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Type 2 diabetes (part 1):
the management of blood glucose

MeReC Briefing Issue Numbers 25 and 26 discuss the management of people with type
2 diabetes. They should be read together. This issue (part 1) introduces the therapeutic
area and focuses on lifestyle interventions and the drug management of blood glucose
levels. Part 2 (Issue Number 26) focuses on the drug management of cardiovascular risk
factors, particularly blood pressure and blood lipids. The management of diabetic
retinopathy and foot disease is outside the scope of these Briefings.

Introduction stroke and peripheral vascular disease (PVD),

which can lead to amputation. Mortality rates
Around 1.3 million people in England are from CHD are up to five-times higher for
currently diagnosed with diabetes, and many people with diabetes, while the risk of stroke is
more might have type 2 diabetes but are not up to three-times higher, compared to people
yet diagnosed.1 The vast majority of people without the disease.1
with diabetes (about 85%) have type 2
diabetes, a chronic and steadily progressive Identification and diagnosis
condition that is more commonly diagnosed in
people over the age of 40.1 With an ageing At the current time, screening for diabetes on
population and the rising incidence of obesity, a population basis is not recommended.
the number of patients with type 2 diabetes in Pregnant women and people with possible
the UK is set to increase.2 diabetic symptoms (e.g. thirst, polyuria,
recurrent infections, neuropathic symptoms,
The importance of managing this increasing vision changes, etc.) should be tested.9
disease burden has been emphasised by the Follow-up and regular testing is also
publication of The National Service recommended for people known to be at
Framework (NSF) for Diabetes1,3 and the increased risk, such as those with a history of
National Institute for Clinical Excellence impaired glucose regulation or diabetes during
(NICE) series of clinical guidelines on the pregnancy.1 However, increased awareness of
management of type 2 diabetes.47 The the signs and symptoms of diabetes could
management of diabetes is an important help identify people earlier, and an underlying
component of the new General Medical diagnosis of diabetes should be considered in
Services (GMS) contract, where a maximum people with hypertension, CHD, PVD or
of 99 points is available in the diabetes section cerebrovascular disease; and in those with
of the quality and outcomes framework.8 multiple risk factors (e.g. obesity, South Asian
descent, over 65 years, family history, etc.).1,9
Although anyone can develop type 2 diabetes,
people with a family history of the condition Diagnosis of diabetes requires a random
and people who are overweight, obese or venous plasma glucose (RPG) test, a fasting
physically inactive are more at risk. People of venous plasma glucose (FPG) test, or an oral
South Asian, African, African-Caribbean and glucose tolerance test (OGTT) to be within the
Middle Eastern descent have a higher than diabetic range (see Table 1 on page 2).9,10 If
average risk of type 2 diabetes, as do less people have diabetic symptoms, then a single
affluent people.1 The long-term complications test is sufficient for diagnosis. However, for
of diabetes are serious and life-threatening. people without symptoms, at least one
Microvascular complications due to small additional glucose test within the diabetic range
blood vessel damage include retinopathy on another day is required.9 Impaired fasting
(which can lead to blindness), nephropathy glycaemia (IFG) and impaired glucose
(which can lead to kidney failure) and tolerance (IGT) are metabolic states,
neuropathy. Macrovascular complications due collectively termed impaired glucose regulation,
to damage to large arteries can also occur, which are intermediate states between normal Date of preparation:
including coronary heart disease (CHD), glucose homeostasis and diabetes mellitus. August 2004

This MeReC Publication is produced by the NHS for the NHS

MeReC Briefing 1
Type 2 diabetes (part 1): the management of blood glucose

Table 1: World Health Organization (WHO) diagnostic Preventing type 2 diabetes with lifestyle
thresholds for venous plasma glucose (mmol/l)9,10 changes or drug treatment

