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Waugh N, Cummins E, Royle P, et al. Newer Agents for Blood Glucose Control in Type 2 Diabetes (Supplement) [Internet]. London: National Institute for Health and Clinical Excellence (UK); 2009 May. (NICE Clinical Guidelines, No. 87S.)

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Newer Agents for Blood Glucose Control in Type 2 Diabetes (Supplement) [Internet].

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2The glucagon-like peptide-1 analogue; exenatide

The glucagon-like peptide-1 analogues are a new class of oral glucose lowering drugs that mimic the endogenous hormone, glucagon-like peptide (GLP-1). GLP-1 is an incretin, a gastrointestinal hormone that is released into the circulation in response to ingested nutrients from food. The mechanism by which food stimulates GLP-1 release from intestinal endocrine cells is not known; however, it may be under the control of neuroendocrine pathways. The effect was discovered after it was noted that the stimulation of release of insulin from the pancreas was greater after oral glucose than after an equivalent amount given intravenously.32

Endogenous GLP-1 has a number of actions.33 It stimulates insulin secretion34, but only in a glucose-dependent manner, so that insulin is not released if glucose is low. The incretin effect stops once the plasma glucose is down to 3 mmol/l.32 It also suppresses glucagon secretion, delays gastric emptying 35 and reduces appetite. It also increases insulin biosynthesis36,37. Therefore, it controls plasma glucose level in a number of ways.38 The reduction of glucagon secretion in type 2 diabetes is also glucose-dependent.39 40

Natural GLP-1 has been shown to affect plasma glucose levels when given by subcutaneous injection41. However it is rapidly broken down by the enzyme dipeptidyl peptidase IV (DPP-4), resulting in a half-life of 1 to 2 minutes.40 32,33 So the endogenous form could only be used via a continuous infusion, and therefore would be impractical for treatment.

The GLP-1 analogues, of which only exenatide is currently available, have the same actions as GLP-1 but are resistant to breakdown by DPP-4. This gives them a much longer half-life than endogenous GLP-1. Other drugs are coming, with liraglutide expected to be licensed in 2009.

Exenatide has the following actions: 42,43

  • Increasing glucose-dependent insulin release
  • Suppressing glucagon secretion in situations where that is inappropriate, such as when glucose level is high
  • Slowing of gastric emptying (which will slow glucose absorption after meals)
  • Reduction of appetite, and hence reduction of food intake
  • Restoration of first phase insulin secretion in people with type 2 diabetes.

Given these actions, it was hoped that the GLP-1 analogues would not be associated with the weight gain seen with some other diabetes drugs. Early reports suggested that weight loss might occur.44 45

Exenatide

Exenatide was originally isolated from the venom of the Gila lizard (Amylin Pharmaceuticals). The peptide from the lizard had similarities with GLP-1, but had greater affinity with the receptor and was resistant to DPP-4.

Exenatide is produced synthetically. It has a short half-life of about 4 hours, and has to be given (by injection) twice daily at present. The drug has been developed for diabetes treatment under the trade name Byetta - (Amylin Pharmaceuticals45 and Eli Lilly46). A longer-acting form, exenatide LAR has been developed and is currently undergoing trials.47 45 It may only have to be given weekly.

The second GLP-1 analogue will be liraglutide, produced by Novo Nordisk.48 It is based on human GLP-1 but with an amino acid substitution and an attached acyl chain, which fosters binding to serum albumin, thereby delaying renal excretion. It has a longer half-life of about 11–13 hours, and so can be given once daily. (N.B. Because the GLP-1 analogues are designed to act mainly at meal-times, though they have some effect beyond those, they are not required during the night). Again, being a digestible peptide, it has to be given by subcutaneous injection. Liraglutide has not yet received a license for use in the UK, and will not be further discussed in this report.

Criteria for considering studies for this review

Types of evidence

For efficacy, randomised controlled trials are the gold standard. Open label extension studies are useful to see if the effects persist, and for the development (or sometimes waning) of side-effects. The drop-out rate may also be a useful guide to tolerability.

For our purposes, we are interested mainly in trials which use standard UK practice as the comparator. Standard practice is set out in the current NICE guideline for type 2 diabetes National Insitute for Health and Clinical Excellence, 2008 2522 /id} and is shown in the flowchart in chapter 1.

Types of interventions

Treatment for a minimum of 12 weeks with exenatide, exenatide long-acting or liraglutide. Twelve weeks is chosen because of the time it takes for glycaemic control to be reflected in HbA1c, but should be regarded as the minimum acceptable rather than satisfactory. Longer duration studies would be better.

The 2002 NICE guideline on management of type 2 diabetes (see flowchart) stated that for individuals with a BMI over 25 kg/m2, the first choice in addition to diet was metformin, and if that was insufficient, an insulin secretagogue should be added. In practice that would be a sulphonylurea; the other secretagogues, the meglitinide agonists, are little used in the UK.

