approach is not recommended due to an absence of head-to-
head comparisons
• Consider drug treatment only after dietary, exercise and behavioural approaches have been started and evaluated
• Consider drug treatment for patients who have not reached their target weight loss or have reached a plateau on dietary, activity and behavioural changes alone
Smoking
Smoking cessation
• Advising and effectively assisting a person to stop smoking is the single most important thing that can be done for health
• All healthcare professionals should take the opportunity to advise smokers to stop smoking, and consider referral to the NHS Stop Smoking Service
Control BP
Blood pressure – what does NICE say?NICE Clinical Guideline 87; May 2009
• Target BP– <140/80mmHg– <130/80mmHg if kidney, eye or cerebrovascular damage
• Drug choices– ACE inhibitor (first-line)– Add CCB or diuretic– Add other drug (CCB or diuretic)– Add alpha-blocker, beta-blocker or potassium sparing diuretic
ACE inhibitors first lineNICE Clinical Guideline 87; May 2009NICE Full Diabetes Guideline 66, 2008
• ACE inhibitors have no significant differences in CV outcomes compared with other antihypertensives but have greater benefits in terms of renal outcomes in those with type 2 diabetes
• Exceptions:
– Afro-Caribbeans who should receive an ACE inhibitor plus either a diuretic or CCB
– Women who may become pregnant should receive a CCB– Those with a continuing intolerance to an ACE inhibitor eg cough
should substitute an A2RB
Blood pressure managementNICE Clinical Guideline 87; May 2009
• Targets– If kidney, eye or cerebrovascular damage, set a target <130/80mmHg– Others, set a target , 140/80mmHg
• If on antihypertensive therapy at diagnosis of diabetes– Review BP control and medication use– Make changes only if BP is poorly controlled or current medications are inappropriate because of
microvascular complications or metabolic problems
• If the person’s BP reaches and consistently remains at the target– Monitor every 4-6 months and check for possible adverse effects of antihypertensive therapy (including
those from unnecessarily low BP)
• Measure BP annually if not hypertensive or with renal disease
• If BP > target, repeat measurements within:– 1 month if > 150/90mmHg– 2 months if > 140/80mmHg– 2 months if > 130/80mmHg and kidney, eye or cerebrovascular damage
Summary of BP management
• BP control is very important in patients with type 2 diabetes
• Before starting drug therapy– Use immaculate technique and do at least two readings on each of three different
occasions
• Drug treatment– In general ACE inhibitors are 1st line, with CCBs or thiazides 2nd line– Think about switching drug classes if no response– No robust evidence that A2RB are superior to ACE inhibitors– No evidence to suggest increased effectiveness with ACE plus A2RB
• Treat the patient, not the BP– Compliance is critical – a drug not taken will not work– Weigh potential benefits to be gained from decreasing BP further against the
acceptability to the patient of aggressive therapy with multiple drugs
Assessing cardiovascular risk
What about assessing CV risk?NICE Clinical Guideline 87; May 2009
• NICE recommends annual review of CV risk:– Assess risk factors– Note changes in personal or family history– Perform a full lipid profile
• Consider to be at high CV risk unless all of the following apply:
– Not overweight– Normotensive– No microalbuminuria– Non-smoker– No high-risk lipid profile– No history of CV disease– No family history of CV disease
Blood lipids
Management of blood lipids (1)NICE Clinical Guideline 87; May 2009
• Offer simvastatin 40mg or a statin of similar efficacy or cost
• Give to those:– Aged 40+ and normal to high CV risk with type 2 diabetes– Aged 40+ and low CV risk with type 2 diabetes but CV risk >20% risk
when assessed using UKPDS risk engine– Aged <40 and poor CV risk factor profile
• Assess lipid profile and modifiable risk factors 1-3 months after starting therapy. Continue to monitor annually
• Do not use in women who may become pregnant unless issues discussed and agreement reached
Management of blood lipids (2)NICE Clinical Guideline 87; May 2009
• Increase to simvastatin 80mg unless TC <4.0mmol/l or LDL <2.0mmol/l
• If there is existing or newly diagnosed CV disease or increased albumin excretion rate consider intensifying therapy with or more effective statin or ezetimibe to achieve a TC <4.0mmol/l or LDL <2.0mmol/l
NICE guidance comparedNICE Diabetes CG 87, May 2009
