NCDs - Non communicable diseases are on the rise especially
Type 2 Diabetes globally but very silently in LMICs like Nigeria, such that no
matter your specialty some relative, friend or total stranger is likely to ask
you about it, because you are a medical doctor -
We share the latest SIGN ( Scottish Intercollegiate Network)
guideline for that reason. - so that you can give informed advice! Courtesy of
Guidelines In Practice UK. READ ON
''Type 2 diabetes: an overview of the SIGN guideline on
pharmacological management of glycaemic contro
Funded by Napp Pharmaceuticals Limited16 August 2018
A review of SIGN 154: Pharmacological management of
glycaemic control in people with type 2 diabetes
Professor Gerard McKay, Consultant Physician, Department of
Endocrinology, Diabetes and Clinical Pharmacology, Glasgow Royal Infirmary
Key points
· A rapid
update of the chapter of SIGN 116 on pharmacological management of glycaemic
control in people with type 2 diabetes was commissioned and published in late 2017
as a standalone guideline, SIGN 154
· The updated
guideline considers the results of cardiovascular outcome trials published
during the development period of the guideline
· Metformin
should be considered as the first-line oral treatment option for all people
with type 2 diabetes
· For
individuals with established cardiovascular disease, evidence of proven
cardiovascular benefit should be considered when choosing SGLT2 inhibitors or
GLP-1 receptor agonists.
SGLT2=sodium glucose co-transporter 2; GLP-1=glucagon-like
peptide-1
Introduction
Historically, the management of hyperglycaemia in type 2
diabetes has been based on lowering glycated haemoglobin (HbA1c) as a surrogate
marker, with only metformin and pioglitazone having cardiovascular outcome
data. For metformin, this was based on a small sub study of the UK Prospective
Diabetes Study (UKPDS),1 and, for pioglitazone, on the improvement in a
secondary endpoint in the PROactive study.2
Following the finding of increased cardiovascular events
with rosiglitazone,3 the regulatory authorities, initially in the USA in
20084 and then in Europe in 2012,5 mandated that all new treatments
for the management of hyperglycaemia show no impact on cardiovascular morbidity
and mortality. This has led to a number of large studies for newer drugs as
part of their clinical development programme. For the most part no impact on
cardiovascular morbidity and mortality, at least over the short term, has been
shown, and there have been additional secondary benefits on weight loss and
reduced incidence of hypoglycaemia. However, four drugs from two classes have
now been shown to improve cardiovascular morbidity and mortality and three of
these drugs, canagliflozin, empagliflozin, and liraglutide are licensed for use
in the UK.6–9
The most recent NICE guidance (NICE Guideline 28
on Type 2 diabetes in adults: management) was first published in 2015 and
does not capture the new cardiovascular evidence,10 while SIGN 116
on The management of diabetes (2010) is considerably out of date.11 Given
the likelihood of new evidence impacting on clinical practice, a rapid update
of the chapter of SIGN 116 on pharmacological management of glycaemic control
in people with type 2 diabetes was commissioned and published in late 2017 as a
standalone guideline: Pharmacological management of glycaemic control in
people with type 2 diabetes (SIGN 154).12
Methodology
The guideline was developed using an adapted version of the
standard SIGN guideline development process. Apart from including one
meta-analysis that pooled randomised controlled trials (RCTs) already included
in the original guideline, section 3 on targets for glycaemic control, was not
updated.12
The rapid review approach for updating the guideline
involved appraisal of five sources of evidence:12
· the
existing guideline, published as a chapter of SIGN 11611
· a series of
systematic reviews developed by the Agency of Healthcare Research and Quality
(AHRQ)
· NICE
Guideline 2810
· a primary
literature search to update these sources up to November 2016
· cardiovascular
outcome trials published during the development period of the guideline (up to
September 2017).