RPG FPG OGTT As type 2 diabetes is a chronic condition with

life-threatening complications, preventing
Diabetes mellitus >11.1 >7.0 >11.1 people progressing from normal glucose
homeostasis, through impaired glucose
Impaired glucose N/A <7.0 >7.8 and <11.1 regulation, to a full clinical diagnosis of
tolerance (IGT) diabetes, is desirable. Risk factors for type 2
diabetes, such as physical inactivity and
Impaired fasting N/A >6.1 and <7.0 <7.8 obesity, are modifiable, and studies have
glycaemia (IFG) shown that lifestyle interventions can help
delay or prevent this progression.
Lifestyle interventions
In one randomised controlled trial (RCT), 522
Lifestyle interventions are key in the overweight people with IGT (mean age 55
prevention and treatment of type 2 diabetes. years, mean body mass index [BMI] 31) were
Dietary interventions and exercise aim to assigned to individualised lifestyle counselling
correct obesity, and improve glycaemic aimed at reducing weight, improving diet and
control, blood pressure control and lipid increasing exercise, or a control group given
control. Together with smoking cessation, general lifestyle advice.17 Individualised
lifestyle interventions aim to reduce premature lifestyle counselling reduced the proportion of
morbidity and mortality from diabetes, people who progressed from IGT to diabetes
particularly premature cardiovascular (3% per year in the intervention group vs. 6%
morbidity and mortality.11 per year in the control group), with a strong
inverse relationship being seen between the
The diet recommended for people with, or at incidence of diabetes and the achievement of
risk of developing, type 2 diabetes is the same lifestyle goals, such as >5% weight reduction.
healthy balanced diet that is recommended for After four years, the cumulative incidence of
the general population. For most people, this diabetes was 11% (95% CI 615%) in the
will include reducing the amount of fat, intervention group and 23% (95% CI 1729%)
particularly saturated fat, they consume; in the control group. In absolute terms, the
increasing fruit and vegetable consumption; number needed to treat (NNT) of nine was low
increasing their intake of fibre-rich starchy i.e. nine overweight people with IGT would
foods such as bread and rice; reducing salt need to undergo lifestyle counselling for four
intake and increasing the amount of fish, years, to prevent one case of diabetes.17
including oily fish, they eat.9,12 Studies of
specific dietary interventions in people with type In another RCT, 3,234 people with IGT (mean
2 diabetes are limited, but those based on age 51 years, mean BMI 34) received standard
energy intake (5560% carbohydrate, 1520% lifestyle recommendations plus metformin,
protein and 2030% fat) have shown modest standard lifestyle recommendations plus
improvements in glycaemic control and lipid placebo, or an intensive programme of
management, as have those where dietary lifestyle modification (with individualised
fibre is increased.11 Diets which are low in fat counselling around goals for weight loss and
and high in fruit and vegetables have also been exercise).18 After three years, the cumulative
shown to reduce blood pressure modestly.13 incidence of diabetes was 29% in the placebo
group, 22% in the metformin group and 14% in
Increasing physical activity is also important to the group receiving intensive lifestyle
help people lose weight and reduce their risk of modification. Both intensive lifestyle
cardiovascular morbidity and mortality. Again, intervention and metformin significantly
studies of exercise effectiveness specifically in reduced the incidence of diabetes compared
people with type 2 diabetes are limited, but with placebo, but lifestyle intervention was
exercise can improve glycaemic control14 and significantly more effective than drug treatment
modestly reduce blood pressure15. There are (P<0.001). To prevent one person developing
also observational data suggesting that diabetes during a three-year period, seven
physically active people have reductions in the people with IGT would need to participate in
relative risk of CHD of 30% to 50% compared the intensive lifestyle intervention programme
with those who are sedentary.16 and 14 would need to receive metformin.18

Key messages for preventing type 2 diabetes: A RCT involving 1,429 people with IGT (mean
age 54 years, mean BMI 31) has also shown
Lifestyle interventions, metformin, acarbose and orlistat can all that acarbose can delay the development of
prevent or delay type 2 diabetes developing in people with impaired diabetes. After a mean of 3.3 years, the
glucose regulation. cumulative incidence of diabetes was 32% with
However, if people are to be targeted for the primary prevention of acarbose and 42% with placebo (hazard ratio
diabetes, lifestyle modifications rather than drug treatment would 0.75; 95% CI 0.630.90; NNT 10). However,
seem preferable in the majority. more gastrointestinal side effects were seen in