NICE Lipids CG 67, May 2008
Type 2 diabetes(CG 87 – formerly 66)
CV risk assessment and lipids (CG 67)
People without established CVD but >20% 10y CVD risk
Simvastatin 40mg,Increase to 80mg if TC >4mmol/l and also LDL >2mmol/l
Simvastatin 40mgNo lipid target
People with established CVD (no ACS) or increased albumin excretion rate (type 2 diabetes)
Simvastatin 40mgConsider intensifying with a ‘more effective’ statin or ezetimibe (if primary hypercholesterolaemia) to achieve TC <4mmol/l or LDL <2mmol/l
Simvastatin 40mgConsider increasing to 80mg if TC >4mmol/l and also LDL >2mmol/l
Lipid modification in T2DMSummary
• Lipid modification is very important
• Baseline risk is the key to the size of absolute benefits
• Most patients should be on a statin
• Simvastatin 40mg is first line– Increase to 80mg if TC >4mmol/l and also LDL >2mmol/l– If existing or newly diagnosed CV disease or increased albumin
excretion rate consider intensifying therapy (with more effective statin or ezetimibe (if primary hypercholesterolaemia) to achieve TC <4mmol/l or LDL <2mmol/l
• NICE recommends fibrates only in particular circumstances
Aspirin
Anti-thrombotic therapyNICE Clinical Guideline 87; May 2009
• NICE says offer aspirin 75mg daily:– To a person who is ≥ 50 years if BP is <145/90mmHg– To a person <50 years and has significant other risk factors (features
of metabolic syndrome, strong early FH of CV disease, smoking, hypertension, microalbuminuria)
• MRHA advice:– Aspirin is not licensed for the primary prevention of vascular events. If
used the balance of benefits and risks should be considered for each individual, particularly the presence of risk factors for vascular disease (including conditions such as diabetes) and the risk of GI bleeding
AspirinSummary
• Aspirin should still be offered to patients with diabetes and evidence of CV disease ie for secondary prevention of CV events
• In primary prevention a more individualised approach should be adopted as the presence of personal risk factors may change the risk : benefit profile
• Aspirin is not licensed for primary prevention
Control blood glucose
What does NICE say?NICE Clinical Guideline 87; May 2009
• Setting a target HbA1c
– Involve the patient in decision making– Encourage the patient to maintain their individual target unless the
resulting side effects or efforts to achieve this impair their quality of life
– Offer therapy (lifestyle and medication) to help achieve and maintain the target level
– Inform the patient with a higher HbA1c that any reduction is advantageous to future health
– Avoid pursuing highly intensive management plans to level of < 6.5%
What does NICE say?NICE Clinical Guideline 87; May 2009
• Levels of HbA1c for addition of extra glucose lowering drugs
– 6.5% (or other higher level) for people on one oral glucose lowering drug
– 7.5% (or other higher level) for people on two or more oral glucose lowering drugs or insulin
• Intensive blood glucose control has benefits but also harms– Reduction in CHD and CVD risk, but no reduction in mortality– Recent studies show mixed results on microvascular endpoints– Increased risk of severe hypoglycaemia– ACCORD: intensive therapy associated with increased risk of death
• Other interventions to reduce CV risk (smoking cessation, exercise, losing weight, controlling BP, lowering cholesterol, taking metformin) may have more benefit overall
• The Goldilocks effect– Observational study identified that HbA1c of about 7.5% is associated with
lowest risk of all-cause mortality (increase above or decrease below) is associated with greater risk
Drug treatment for blood glucose control
Hypoglycaemic drugs used in type 2 diabetesBNF 60, September 2010
Class Drug NICE guidance
Biguanidines Metformin CG87
Sulphonylureas Glibenclamide, gliclazide CG87
Rapid acting insulin secretagogues
Nateglinide, repaglinide CG87
Glitazones Pioglitazone CG87
Rosiglitazone CG87
Gliptins (DPP-4 inhibitors) Sitagliptin CG87
Vildagliptin CG87
Saxagliptin None
GLP-1 mimetics Exenatide CG87
Liraglutide TA203
Insulins Human NPH insulin etc CG87
Long acting insulin analogues
Insulin detemir CG87
Insulin glargine CG87
Drug treatment for blood glucose controlBased on NICE Clinical Guideline 87; May 2009
What does the NICE guideline say (1)NICE Clinical Guideline 87; May 2009
MeReC Rapid review No. 355• Same levels of HbA1c for addition of extra glucose lowering drugs