So the most relevant comparisons are;

  1. The addition of a GLP-1 analogue to standard combination therapy when that is insufficient to achieve good control, i.e.
    • metformin + a sulphonylurea versus metformin + sulphonylurea + a GLP-1 analogue
    A variant might use two insulin sensitisers;
  2. In those who cannot tolerate metformin, a glitazone might be used in combination therapy instead;
    • sulphonylurea + a glitazone versus sulphonylurea + glitazone + GLP-1 analogue

One outcome of interest will be progression to insulin treatment.

3.

Another option suggested in the NICE guideline was to add a glitazone to the metformin and sulphonylurea combination, i.e. triple therapy. If that fails, insulin treatment is the next step, usually with a long-acting basal insulin, with metformin and perhaps the other drugs continued. So another possible comparison would be to try a GLP-1 agonist instead of insulin;

  • Metformin + sulphonylurea + glitazone + GLP-1 agonist versus basal insulin + metformin + sulphonylurea + glitazone.

4.

In those who have started insulin recently, there could be a case for stopping insulin and trying a GLP-1 analogue, so a further comparison is;

  • insulin (with or without oral agents) versus oral agents + a GLP-1 analogue

This is not a licensed use. The FDA patient information sheet49 states that;

Byetta is not a substitute for insulin in patients whose diabetes requires insulin treatment”.

5.

This comparison looks at adding exenatide to metformin monotherapy, and was included at the request of the GDG which felt that there were some overweight patients in whom the further weight gain likely with the usual second-line combinations of adding a sulphonylurea (or a glitazone) was so undesirable that a GLP1 agonist should be considered instead, given the likelihood of weight loss.

Ideally, the comparison would be of metformin + exenatide versus metformin + a gliptin but at the time of writing, no such trials had been done, so comparison 5 is:

Licensed indications

The licensed indications vary a little between Europe and the USA. The EMEA approved indications are;

“Byetta is indicated for the treatment of type 2 diabetes mellitus in combination with metformin, and/or sulphonylureas in patients who have not achieved adequate glycaemia control on maximmaly tolerated doses of these oral therapies”.

The FDA approval includes the glitazones:49;

“Byetta is indicated as adjunctive therapy to improve glycemic control in patients with type 2 diabetes mellitus who are taking metformin, a sulfonylurea, a thiazolidinedione, a combination of metformin and a sulfonylurea, or a combination of metformin and a thiazolidinedione, but have not achieved adequate glycemic control.”

Current evidence for effectiveness of glucagon-like peptide analogues in type 2 diabetes

Appendix 2 shows all the trials. Most of the studies were parallel-group, randomised controlled trials (Barnett 200750 was a crossover trial). The majority of studies appear to have been conducted in North America and/or Europe, with the exception of one that was conducted entirely in Japan (Seino 200751). Four studies (Barnett 200750, Davis 200752, Heine 200653 and Nauck 200754) were reported as non-inferiority/equivalence trials.

Excluded studies

The studies in the Table 2 below were excluded for the reasons given. Some of these trials provided useful information, for example showing that the GLP-1 agonists were effective in lowering plasma glucose compared to placebo, or were early dose-ranging studies, but were not relevant to our key comparisons.

Table 2. Excluded GLP-1 trials.

Table 2

Excluded GLP-1 trials.

Included studies

Seven trials were relevant for our purposes, and are listed below, under the relevant comparisons. The quality of the trials seems reasonable, though some details were not reported, and insulin when a comparator may not have been optimally used. Table 3 gives the details.

Table 3. Quality of included GLP-1 trials.

Table 3

Quality of included GLP-1 trials.

Comparison 1 – addition of GLP-1 analogue to dual combination therapy

Kendall 2005

Kendall and colleagues58 recruited 733 people with type 2 diabetes whose control was inadequate (HbA1c 7.5 to 11%) on dual therapy with metformin and a sulphonylurea. Their average age was 55 years (range 22 to 77), and mean BMI was around 34 kg/m2. They were recruited from 91 centres in the USA, an average of 8 recruits per centre. Most were Caucasian, with about 11% Black and 16% Hispanic. Mean duration of diabetes was about nine years.

There were three arms – placebo controls, exenatide 5 μg BID and exenatide 10 μg BID (after four weeks on 5 μg).

Zinman 2007

Zinman and colleagues59 recruited 233 patients whose control was inadequate on a glitazone with or without metformin, but about 80% were on metformin. They came from 49 centres in Canada, the US and Spain, an average of just under five per centre. Mean age was 56 (range 21 to 75), and their mean BMI was 34 kg/m2.

These patients came from a larger group of 435 who were screened for entry. Discontinuation rates differed, with 71% of the exenatide group completing compared to 86% of the placebo group. The commonest reason for discontinuation was adverse events (19 of 121 on exenatide versus 2 of 112 on placebo). Exenatide was started at 5 μg twice daily for 4 weeks, increased to 10 μg for the remaining 12 weeks.