A consultation period was held to further validate the
finalised guideline as an evidence-based approach to help practitioners manage
glycaemic control in people with type 2 diabetes; this included the publication
of an algorithm to guide choice of first, second, and third-line agents (Figure
1).12
Figure 1: Algorithm for glucose lowering12
Metformin
When compared with placebo or other agents, metformin is an
effective blood glucose-lowering therapy.13
An AHRQ analysis showed that, when used as monotherapy,
there was very little variation between the currently available classes of
glucose-lowering medication.12,14
Adverse effects
Gastrointestinal side-effects are the most common adverse
events associated with metformin therapy.14 The risk of hypoglycaemia is
low, and weight gain is not a feature.14 The evidence shows that there is
no risk of lactic acidosis specifically related to metformin use,14 but
SIGN 154 advises using with caution in patients with moderate renal impairment.12
Cardiovascular morbidity and mortality
There has been no new evidence relating to cardiovascular
morbidity and mortality since UKPDS 34, which showed cardiovascular
benefit of metformin in overweight patients with type 2 diabetes.1,12
Metformin should be considered as the first-line oral
treatment option for all people with type 2 diabetes.12
Sulphonylureas
Sulphonylureas have been shown to be effective at lowering
blood glucose levels.12,15 Evidence from trials comparing sulphyonylureas
with newer agents supports this, although these studies were designed to look
at adverse effects, rather than directly comparing HbA1c reduction.12
Adverse effects
Compared with newer agents, there are higher rates of
hypoglycaemia and increased weight gain when using sulphonylureas.12,15 Sulphonylureas
should be used with caution in patients with mild or moderate renal impairment
and avoided in people with severe renal impairment.12
Cardiovascular morbidity and mortality
There is no clear evidence to suggest that sulphonylureas
are associated with increased cardiovascular morbidity and mortality.12
Sulphonylureas should be considered as first-line treatment
in people with type 2 diabetes who are intolerant of, or who have
contraindications to, metformin, or as a second- or third-line add-on
treatment. Caution should be used in those at risk of hypoglycaemia e.g. the
elderly.12
Thiazolidinediones
Pioglitazone is the only thiazolidinedione (TZD) with
marketing authorisation in the UK, and evidence supports its use for lowering
blood glucose.12
Adverse effects
Pioglitazone is associated with weight gain, due, at least
in part, to fluid retention, and there is also a risk of bladder cancer.12,16 As
a class, TZDs are associated with an increased risk of fractures (in both men
and women).12,17
There is no contraindication to using pioglitazone in renal
impairment.18
Cardiovascular morbidity and mortality
The PROactive study showed, as a secondary endpoint,
improved cardiovascular outcomes with pioglitazone compared with placebo,19 but
this is at the expense of an increased risk of heart failure.12,20
Pioglitazone should be considered for dual or triple therapy
in the management of type 2 diabetes but should not be used in
patients with heart failure. The risk of fracture should be considered with
long-term use.12
DPP-4 inhibitors
Five dipeptidyl peptidase-4 (DPP-4) inhibitors are currently
available in the UK, all have been shown to lower blood glucose,12 but the
effect, at times, is modest.
Adverse effects
The evidence shows that DPP-4 inhibitors are associated with
neither weight gain nor hypoglycaemia.12
Dose reduction for all DPP-4 inhibitors except linagliptin
is required in renal impairment.12
Cardiovascular morbidity and mortality
At the time of developing the guideline, three major
cardiovascular outcome studies had been published for alogliptin (EXAMINE),
saxagliptin (SAVOR-TIMI 53), and sitagliptin (TECOS), showing no increase in
cardiovascular morbidity and mortality compared with placebo or usual care.21–23There
was, however, an increase in the rate of hospitalisation for heart failure in
people treated with saxagliptin compared with placebo.22
DPP-4 inhibitors should be considered for dual or triple
therapy in the management of type 2 diabetes.12
SGLT2 inhibitors
The evidence reviewed supports all sodium glucose
co-transporter 2 (SGLT2) inhibitors as having efficacy for lowering blood
glucose both as monotherapy and in combination with other glucose-lowering
agents.12 There is, however, no evidence to support the use of SGLT2
inhibitors over metformin for monotherapy.12
Adverse effects
The risk of hypoglycaemia with SGLT2 inhibitors is low and
there is evidence to support significant weight loss as a secondary benefit.12 The
most common reported side-effect is genital mycotic infections, and there is
also an increased risk of diabetic ketoacidosis.12
In one trial, canagliflozin was associated with a higher
rate of fractures and lower limb amputation compared with placebo.7 Although
the risk of lower limb amputation has not been seen in clinical trials for