– 6.5% (or other higher level) for people on one oral glucose lowering drug– 7.5% (or other higher level) for people on two or more oral glucose lowering drugs or
insulin
• Metformin still first line hypoglycaemic drug– Sulphonylurea is an option if:
• Patient is not overweight• A rapid therapeutic response is required• Metformin is contraindicated / not tolerated
• If blood glucose control is inadequate on monotherapy dual therapy with metformin and a sulphonylurea remains the usual second line therapy– Rapid acting insulin secretagogues (rapaglinide and nateglinide) still only recommended
as a consideration for people with erratic lifestyles– Other alternatives may be considered in particular patient circumstances
What does the NICE guideline say (2)NICE Clinical Guideline 87; May 2009
MeReC Rapid review No. 355
• Glitazones (and gliptins) can be considered for dual therapy with either metformin or sulphonylurea
• Pioglitazone, sitagliptin or vildagliptin should be continued only if the person has a beneficial metabolic response (reduction of at least 0.5% in HbA1c in 6 months)
• Which to choose?– Gliptin may be preferred if further weight gain would be a significant
problem– Glitazone may be preferred if a person has marked insulin insensitivity
What does the NICE guideline say (3)NICE Clinical Guideline 87; May 2009
MeReC Rapid review No. 355
• Normal third line option is insulin in addition to metformin and a sulphonylurea
• Intermediate acting human isophane insulin (human NPH insulin) remains preferred basal insulin taken at bedtime or twice daily according to need
• Combining pioglitazone with insulin can be considered in a person with previous marked glucose lowering response to glitazone, or person on high-dose insulin whose blood glucose is inadequately controlled
What does the NICE guideline say (4)NICE Clinical Guideline 87; May 2009
MeReC Rapid review No. 355• What are the alternatives to insulin?
– Sitagliptin or glitazones can be considered for triple therapy with metformin and SU instead of insulin if insulin is unacceptable / inappropriate because of:• Employment• Social issues related to hypoglycaemia• Injection anxieties• Other personal issues• obesity
– Exenatide can be used for triple therapy in addition to metformin and SU if• BMI ≥ 35kg/m² in people of European descent and specific psychological / medical problems
associated with high body weight• BMI < 35kg/m² and insulin would have significant occupational implications or weight loss
would benefit other significant obesity related comorbidities
– Exenatide should be continued only if the person has a beneficial metabolic response (reduction of at least 1% in HbA1c and a body weight loss of at least 3% of initial body weight at 6 months)
Established oral hypoglycaemics
MetforminSulphonylureas
• Step up dose of metformin to minimise GI side effects; consider trial of MR metformin if tolerability prevents continuation
• Review metformin if serum creatinine > 130 or eGFR <45
• Stop metformin if serum creatinine >150 or eGFR <30
Newer agents
GlitazonesGliptins
GLP-1 mimetics
How do the newer drugs compare?NICE Clinical Guideline 66; May 2008NICE Clinical Guideline 87; May 2009
Positives Negatives
GlitazonesPioglitazone
OralSimilar HbA1c reductions to metformin or SU
Safety concerns (HF, fractures)Weight gainCost
GliptinsSitagliptinVildagliptinSaxagliptin
OralSimilar HbA1c reductions to glitazonesNo weight gain
No long term safety dataCost
GLP-1 mimeticsExenatideLiraglutide
Similar HbA1c reduction to insulinWeight loss
ParenteralNo long term safety dataCost
Glitazones
Pioglitazone
• Can be used 2nd line as dual therapy with metformin or SU if either is CI / not tolerated, or if significant risk of hypoglycaemia with SU
• Can be used 3rd line as triple therapy with metformin or SU BUT insulin preferred
• Only use glitazones if beneficial metabolic response
• Pioglitazone– CI in heart failure– Monitor for signs / symptoms of fluid retention, weight gain or oedema– Stop treatment if any deterioration in cardiac status occurs– Do not commence / continue in people with higher risk of fracture
Gliptins
Oral DPP-4 inhibitorsSitagliptin and Vildagliptin
• Sitagliptin and vildagliptin can be 2nd line agents (at HbA1c ≥ 6.5%), as dual therapy with metformin or SU if either of these is CI or not tolerated, or hypoglycaemia on SU a particular issue
• Sitalgliptin can be a 3rd line agent, as triple therapy with metformin and SU if glycaemic control is insufficient (HbA1c ≥ 7.5%) BUT insulin is preferred