2 MeReC Briefing
Type 2 diabetes (part 1): the management of blood glucose

the acarbose group, and 13% of patients NICE set targets for blood glucose control,
taking acarbose discontinued the trial early blood pressure, etc. (see Table 2 on page 8).4,5
because of these.19 However, reaching these 'gold standards' can
be demanding. Multiple lifestyle interventions
Recently, the XENDOS study has shown that and drug treatments are often required and
orlistat plus lifestyle changes produces a individual targets should be agreed with each
greater reduction in the incidence of type 2 patient, as such aggressive therapy of each
diabetes than lifestyle changes alone.20 In this individual risk factor, whilst evidence based,
RCT, 3,305 patients with a BMI >30kg/m2 may not be appropriate for all.9
(mean BMI 37, mean age 43 years, 79% with
normal glucose tolerance and 21% with IGT) Drug management of blood glucose
were randomised to lifestyle changes plus
either orlistat or placebo for four years. For decades, the treatment of type 2 diabetes
However, only 52% of the orlistat group and has focused primarily on controlling blood
34% of the placebo group completed glucose. Managing this risk factor is important,
treatment. Using an intention to treat analysis, but in isolation it is not the key to preventing
mean weight loss was 5.8kg with orlistat and premature morbidity and mortality in these
3.0kg with placebo (P<0.001) after four years. people. In the UK Prospective Diabetes Study
Over the same time, the incidence of type 2 (UKPDS) the largest RCT in patients with
diabetes was reduced from 9.0% in the type 2 diabetes (see Panel 1 for details)
placebo group to 6.2% in the orlistat group tight control of blood pressure rather than
(hazard ratio 0.63; 95% CI 0.460.86; NNT blood glucose was most effective in preventing
36). This reduction was primarily due to diabetes-related endpoints and death (see
benefits in the population of patients with IGT.20 Part 2: MeReC Briefing Issue Number 26).

Although metformin, acarbose and orlistat Type 2 diabetes is a progressive disease,

have been shown to prevent or delay type 2 therefore, most patients will require drug
diabetes developing in people with impaired therapy in addition to dietary and lifestyle
glucose regulation, lifestyle modifications changes to control their blood glucose levels
rather than drug treatment would seem at some point. Typically, patients who initially
preferable if these people are to be targeted respond to diet will progress to requiring an
for primary prevention. oral hypoglycaemic agent, then to a
combination of oral hypoglycaemics, and
Management of type 2 diabetes finally to insulin, in order to control their blood
glucose to target levels (see Figure 1 on
Managing people with type 2 diabetes aims to page 7).4,21 The benefits of pursuing optimal
reduce complications by careful control of glycaemic control aggressively with
blood glucose and cardiovascular risk factors, increasingly complex drug therapy must,
in particular blood pressure and lipids, as well therefore, be considered on an individual
as managing diabetic renal disease, patient basis. Management decisions should
retinopathy and foot disease. Management take into account the patient's risk of micro-
needs to be multifactorial and it is appropriate and macrovascular complications, their
that guidelines such as those produced by acceptability of polypharmacy, the need to

Panel 1: The UK Prospective Diabetes Study (UKPDS)23,25,35,36

UKPDS was a 20-year trial, which recruited over 5,000 patients In the blood pressure (BP) part of the study, patients were
with type 2 diabetes in 23 clinical centres based in England, randomised to either tight BP control or less tight BP control.
Northern Ireland and Scotland. The blood glucose control part of Tight control aimed for a BP <150/85mmHg with either captopril
the study was started in 1977 and the blood pressure part of the or atenolol as the main treatment. Less tight control aimed for a
study was started in 1987. The study finished in 1997, with BP <180/105mmHg avoiding ACE inhibitors or -blockers.
results published for the first time in 1998. UKPDS was designed
to answer three main questions in patients with type 2 diabetes: Predefined clinical endpoints were aggregated for analyses into:

Can intensive blood glucose control reduce the risk of Any diabetes-related endpoint (sudden death, death from
complications? hyperglycaemia/hypoglycaemia, fatal or non-fatal MI, angina,
In patients with high blood pressure, can tight blood pressure heart failure, stroke, renal failure, amputation, vitreous
control reduce the risk of complications? haemorrhage, retinal photocoagulation, blindness in one eye,
Does any specific treatment for blood glucose or blood or cataract extraction).
pressure control offer any particular benefit? Diabetes-related death (death from MI, stroke, PVD, renal
disease, hyperglycaemia or hypoglycaemia, and sudden death).
In the blood glucose part of the study, patients were randomised All-cause mortality.
to intensive control initially with a sulphonylurea MI (fatal and non-fatal) and sudden death.
(chlorpropamide, glibenclamide or glipizide) or insulin, or Stroke (fatal and non-fatal).
conventional control primarily with diet. In a sub-study of some Amputation or death from PVD.
overweight patients, intensive treatment was initiated with Microvascular complications (retinopathy requiring
metformin. Intensive control aimed for a fasting plasma glucose photocoagulation, vitreous haemorrhage, or fatal/non-fatal
(FPG) <6mmol/l and conventional control, FPG <15mmol/l. renal failure).

