Glucagon-like peptide-1 analogues for type 2 diabetes
BMJ 2011; 342 doi: https://doi.org/10.1136/bmj.d410 (Published 16 February 2011) Cite this as: BMJ 2011;342:d410
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Dear Editor,
The article by Wilding and Hardy about GLP-1 analogues for type 2
diabetes(1) is very timely. We agree that the GLP-1 analogues are
currently more expensive than established treatments. However we would
like to point out that non-analogue human insulins such as Insulatard and
Humulin I, do have a cost advantage when compared with the GLP-1 analogues
(30-day cost for Insulatard at a dose of 25 units per day is GBP9.54 and
GBP14.22 for Humulin I versus GBP68.24 for exenatide 10mcg twice daily and
GBP78.48 for liraglutide 1.2mg daily(2)).
In addition, bariatric surgery is emerging as a further treatment
option for people with type 2 diabetes and BMI >35(3). This
intervention can provide short-term and long-term (up to 10 years)
significant and sustained reductions in weight (48-72% reduction in excess
weight(4)) and glycated haemoglobin (48-98% of people with type 2 diabetes
and BMI >30 who underwent bariatric surgery are able to achieve a
glycated haemoglobin <6.2% without anti-diabetic medication(4)). The
NHS Choices website (accessed on 22 February 2011) quotes prices of
GBP5000-GBP15000 for bariatric surgery, while the approximate 10-year cost
of exenatide and liraglutide are GBP6800 and GBP7800 respectively.
However, the reductions in weight and glycated haemoglobin achieved with
GLP-1 analogues are small (around 3kg and 1% respectively(1)) and as yet
there is no data available for the long-term effectiveness of GLP-1
analogues.
As with many other chronic diseases, well-designed trials are
required to provide an
appropriate evidence base to guide the ongoing management of type 2
diabetes, especially as the treatment options available have increased in
number and complexity.
Dr Chioma Otti, Diabetes and Endocrinology ST4(a)
Dr Vasiliki Kolovou, Diabetes and Endocrinology ST4(a)
Dr Devasenan Devendra, Diabetes and Endocrinology Consultant(a) &
Honorary Senior Clinical Lecturer(b)
a Jeffrey Kelson Centre, Central Middlesex Hospital, Northwest
London NHS Trust, NW10 7NS
b Department of Investigative Sciences, Imperial College London
1. Wilding JPH and Hardy K. Glucagon-like peptide-1 analogues for
type 2 diabetes. BMJ 2011;342:433-435
2. British National Formulary 60; September 2010
3. CG43 Obesity: NICE Guideline.
http://www.nice.org.uk/nicemedia/live/11000/30365/30365.pdf. Accessed on
23 February 2011.
4. Colucci RA. Bariatric surgery in patients with type 2 diabetes: a
viable option. Postgrad Med 2011;123(1):24-33
Competing interests: No competing interests
Wilding and Hardy's review of the glucagon-like peptide-1 analogues
for type 2 diabetes1 is a timely addition to the BMJ's new Therapeutics
series, since these drugs are being increasingly recommended for use as
third line treatment for obese patients with type 2 diabetes. However,
such recommendations ignore the authors' caution that "Data on long term
effects of GLP-1 analogues on vascular complications are not yet available
from current trials." In other words, we have no idea at present whether
their use is beneficial or harmful in relation to the outcomes that matter
most to people with diabetes.
Recommendation of GLP-1 analogue treatment appears to ignore both the
recent studies of intensified glucose lowering2 and the lessons learnt
from rosiglitazone.3 The fact that these new agents have a plausible and
attractive mode of action, and tend to promote weight loss, should not
blind us to the fact that the only proof that counts is measured in hard
long-term end-points. Later in their article, the authors argue that data
are needed on 'cardiovascular safety,' implying that the use of glucose-
lowering agents in these patients is largely aimed at reducing the risk of
microvascular complications. Exenatide and liraglutide reduce
concentrations of HbA1c by around 1%1, which is of similar degree to the
lowering seen in the intensified glucose lowering studies.2 These studies,
however, failed to show significant reductions in the incidence of
blindness and renal failure over a mean follow-of 4.4 years despite
comprising, respectively, 54,000 and 118,000 patient-years of
observation. If it were simply that these studies lacked adequate power,
and larger numbers proved the point estimates of benefit to be
significant, expressed as absolute risk reduction for 1000 patients
similar to their case example treated for 5 years, this corresponds to
point estimates of 3.7 fewer people developing blindness and 1.6 fewer
developing renal failure.2 This implies that drug treatment costs with
exenatide would be ?1.13m to prevent one case of blindness, and ?2.60m for
one of renal failure. The costs with liraglutide would be 15% higher.