• Only continue gliptins if beneficial metabolic response– Reduction of at least 0.5% in HbA1c in 6 months
• Only sitagliptin is licensed for use with metformin and a SU
GLP-1 mimetics
Parenteral exenatide or liraglutide
• Exenatide can be a 3rd line agent as triple therapy with metformin and SU is glycaemic control is insufficient (HbA1c ≥ 7.5%) and – BMI ≥ 35kg/m² in people of European descent and specific
psychological / medical problems associated with high body weight, or– BMI < 35kg/m² and insulin would have significant occupational
implications or weight loss would benefit other significant obesity related comorbidities
• NPH insulin is preferred– Can be used instead of insulin or if insulin unacceptable or inappropriate
• Only continue exenatide if beneficial metabolic response– Reduction of at least 1% in HbA1c and weight loss of at least 3% of initial
body weight at 6 months
Insulin
Human NPH insulinLong-acting insulin analogues
(insulin determir, insulin glargine)
What is the guidance from NICE?NICE Clinical Guideline 87; May 2009
• Usual 3rd line option is to initiate insulin therapy in addition to metformin and SU
• Intermediate acting human isophane insulin (human NPH insulin) remains preferred basal insulin, taken at bedtime or twice daily according to need
Summary
• Increasing number of people with diabetes being identified and recorded
• Costs of dispensing for diabetes increasing markedly
• Managing type 2 diabetes is multifactorial and requires individualised evidence based care of several risk factors– Keep it “simple and safe”
• Blood glucose control is important. Helping patients stop smoking, implement lifestyle changes (diet and exercise), control their BP, and encouraging them to take a statin and metformin may be more effective at preventing adverse cardiovascular outcomes and death than intensive control of blood glucose alone
Case studies
• Case 1 - Initial management of type 2 diabetes
• Case 2 - Ongoing management of type 2 diabetes
• Case 3 - Prevention of type 2 diabetes
Case study 1
• Ted is a 56y old salesman. He is married to Carol. He smokes 20 cigarettes per day and drinks 2-3 units of alcohol per day. He spends a lot of time driving. Recently he has needed to pass urine more frequently. His older brother recently had a MI. Urine dipstick shows marked glycosuria suggesting type 2 diabetes. He does not have proteinuria or microalbuminuria
What further investigation(s) would you do (if any) to confirm a diagnosis of diabetes to WHO standards?
• WHO guidelines on definition and diagnosis says appropriate diagnostic tests are either: – Oral glucose tolerance test (gold standard test)
• Identifies those with impaired glucose tolerance– Fasting plasma glucose test or
• This test alone fails to diagnose approximately 30% of cases of previously undiagnosed diabetes
• May be a more acceptable test to have
• Dipstick has low sensitivity (missed nearly 4/5ths of those who really have diabetes
• Random plasma glucose has poor sensitivity and specificity compared with the OGTT and FPG test
• Ted decides to have the FPG test which comes back at 12mmol/l
• As he has symptoms suggestive of diabetes you diagnose that he has type 2 diabetes on the basis of this single abnormal result
• If he was asymptomatic at lest one other additional abnormal glucose level is essential
When explaining the diagnosis of type 2 diabetes to Ted what other information should be given?
• Education is a central part of management
• Structured education should be offered to all at the time of diagnosis with annual reinforcement and review
• The preferred format in NICE guidance are group educational programmes
• Suitable topics to cover include:– Nature of diabetes– Day to day management of diabetes– Specific issues– Living with diabetes– ‘Sick day’ rules
Have structured education programmes been shown to be effective in improving management and reducing complications of type 2 diabetes?
• Ted’s smoking history, age, sex, family history and now type 2 diabetes suggest that he is at high risk of macrovascular (CVD eg MI and stroke) and microvascular disease (retinopathy, renal disease and peripheral neuropathy)
• Further clinical examination and blood test results for him are as follows:
• BP = 152/94mmHg• BMI = 31kg/m²• HDL cholesterol = 0.9mmol/l• LDL cholesterol = 2.2mmol/l• Total cholesterol = 5.5mmol/l• HbA1c = 7.5%
Should you do a formal assessment to determine Ted’s risk of CVD?