MeReC Briefing 3
Type 2 diabetes (part 1): the management of blood glucose

balance requirements to control blood glucose Which drugs should be used initially to
with requirements to also control control blood glucose?
cardiovascular risk factors, and the need to
use resources carefully on a population basis. Metformin
When blood glucose is inadequately controlled
NICE guidelines recommend that blood glucose with lifestyle interventions, metformin is the
control is assessed by haemoglobin A1c first-line drug of choice in all patients with type
(HbA1c) measurements every two to six 2 diabetes, particularly those who are
months, and, for each individual, a target overweight (BMI >25kg/m2) (see Figure 1 on
HbA1c level of between 6.5% and 7.5% should page 7).4 Sulphonylureas are an alternative in
be set.4 Average HbA1c levels in UK clinics are patients who are not overweight.4 However,
7.4% after an estimated five-year duration of metformin is the only oral hypoglycaemic
type 2 diabetes, and at least 8% thereafter, agent that has been shown to reduce
often while on insulin treatment.22 Therefore, for macrovascular complications and death.25
many patients, these targets are a significant Metformin is also associated with fewer
challenge and may not be achievable. hypoglycaemic attacks than sulphonylureas
and does not cause weight gain.25,26
Target HbA1c levels are based on evidence
from UKPDS, where intensive blood glucose UKPDS studied metformin mainly in
control with sulphonylureas or insulin overweight patients because, when the trial
reduced the risk of diabetes-related was started, metformin was generally
endpoints compared with conventional blood prescribed only in such patients. In a RCT of
glucose control primarily with diet.23 Intensive 753 overweight patients (>120% ideal body
control resulted in a median HbA1c over 10 weight), intensive blood glucose control with
years of 7.0% and conventional control, a metformin significantly reduced diabetes-
median of 7.9%.23 related endpoints compared with conventional
blood glucose control primarily with diet.25 The
Tighter blood glucose control reduced the incidence of any diabetes-related endpoint was
incidence of any diabetes-related endpoint from reduced from 38.9% in the conventional group
38.5% in the conventional group to 35.3% in the to 28.7% in the metformin group over a median
intensive group over a median of 10 years of 10.7 years (RR 0.68 [95% CI 0.530.87];
(RR 0.88 [95% CI 0.790.89]; NNT 32). This NNT 10). In contrast to intensive blood glucose
was mainly due to a reduction in microvascular control with sulphonylureas or insulin,
endpoints (10.6% vs. 8.2% for the composite of metformin reduced diabetes-related death
retinopathy, vitreous haemorrhage or renal (NNT 20), all-cause mortality (NNT 15) and MI
failure; RR 0.75 [95% CI 0.600.93]; NNT 42), in (NNT 16) compared with conventional blood
particular the need for retinal photocoagulation glucose control. Median HbA1c levels over 10
(NNT 37). There were no differences between years were 7.4% in the metformin group and
the groups in visual acuity or blindness.23 8.0% in the conventional treatment group.25
Diabetes-related deaths, all-cause mortality or
macrovascular endpoints such as myocardial In a secondary analysis of 342 overweight
infarction (MI) and stroke were not significantly patients allocated metformin and 951
reduced, although the difference in MI was of overweight patients allocated either
borderline significance (P=0.052).23 sulphonylureas or insulin, metformin was more
effective in reducing any diabetes-related
Observational data from UKPDS suggested endpoint (P=0.0034), all-cause mortality
that there was no threshold HbA1c level below (P=0.021), and stroke (P=0.032). These
which benefits were no longer seen, and that improvements with metformin over
the nearer to normal the level (<6.0%), the sulphonylureas/insulin seem not to be explained
better.24 Hence, target HbA1c levels outlined in purely by glycaemic control, as HbA1c levels
the NICE guideline are a range, from 6.5% to were similar between the groups.25
7.5%, rather than a specific value.4
Although these results relate to overweight
What about self-monitoring of blood patients, metformin is an appropriate choice in
glucose levels? both overweight and non-overweight patients.
Most people with type 2 diabetes are
Many people with diabetes self-monitor their overweight (at entry to UKPDS, BMI was
blood glucose levels. However, there is little >25kg/m2 in 75% of patients and >30kg/m2 in
evidence to support self-monitoring in all 35%) and metformin lowers blood glucose in
patients with type 2 diabetes, unless it forms patients, irrespective of the degree of obesity.25
part of a wider programme of management.
NICE guidelines state that self-monitoring Because of the rare, but serious, potential
should not be considered as a stand-alone side effect of lactic acidosis with metformin,
intervention, but only as part of an it is contraindicated in people with renal
integrated self-care programme.4 This was impairment or those at risk of a sudden
discussed in more detail in MeReC Bulletin deterioration in renal function, e.g. from shock,
Vol 13, No 1, 2002. recent MI, etc. Metformin is contraindicated