The lessons of the large intensified glucose lowering studies were
twofold: firstly, that this treatment approach is without benefit on
cardiovascular mortality; and secondly, that risk reduction for hard
microvascular endpoints is proportionately substantially less than that
expected from surrogate endpoints. 2 What has become apparent from the
rosiglitazone saga is that the impact of newer glucose lowering agents on
cardiovascular disease is impossible to predict from their effects on a
plethora of risk factors3 - something which also invalidates many of the
conclusions from cost-benefit estimates. These facts should predicate a
complete revision of the requirements for licensing these new drugs, with
HbA1c reduction alone no longer being adequate proof of benefit. Moreover,
patients who have these drugs recommended should be told that there are no
long-term outcome data yet to provide their benefit or exclude their risk.
John S Yudkin <j.yudkin@ucl.ac.uk>
Richard Lehman
Harlan M Krumholz
1. Wilding JPH and Hardy K. Glucagon-like peptide-1 analogues for
type 2 diabetes. BMJ 2011: 342: d410.
2. Yudkin JS, Richter B and Gale EAM. Intensified glucose lowering in type
2 diabetes: time for a reappraisal. Diabetologia (2010) 53: 2079-2085.
3. Lehman R, Yudkin JS and Krumholz HM. Licensing drugs for diabetes. BMJ
(2010) 341: c4805.
Competing interests: No competing interests
Wilding and Hardy summarise the evidence for GLP-1 analogues well.
These drugs seem to have been rapidly taken up by diabetologists. Yet when
there are no long term trials it seems that some have learnt nothing from
the rush into rosiglitazone.
As Wilding and Hardy state "Neither exenatide nor liraglutide has been
formally studied with, or has a licence for use in combination with,
insulin; however, exenatide is sometimes used with insulin in clinical
practice"
They are being economical with the truth. In West Lothian and we are
assured by our local diabetologists that their prescribing is in line with
the rest of the country and in West Lothian approximately one third of
patients on exenatide or liraglutide are also on insulin. Our
diabetologists quote an Association of British Clinical Diabetologists
audit showing that 36% of those on GLP-1 analogues were also on insulin.
The cost issue is hard to swallow Wilding and Hardy suggest that there is
a good financial case as these patients would instead be put on insulin.
However the prescribing of GLP-1 analogues has generated a cost pressure
for West Lothian CHCP of ?280,000 with no concomitant drop in insulin
costs.
Under "tips for patients" they state "Exenatide [or liraglutide] is a
relatively new medicine for diabetes that is given by injection. It may
also lead to some weight loss. You will be given the drug for a trial
period, and it will only be continued after six months if it improves your
glucose control and lowers your body weight (according to national
guidelines for diabetes (NICE)). We will agree the target figures for your
glucose and body weight when you are given your first injection."
There are, as they state NICE guidelines for the use of GLP-1 analogues, I
have seen no evidence that these are being adhered to.
I note that Wilding and Hardy have received payments from nine and eight
drug companies respectively and I do wonder with rosiglitazone and now GLP
-1 analogues how much the diabetic specialist world is in the pay of big
pharma.
Competing interests: I sit on various prescribing committees in Lothian.
Glucagon-like peptide-1 analogues for type 2 diabetes
how do the glucagon-like peptide-1 analogues compare to Dipeptidyl
peptidase-4 inhibitors in terms of comparative efficacy? would the
convenience of oral dosing favour the use of the later.
Competing interests: No competing interests