• No• Nearly all people with type 2 diabetes are at high CVD risk• People with type 2 diabetes are considered at high risk unless they have
all of the following:– Not overweight– Normotensive– No microalbuminuria– Non-smoker– No high-risk lipid profile– No history of CVD– No FH of CVD
• He has type 2 diabetes, is overweight, may be hypertensive, is a smoker and has a FH of CVD
How should ‘high risk of CVD’ be explained to him?
• He should be given information about his absolute risk of CVD and the benefits and harms of an intervention over a 10 year period using appropriate diagrams and text
• Use everyday jargon free language
• He should be involved in developing a shared management plan that will include lifestyle changes acceptable to him
What lifestyle advice should be given to him to reduce his CV risk?
• Stop smoking• Adopt a cardioprotective diet• Take regular exercise• Manage his weight• Keep alcohol intake below recommended levels
Should Ted start taking an antihypertensive medication on the basis of these results?
• No
• Offer lifestyle advice (diet and exercise) on how to help reduce BP
• Further measurements are required to confirm hypertension
Should Ted start taking a lipid lowering medication on the basis of these results?
• Yes
• Irrespective of initial levels, people with type 2 diabetes aged 40 years and over should be considered for treatment with simvastation 40mg daily unless they are at low CV risk
• He should start on 40mg daily and the profile assessed 1-3 months later. The dose should be increased to 80mg unless his TC is <4mmol/l or his LDL is <2mmol/l. If either figure is below that level increasing the dose is not recommended
Should Ted start blood glucose lowering therapy immediately, and if so what is the most appropriate 1st line treatment for him?
• Metformin – start at low dose and step up gradually over weeks to minimise the risk of GI side effects
• Use a sulphonylurea if:– Not overweight– Metformin contraindicated– Rapid response required due to hyperglycaemic symptoms
What parameter should be measured to determine blood glucose control and how should this be monitored?
• HbA1c
• Measure at 2-6 monthly intervals (tailored to individual need) until blood glucose is stable on unchanging therapy
• Once blood glucose level and blood glucose lowering therapy are stable measure HbA1c every 6 months
Should Ted monitor his blood glucose?
• Advantages– Enables him to see the effects of lifestyle interventions on his blood
glucose levels
• Disadvantages– Time consuming– Painful– Potentially raises anxiety– Unnecessary expense
Should Ted take an antiplatelet drug?
• Aspirin is effective for secondary prevention of CV events
• NICE recommends 75mg aspirin in those who are: – ≥ 50 years old– If BP is < 145/90mmHg
• New data suggests that aspirin is ineffective for the primary prevention of CV events in patients with type 1 or type 2 diabetes and asymptomatic peripheral arterial disease (a risk factor for CVD)
• Weight up pros and cons
Case study 2
• Two months later he has stopped smoking with the help of a smoking cessation service. He continues to drink 2-3 units per day. He has lost some weight and is doing more exercise but he has now been diagnosed with hypertension. You decide to offer him drug treatment for his hypertension
What is the first choice antihypertensive for him?
• Angiotensin-converting enzyme inhibitor (ACE-1)• Exceptions
– African-Caribbean descent– women for whom there is a possibility of becoming pregnant
• NICE found no significant differences in terms of cardiovascular (CV) outcomes when treatment with ACEIs was compared with other antihypertensive therapies
• ACEIs also failed to demonstrate superiority over other agents on the basis of BP-lowering power
• However, the evidence suggested that treatment with an ACEI is related to greater benefits in terms of renal outcomes in patients with type 2 diabetes compared with other BP-lowering agents
What target BP is appropriate for him and how often should his BP be monitored?