4 MeReC Briefing
Type 2 diabetes (part 1): the management of blood glucose

in people with a serum creatinine Key messages for blood glucose:

>130micromol/l.4 However, it has been
suggested that raising this cut-off to The management of blood glucose is important, but aggressively
>150micromol/l would be more sensible, pursuing glycaemic targets should be balanced against
allowing more patients to benefit from this requirements to also manage cardiovascular risk factors such as
life-saving drug.27 blood pressure and blood lipids.
In people with type 2 diabetes, an individual target HbA1c level of
Sulphonylureas between 6.5% and 7.5% should be set.
For people in whom metformin is Metformin is the first-line drug of choice in all people with type 2
contraindicated or not tolerated, or in patients diabetes, particularly those who are overweight. A sulphonylurea is
who are not overweight, a sulphonylurea a suitable alternative if metformin is contraindicated or not tolerated,
is a suitable first-line alternative. There is or if the patient is not overweight.
very little evidence on which to base the If monotherapy fails to control blood glucose adequately,
choice of sulphonylurea. Chlorpropamide and combination treatment with metformin plus a sulphonylurea is the
glibenclamide were the main sulphonylureas next option. Only if this combination is contraindicated, poorly
used in UKPDS, where tight blood glucose tolerated or, again, fails to control blood glucose adequately should
control with these or insulin reduced other drugs be considered.
microvascular endpoints.23 However, both
of these are long-acting agents associated and, at the current time, there is only limited
with a greater risk of hypoglycaemia. evidence to support the use of this
Chlorpropamide, in particular, is associated combination. Glitazones are also
with more side effects than other contraindicated for use in combination with
sulphonylureas and is no longer insulin. Recently, both rosiglitazone and
recommended.28 Shorter-acting agents, such pioglitazone have been licensed for
as tolbutamide, gliclazide, glimepiride or monotherapy in type 2 diabetes. However, the
glipizide are generally preferred. However, all licence is very specific for use in patients,
patients taking sulphonylureas should be particularly overweight patients, who cannot
made aware of the risk of hypoglycaemia.4 use metformin because of intolerance or a
contraindication. Glitazones are more
What happens when monotherapy fails? expensive than sulphonylureas, which would
be the conventional choice in these patients,
If monotherapy with either increasing doses of and data comparing these two classes of drugs
metformin or a sulphonylurea fails to control are limited. To date, there are no trials studying
blood glucose adequately, the next option is the effects of glitazones on the long-term
combination therapy with metformin plus a clinical outcomes of type 2 diabetes, such as
sulphonylurea (see Figure 1 on page 7).4 microvascular or macrovascular complications,
Only if this combination is contraindicated, and their long-term safety is still unknown.
poorly tolerated or, again, fails to control blood
glucose adequately, should other drugs be Is there a role for rapid-acting insulin
considered. As outlined above, the need to secretagogues?
pursue blood glucose targets aggressively with
polypharmacy must be considered in the NICE guidelines recommend that the rapid-
context of the need to also treat cardiovascular acting insulin secretagogues, nateglinide and
risk factors such as blood pressure and lipids. repaglinideq, may have a role in attaining tight
glucose control in patients with non-routine
When are glitazones an option? daily patterns.4 Nateglinide is only licensed for
combination treatment with metformin, if
NICE guidelines recommend that glitazones patients are not adequately controlled on
(rosiglitazoneq or pioglitazoneq) should only be maximally tolerated doses of metformin alone.
considered in combination with either Repaglinide is licensed for monotherapy and in
metformin or a sulphonylurea if the patient is combination with metformin.
unable to take metformin plus a sulphonylurea
because of intolerance or a contraindication to Nateglinide and repaglinide have a rapid onset
one of these drugs.29 The original NICE and short duration of action and are taken
guidance on rosiglitazone from 200030 and the before meals. They may have a limited place
NICE diabetes guideline4 recommended that in patients with irregular meal times where
glitazones could also be used in combination glycaemic control has proved difficult with
with metformin or a sulphonylurea if metformin other oral drugs.31 However, nateglinide and
plus a sulphonylurea failed to control blood repaglinide are more expensive than
glucose adequately. However, this conventional treatment with metformin and/or
recommendation was removed from the sulphonylureas and, at the current time, there
updated glitazone guidance published in is no data on whether these newer drugs
2003,29 as NICE no longer considered that the reduce the microvascular and macrovascular
evidence supporting this use was sufficient. complications of type 2 diabetes. Like
sulphonylureas, rapid-acting insulin secret-
Glitazones are not licensed for use as triple agogues can cause hypoglycaemia and
therapy, i.e. with metformin and a sulphonylurea, patients should be made aware of this.4