other agents in this class the European Medicines Agency has recommended that
the product information of all SGLT2 inhibitors contains information on the
risk of lower limb amputation.12,24
There is some evidence that canagliflozin is beneficial in
early diabetic nephropathy; it should be noted that SGLT2 inhibitors should not
be initiated in individuals with chronic kidney disease and in the event of a
decrease in estimated glomerular filtration rate, treatment should be adjusted
depending on the individual agent.12
Cardiovascular morbidity and mortality
There have been two large cardiovascular outcomes studies in
this class: EMPA-REG and CANVAS for empagliflozin and canagliflozin,
respectively.7,8 Both studies recruited patients with type 2 diabetes and
a high risk of cardiovascular disease and those who were treated with an SGLT2
inhibitor had improved cardiovascular outcomes compared with placebo.7,8,12
SGLT2 inhibitors should be considered as add on to metformin
in people with type 2 diabetes. In individuals with established cardiovascular
disease SGLT2 inhibitors with proven cardiovascular benefit should be
considered (empagliflozin or canagliflozin).1 2
GLP-1 receptor agonists
There is evidence to support the efficacy of all
glucagon-like peptide-1 (GLP-1) receptor agonists for lowering blood glucose,
mainly as add on to oral therapy, but also in combination with insulin.12
Adverse effects
The main side-effect resulting in discontinuation is
gastrointestinal upset, GLP-1 receptor agonists are not associated with severe
hypoglycaemia, unless used in combination with other blood glucose-lowering
agents that are known to have this effect.12 Weight loss is a feature of
this drug class.12 No dose adjustment is required in mild renal
impairment, but advice for use and dose alteration in moderate and severe renal
impairment varies between individual drugs.12
Cardiovascular morbidity and mortality
In a study of patients with established cardiovascular
disease, once-daily liraglutide showed improved outcomes compared with placebo,9 while
both once‑daily lixisenatide and once-weekly exenatide have demonstrated
cardiovascular non-inferiority compared with placebo (placebo and standard of
care).25,26
Glucagon-like peptide-1 receptor agonist therapy should be
considered in people with a body mass index ≥30kg/m2 (or ethnicity‑adjusted
equivalent) in combination with oral agents or insulin as third- or fourth-line
treatment.12 They are an alternative to insulin when oral agents are
inadequate and, in those with established cardiovascular disease, GLP-1
receptor agonists with proven cardiovascular benefit, currently liraglutide,
should be considered.12
Insulin
All insulin preparations have efficacy in treating
hyperglycaemia. When moving from oral to insulin therapy metformin should be
continued but consideration should be given to discontinuing other
glucose-lowering agents.12 Insulin is usually started as once-daily NPH insulin,
but basal analogues can be considered if there are problems with recurrent
hypoglycaemia or when an individual requires assistance with injections.12 Mixed
insulin or prandial insulin are both valid options when intensifying treatment
with the aim of optimising glycaemic control while minimising the risk of
hypoglycaemia and weight gain.12
Conclusion
The updated guideline on the Pharmacological management
of glycaemic control in people with type 2 diabetes (SIGN 154) was
published in November 2017.12 The guideline is not intended to be overly
prescriptive, but provides information to support the selection of appropriate
treatment for individuals, guided by specific patient characteristics and
needs.
Treatment choice should not exclude basic advice on the need
for increased activity or dietary modification—the potential to deliver this as
part of routine primary care was demonstrated in the recently published DiRECT
study.27
The updated guideline also prompts the prescriber to review
treatment efficacy/safety at 3–6 months and to make changes, if
necessary.
Underpinned by robust evidence and accompanied by an
easy-to-follow treatment algorithm that can be used in the delivery of routine
clinical care, the updated guideline should help improve the treatment of those
with type 2 diabetes. Initial feedback on the guideline and its role in
management has been positive.
Conflicts of interest
Professor McKay has received an honorarium from Napp
Pharmaceuticals Limited for his work on this article and has been paid by many
companies for advisory work and presentations relating to the management of
type 2 diabetes. Professor McKay was a member of the guideline update group for
SIGN 154.''
Joseph Ana.
AFRICA
CENTRE FOR CLINICAL GOVERNANCE RESEARCH & PATIENT SAFETY
@Health Resources
International (HRI) WA.
National Implementing Organisation: 12-Pillar Clinical Governance
National Implementing Organisation: PACK Nigeria Programme for PHC
Publisher The BMJ West Africa & Journal of Health Practice
Nigeria: 8 Amaku
Street, State Housing & 20 Eta Agbor Road, Calabar.
Tel: +234 (0) 8063600642
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