• Below 140/80 mmHg as there is no evidence of kidney, eye or cerebrovascular damage
• If Ted had any signs of kidney, eye or cerebrovascular damage the target would be lower, less than 130/80 mmHg
• Monitor BP every 1-2 months and intensify therapy accordingly
• If Ted's BP is not reduced to <140/80mmHg or an individually agreed target with an ACEI add a thiazide diuretic or calcium-channel blocker
• If the target is not reached on dual therapy add the other drug
• If Ted's BP is still not reduced to the agreed target on triple therapy, an alpha blocker, a beta blocker or a potassium sparing diuretic (the last with caution if taking an ACEI or angiotension-2 receptor antagonist) can be added
• However, the potential benefits to be gained from decreasing BP ever further must be weighed against the acceptability to the patient of aggressive therapy with multiple drugs
• When Ted has attained and is consistently at his BP target, monitoring of BP should be every 4-6 months.
• Ted attends for a further diabetes check up 8 months after diagnosis. He has lost a bit more weight, is exercising and adjusted his diet. His initial diabetes symptoms have improved. His has continued to stop smoking. His BP 8 weeks ago was stable. He started metformin 2 months after diagnosis as his HbA1c had increased to 7.8%. He is now taking 1g daily
• His current medication is:– Ramipril 5mg daily– Bendroflumethazide 2.5mg OD– Sinvastatin 40mg OD– Metformin 500mg BD
• He injured his knee and was prescribed diclofenac 75mg BD which he has taken regularly for 2 months
• Latest results show:– BP 138/80mmHg– BMI 27kg/m²– HDL = 1.1mmol/l– LDL = 2.2mmol/l– TC = 3.6mmol/l– HbA1c = 8.1%– Negative for microalbuminuria / proteinuria
• He previously tried to increase his dose of metformin but this gave him diarrhoea
How concerned are you that his HbA1c is 8.1%. How would you suggest managing this?
• The evidence that tight control of blood glucose prevents complications of diabetes is controversial
• The UKPDS study showed that while taking metformin and controlling blood pressure reduces the risk of diabetic complications (including cardiovascular events and death from diabetic complications), controlling blood glucose using a sulfonylurea or insulin-based regimen had no statistically significant beneficial effect on all-cause mortality, macrovascular events or most microvascular events. Tight control of blood glucose to achieve an HbA1c of less than 6% may even be associated with harm
• NICE advises agreeing individual targets for HbA1c which may be above the aspiration of less than 6.5%. For most people, keeping blood glucose levels below about 10mmol/L will prevent symptoms associated with hyperglycaemia and Ted should be encouraged to try and achieve this
• Also in keeping with NICE guidance, an HbA1c target of 7% to 7.5% is a reasonable aspiration for Ted given that he has expressed that he hates taking tablets and is not prepared to put up with diarrhoea again, or feeling unwell, especially as he is training for the walk. This may be feasible to attain without increasing the risk of harm, from possible hypoglycaemic episodes and the need for multiple hypoglycaemic agents
• As Ted is already taking a statin, has good control of his blood pressure, is leading a healthier lifestyle and, most important of all, has stopped smoking, he will have significantly reduced his risk of having a cardiovascular event
• Maximising the metformin regimen may be worth attempting. The usual maximum dose for metformin is 2 g/day in divided doses, so Ted is currently only taking one-half of the maximum licensed dose. The side effect of diarrhoea is usually transient, so Ted should be encouraged to persevere for an adequate trial period. Other gastrointestinal (GI) side effects such as anorexia, nausea and vomiting are more common at higher doses of metformin, but again may be transient. Taking an extra metformin 500 mg tablet at lunchtime rather than two tablets at night may reduce the GI side effects Ted previously experienced
• NICE recommend that metformin therapy should be stepped up gradually over weeks to minimise the risk of GI side effects
• NICE found that there was no evidence that the use of extended-release metformin preparations reduced GI side effects, so recommends that these products should only be considered for a trial where GI tolerability prevents continuation of metformin therapy
• Caution is needed when prescribing metformin, or increasing the dose, in people with renal impairment, so before increasing the dose of metformin Ted's renal function should be checked. This is particularly important as he has recently been prescribed and is taking diclofenac, a NSAID
• NICE recommends that the metformin dose should be reviewed if serum creatinine exceeds 130micromol/litre or the estimated glomerular filtration rate is below 45mL/min/1.73 m2. Metformin should be stopped if serum creatinine exceeds 150micromol/litre or the estimated glomerular filtration rate is below 30mL/min/1.73 m2. Metformin should be prescribed with caution in people at risk of a sudden deterioration in kidney function and those at risk of estimated glomerular filtration rate falling below 45mL/min/1.73 m2. However, the benefits of metformin therapy should be discussed with a person with mild to moderate liver dysfunction or cardiac impairment so that due consideration can be given to the cardiovascular-protective effects of this drug
• Metformin is the only oral hypoglycaemic drug that has been shown to reduce macrovascular complications in high-quality randomised controlled trials, and it remains the drug of choice for first-line use in the majority of patients with type 2 diabetes
If Ted did still have symptoms and his blood glucose remained extremely high which second glucose lowering
treatment would be the most appropriate choice?