MeReC Briefing 5
Type 2 diabetes (part 1): the management of blood glucose

What about acarbose? to four years use. Patients taking sibutramine

and orlistat should be closely monitored for
For patients unable to use other oral drugs, side effects. Sibutramine is contraindicated in
NICE guidelines recommend that acarbose is patients with inadequately controlled
an alternative.4 However, its use is limited by hypertension, and specific blood pressure and
gastrointestinal side effects. In a placebo- pulse rate monitoring is required for all
controlled trial involving 1,946 patients with patients taking the drug. See the full NICE
type 2 diabetes (who were previously enrolled guidance33,34 and Summaries of Product
in UKPDS), compliance rates after three years Characteristics for details.
were significantly lower in the group given
acarbose in addition to pre-existing therapy Drug management of cardiovascular risk
compared with the group given placebo (39% factors
vs. 58%, P<0.0001).32 This non-compliance
with acarbose was mainly due to the This is covered in detail in Part 2: MeReC
increased proportion of patients reporting Briefing Issue Number 26.
flatulence (30% vs. 12%, P<0.00001) and
diarrhoea (16% vs. 8%, P<0.0001). Acarbose 1 Department of Health. National Service Framework for Diabetes:
did improve glycaemic control over three Standards. London: Department of Health; November 2002.
Available from: URL: Accessed July 2004.
years, irrespective of what other therapy 2 The Audit Commission. Testing times. A review of diabetes services
patients were receiving. However, the trial was in England and Wales. London: Audit Commission; April 2000.
3 Department of Health. National Service Framework for Diabetes:
not large enough to provide any information on Delivery Strategy. London: Department of Health; November 2002.
whether acarbose reduced microvascular or Available from: URL: Accessed July 2004.
4 National Institute for Clinical Excellence. Management of type 2
macrovascular events.32 diabetes: management of blood glucose. Inherited Clinical
Guideline G; September 2002. Available from: URL: Accessed July 2004.
When should insulin be considered? 5 National Institute for Clinical Excellence. Management of type 2
diabetes: management of blood pressure and blood lipids.
Inherited Clinical Guideline H; October 2002. Available from:
As type 2 diabetes progresses, and diet plus URL: Accessed July 2004.
optimised oral hypoglycaemic drugs fail to 6 National Institute for Clinical Excellence. Management of type 2
diabetes: renal disease prevention and early management.
control blood glucose adequately, individually Inherited Clinical Guideline F; February 2002. Available from:
tailored insulin therapy may need to be URL: Accessed July 2004.
7 National Institute for Clinical Excellence. Management of type 2
considered. Choice of insulin type and diabetes: retinopathy screening and early management.
regimen should be based on local experience, Inherited Clinical Guideline E; February 2002. Available from:
URL: Accessed July 2004.
patient preference and relative costs, as there 8 Investing in General Practice. The New General Medical
is little research evidence in this area.4 When Services Contract. British Medical Association. 2003. Available
from: URL: Accessed July 2004.
patients are being transferred to insulin from 9 Diabetes UK. Recommendations for the management of diabetes
metformin plus another oral agent, metformin in primary care. Second edition, October 2000. Available from:
URL: Accessed July 2004.
should be continued. If the patient is taking a 10 Definition, diagnosis and classification of diabetes mellitus and its
sulphonylurea plus another oral agent (not complications. Report of a WHO consultation. Part 1: diagnosis and
classification of diabetes mellitus. World Health Organization. 1999.
metformin), the sulphonylurea should be 11 McIntosh A, Hutchinson A, Home PD, et al. Clinical guidelines
continued.4 This combination treatment of and evidence review for type 2 diabetes: management of blood
glucose. Sheffield: ScHARR, University of Sheffield. 2001.
insulin plus an oral agent aims to improve 12 The Health Development Agency. Coronary heart disease.
glycaemic control.11 Patients receiving insulin Guidance for implementing the preventive aspects of the
national service framework.
therapy need to be advised about the risk of 13 Appel LJ, Moore TJ, Obarzanek E, et al. A clinical trial of the
hypoglycaemia and be alert to it.4 effects of dietary patterns on blood pressure. N Engl J Med
14 Boul NG, Haddad E, Kenny GP, et al. Effects of exercise on
Management of obesity glycaemic control and body mass in type 2 diabetes mellitus. A
meta-analysis of controlled clinical trials. JAMA 2001;286:121827.
15 Whelton SP, Chin A, Xin X, et al. Effect of aerobic exercise on
The dietary, exercise-based and drug blood pressure: a meta-analysis of randomized, controlled trials.
Ann Intern Med 2002;136:493503.
management of obesity was discussed in 16 Foster C, Murphy M, Nicholas JJ, et al. Primary Prevention. Clin
MeReC Briefing, No 16, 2001. The NICE Evid 2004;11:16396.
17 Tuomilehto J, Lindstrm J, Eriksson JG, et al. Prevention of type
guidance for orlistat and sibutramine 2 diabetes mellitus by changes in lifestyle among subjects with
recommends that these anti-obesity drugs impaired glucose tolerance. N Engl J Med 2001;344:134350.
18 Diabetes Prevention Program Research Group. Reduction in the
should only be prescribed for people with type 2 incidence of type 2 diabetes with lifestyle intervention or
diabetes if they have a BMI >27kg/m2 metformin. N Engl J Med 2002;346:393403.
19 Chiasson J-L, Josse RG, Gomis R, et al. Acarbose for prevention
(sibutramine) or >28kg/m2 (orlistat) and they of type 2 diabetes mellitus: the STOP-NIDDM randomised trial.
have previously made serious attempts to lose Lancet 2002;359:20727.
20 Torgerson JS, Hauptman J, Boldrin MN, et al. Xenical in the
weight by diet and exercise.33,34 These drugs prevention of diabetes in obese subjects (XENDOS) study.
should always be prescribed in conjunction with Diabetes Care 2004;27:15561.
21 Turner RC, Cull CA, Frighi V, et al. Glycemic control with diet,
lifestyle advice, support and counselling, and sulfonylurea, metformin, or insulin in patients with type 2
should only be used beyond three to six months diabetes mellitus: progressive requirement for multiple therapies
(UKPDS 49). JAMA 1999;281:200512.
if significant weight loss is being achieved. 22 Winocour PH. Effective diabetes care: a need for realistic
targets. BMJ 2002;324:157780.
23 UK Prospective Diabetes Study (UKPDS) Group. Intensive
Sibutramine is licensed for a maximum blood-glucose control with sulphonylureas or insulin compared
treatment period of 12 months. Orlistat was with conventional treatment and risk of complications in patients
with type 2 diabetes (UKPDS 33). Lancet 1998;352:83753.
licensed for a maximum period of 24 months. 24 Stratton IM, Adler AI, Neil AW, et al. Association of glycaemia
However, with the publication of the XENDOS with macrovascular and microvascular complications of type 2
diabetes (UKPDS 35): prospective observational study. BMJ
study,20 there is now clinical data supporting up 2000;321:40512.

6 MeReC Briefing
Type 2 diabetes (part 1): the management of blood glucose

25 UK Prospective Diabetes Study (UKPDS) Group. Effect of 31 q

Nateglinide and qrepaglinide for type 2 diabetes? Drug Ther Bull
intensive blood-glucose control with metformin on complications 2003;41:524.
in overweight patients with type 2 diabetes (UKPDS 34). Lancet 32 Holman RR, Cull CA, Turner RC, et al. A randomised double-
1998;352:85465. blind trial of acarbose in type 2 diabetes shows improved
26 Johansen K. Efficacy of metformin in the treatment of NIDDM. glycemic control over 3 years (UK Prospective Diabetes Study
Meta-analysis. Diabetes Care 1999;22:3337. 44). Diabetes Care 1999;22:9604.
27 Jones GC, Macklin JP, Alexander WD. Contraindications to the 33 National Institute for Clinical Excellence. Guidance on the use of
use of metformin. Evidence suggests that it is time to amend the orlistat for the treatment of obesity in adults. Technology
list. BMJ 2003;326:45. Appraisal No. 22. March 2001. Available from: URL:
28 British National Formulary. No 47. London: British Medical Accessed July 2004.
Association/Royal Pharmaceutical Society of Great Britain; 34 National Institute for Clinical Excellence. Guidance on the use of
2004. sibutramine for the treatment of obesity in adults. Technology
29 National Institute for Clinical Excellence. Guidance on the use of Appraisal No. 31. October 2001. Available from: URL:
glitazones for the treatment of type 2 diabetes. Technology Accessed July 2004.
Appraisal No. 63. August 2003. Available from: URL: 35 UK Prospective Diabetes Study Group. Tight blood pressure Accessed July 2004. control and risk of macrovascular and microvascular complications
30 National Institute for Clinical Excellence. Guidance on in type II diabetes: UKPDS 38. BMJ 1998;317:703713.
rosiglitazone for type 2 diabetes mellitus. Technology Appraisal 36 UKPDS website. Available from: URL:
No. 9. August 2000. Available from: URL: Accessed
Accessed July 2004. July 2004.