• If increasing the dose of metformin is not possible, and blood glucose control remains or becomes inadequate with metformin alone, then a sulphonylurea drug should be added. NICE recommend a sulphonylurea with a low acquisition cost (but not glibenclamide)
• A recent systematic review found that newer, more expensive oral hypoglycaemic agents offer no advantages over metformin and sulphonylureas. In addition, the evidence of benefit for newer agents on patient orientated, clinical outcome data, such as effects on CV endpoints, is very limited
• Thiazolidinedione (glitazone) treatment is also an option in people with HbA1c levels of at least 6.5% either in addition to a sulphonylurea if metformin is not tolerated or contraindicated, or in addition to metformin if a sulphonylurea is not appropriate eg if hypoglycaemia is a particular issue. However, there is less experience with these drugs and there are on going safety concerns
If Ted wished to use insulin to control his blood glucose what would be the preferred regimen?
• NICE recommend intermediate acting human isophane insulin (or human NPH insulin as it is also called) as the preferred basal insulin, taken at bed-time or twice-daily according to need
• For Ted they would recommend continuing metformin and sulphonylurea treatment when insulin is initiated, reviewing the use of the sulphonylurea if hypoglycaemia occurs
• If using insulin is likely to be unacceptable to Ted or ineffective, NICE suggest that glitazones can be added to metformin and a sulphonylurea
If considering glitazone treatment what issues should be discussed with Ted?
• Lack of evidence of long-term benefit from taking a glitazone
• There is no convincing evidence that patient-orientated outcomes, such as mortality, morbidity, adverse effects, costs or quality of life, are positively influenced by either pioglitazone or rosiglitazone
• There is consistent evidence that both rosiglitazone and pioglitazone can cause weight gain, fluid retention, and lead to new or worsening heart failure. This is not a rare occurrence, and can be serious and sometimes fatal
• Glitazones increase the risk of fractures. This has been seen in women, not men
Should Ted continue to monitor his blood glucose?
• As Ted has established diabetes relatively well-controlled with oral drugs and monitors his blood glucose infrequently, little is to be gained in promoting self-monitoring blood glucose (SMBG), even with an education programme
• SMBG should be reserved for patients with type 2 diabetes treated with insulin and conceivably, in some very specific circumstances, such as patients who are at risk of hypoglycaemia during intercurrent illness or fasting
• Attention and resources could then be directed to interventions likely to make a difference to patients' symptoms and CV risk, these include support and advice around nutrition, exercise, smoking cessation, and foot care, etc
What concerns would you have regarding Ted taking a NSAID?
• NSAIDs can cause GI, CV and renal side effects, all of which are relevant to Ted
• As Ted is at high risk of a CV event due to his type 2 diabetes, smoking history, history of hypertension and his family history, and has had GI side effects with metformin already, it is appropriate to review the need for an NSAID, and consider conventional analgesia and/or non-pharmacological management of his knee problem
• If treatment with an NSAID is essential the choice of drug should be reviewed
• Diclofenac 150 mg/day appears to be associated with an excess risk equivalent to about 3 extra CV events per 1000 users treated for 1 year. Low-dose ibuprofen (less than or equal to 1200 mg/day) and naproxen (1000 mg/day) appear to be associated with a lower risk, so may be a more appropriate anti-inflammatory drug choice for Ted, as he is already at high risk of a CV event
• Of the traditional NSAIDS, low-dose ibuprofen is associated with a lower GI risk than diclofenac and naproxen. Clinicians should consider prescribing a proton pump inhibitor (PPI) with any NSAID to reduce the risk of adverse GI effects, particularly in those who are at high GI risk (includes anybody aged 65 years or older) and long-term NSAID users
• NSAIDs can provoke renal failure, especially in patients with renal impairment, and this can limit the utility of many drugs but for Ted it can cause problems with metformin in particular