Figure 1: Treatment algorithm for management of blood glucose in type 2 diabetes (adapted from the NICE
clinical guideline on management of blood glucose4)

Measure HbA1c at 2 to 6 monthly intervals. Set target HbA1c between 6.5% and 7.5%

Work with patient on lifestyle changes (weight loss, increased exercise, etc) and offer
ongoing patient education. Lifestyle changes should continue throughout any addition
of drug therapy.

Are lifestyle changes controlling blood glucose adequately?

i i yes

Consider metformin first line, especially in overweight Continue to measure

patients (BMI >25kg/m2) HbA1c every 6
Consider a sulphonylurea first line if metformin is contra- months
indicated or not tolerated, or if the patient is not overweight

Is blood glucose control adequate?

i i yes

Consider metformin plus a sulphonylurea as combination

Continue to measure
therapy HbA1c every 6
If either metformin or a sulphonylurea is contraindicated months
or not tolerated, consider a glitazone in combination with
current therapy

Is blood glucose control adequate?

i i yes

Consider insulin therapy

Continue to measure
When insulin is indicated:
HbA1c every 2 to 6
- when transferring from metformin + another oral agent,
continue metformin
- when transferring from a sulphonylurea + another oral
agent (not metformin), continue sulphonylurea
Glitazones are contraindicated with insulin

MeReC Briefing 7
Table 2: Lifestyle, risk factor, and therapeutic targets for prevention of micro- and macrovascular complications in patients with type 2 diabetes based on

The National
ment provides
NICE clinical guidelines 46

used todecisions
National Institute
Patients with established CVD Patients without established CVD at higher risk Patients without established CVD at lower risk

with the


and dissemination
inform decisions

(10-year coronary event risk >15%) (10-year coronary event risk <15%)

on service


the ability
Encourage smoking cessation, weight loss (if overweight) and increased physical activity in all patients

to secure


NICE considers
to secure

service organisation
Target HbA1c 6.5% to 7.5% for all patients

NICE considers
Blood glucose

value value
Set target based on individual's risk of microvascular and macrovascular complications

the work
and delivery.
The lower target is preferred if significant risk of macrovascular complications, the higher target if risk of iatrogenic hypoglycaemia

for money

and This
for money

in theinuse

BP >160/100mmHg treat all patients to target <140/80mmHg

this organisation
BP >140/80mmHg AND microalbuminuria or proteinuria treat all patients to target <135/75mmHg (ACE inhibitor first choice)



This publication

of this organisation
of NHS

BP >140/80mmHg to <160/100mmHg BP >140/80mmHg to <160/100mmHg BP >140/80mmHg to <160/100mmHg

treat to target <140/80mmHg treat to target <140/80mmHg no treatment initially, reassess every 6 months

to be oftovalue

the viewsthe
be oftovalue

of the
Fasting TG >10mmol/l treat all patients and consider referral

in its in
the NHS

to the
diabetes (part 1): the management of blood glucose

by by
its work
in NHS
TC >5.0mmol/l (LDL-C >3.0mmol/l) OR TC >5.0mmol/l (LDL-C >3.0mmol/l) OR TC >5.0mmol/l (LDL-C >3.0mmol/l) OR

of theand
Blood lipids


TG >2.3mmol/l to <10mmol/l TG >2.3mmol/l to <10mmol/l TG >2.3mmol/l to <10mmol/l

and enables

treat to target of TC <5.0mmol/l or 2025% treat to target of TC <5.0mmol/l or 2025% Discuss CHD risk with patient, consider drug


in England
reduction or LDL-C <3.0mmol/l or 30% reduction, reduction or LDL-C <3.0mmol/l or 30% reduction, treatment at higher levels of cholesterol or TG,

and enables
whichever is the greater reduction whichever is the greater reduction reassess annually if treatment not started

and Wales

not necessarily

Telephone: 0151 794 8146 Fax: 0151 794 8139

The National Prescribing Centre, The Infirmary, 70 Pembroke Place, Liverpool, L69 3GF
it to influence
a funding
75mg aspirin daily

it to influence

a funding

and not necessarily

75mg aspirin daily (before starting aspirin, reduce SBP to <145mmHg and no treatment

those of the
maintain this)



and recommends
CVD = cardiovascular disease, HbA1c = haemoglobin A1c, BP = blood pressure, SBP = systolic blood pressure, TG = triglycerides, TC = total cholesterol, LDL-C = low-density lipoprotein cholesterol

that it bethat
of the Institute.

it be

MeReC Briefing