Concerns about the study by Zinman and colleagues were raised by Malozowski 2007.60 These included;

  • the representativeness of the included patients. Their control was inadequate, but many were not on maximal doses of other oral drugs. Also, 21% were not on any metformin, which should be first-line therapy.
  • The lack of reinforcement of lifestyle interventions such as diet; no details were given of educational input. (So care before starting exenatide does not appear to have been optimised).
  • There was a significant drop-out rate especially in the exenatide group, with 71% completing the trial.
  • Full details of adverse events were not published, nor details of whether there were any sub-groups more susceptible to the side-effects (though with their relatively small numbers, Zinman and colleagues would not have the power to do much in the way of subgroup analysis.)
  • The study duration, 16 weeks, was too short in a chronic disease.

Comparison 2 – patients intolerant of metformin where a sulphonylurea plus glitazone combination was the standard arm comparator, versus that plus a GLP-1 analogue

No studies were found.

Comparison 3 – insulin + oral agents versus GLP-1 analogue + oral agents

Heine 2005

Heine and colleagues53 recruited 551 patients in 82 centres in 13 countries, an average of just under 7 per centre. Mean age was 59 (range 30 to 75) and mean duration of diabetes was 9.6 years. They were less overweight than in some other studies, with mean BMI 31 kg/m2. On dual therapy with metformin and sulphonylurea (at maximum doses), HbA1c was between 7 and 10%. Those with recent severe hypoglyaemia were excluded.

Patients were randomised to have glargine (starting at 10 units, titrated to achieve FBG <5.6 mmol/l) or exenatide (10 μg BID) added to their oral agents. The dosage of the oral drugs was fixed unless hypoglycaemia was a problem, in which case the sulphonylurea dose was halved. 19 % of the exenatide group and 10% of the glargine group withdrew from the study. The proportions withdrawing because of adverse events were 9.5% for exenatide and 0.7% for glargine.

Nauck 2007

Nauck and colleagues54 compared twice daily exenatide with twice daily biphasic insulin aspart 30/70) in 505 patients whose control was not good enough (mean HbA1c 8.6 %; inclusion range 7% to 11%) on dual therapy with optimal doses of metformin and sulphonylurea. Those with recent severe hypoglycaemia were excluded. The oral agents were continued in unchanged dosage, unless hypoglycaemia occurred, in which case the dose of sulphonylurea was halved in the exenatide group. (In the insulin group, the insulin was reduced).

As in other studies, those randomised to exenatide started on 5 μg twice daily and increased to 10 μg (if tolerated – it was in 80%) after four weeks. The dosage of biphasic aspart was left to each investigator to adjust, according to glucose control and hypoglycaemia.

The study was carried out in 13 countries but the number of centres is not given. The trial was powered for equivalence, defined as a difference in HbA1c of not more than 0.4%. Of the 505 randomised, 199 (79%) of 253 on exenatide and 223 (90%) of the 248 on insulin completed the study. The difference was mainly due to withdrawals because of side-effects − 20 withdrawals in the exenatide group and none in the insulin group.

Home61 had concerns about the study by Nauck and colleagues, including:

  • the exenatide regimen was optimised but the biphasic insulin was not. The total daily insulin dose was lower than usually seen (it was 24 units/day at the end of one year).
  • blood glucose control was relatively poor in the insulin group, with a reduction of 0.9% in HbA1c, lower than seen in most recent treat-to- target studies of insulin in type 2 diabetes.
  • puzzlement about the use of an aspart product, from a rival manufacturer to the sponsor of the study (Lilly), when they could have used their own similar product. Exenatide is made by Lilly, who also produce the Humalog biphasic insulin.

The authors62 mounted a reasonable defence against most of these points, but could not explain why insulin doses were not raised in pursuit of better control.

Barnett 2007

Strictly speaking this study50 does not meet our inclusion criteria, because it recruited patients with inadequate control on either metformin or a sulphonylurea, but we include it in order to have more than one trial against glargine, and hence more data on relative effect size. The study was carried out in 26 places in six countries (not including the UK) and recruited 138 patients, to a cross-over trial of 10 μg exenatide twice daily or glargine titrated to achieve a satisfactory fasting glucose level. The baseline HbA1c was 9%. Mean age was 55 years, and baseline BMI 31. It was funded by the manufacturer, Eli Lilly.

Comparison 4 – patients already on insulin: replacement by GLP-1

This comparison is included for completeness and interest, but note that it is not currently a licensed indication.

Davis 2007

Davis and colleagues52 recruited 51 patients who were already on insulin (various forms, for about three years) in combination with oral agents (mostly metformin alone or with a sulphonylurea). Randomisation was 2:1 in favour of exenatide. Mean age was 53, mean BMI 34 kg/m2, and mean duration 10 years. The study was carried out in five centres in the USA (average 10 patients per centre).

There were more withdrawals in the exenatide group (14 of 33) than in those remaining on insulin (1 of 16). The commonest reason was loss of glycaemic control on exenatide. An editorial by Rosenstock and Fonseca63 made a number of criticisms, starting with the comment that “the scientific value is rather unclear, but the marketing appeal is obvious”. This may be a little harsh, since one aim of the study was to see if people with type 2 diabetes who had relatively recently started insulin, could manage without it. More pertinent points were that insulin treatment was not optimised, and that the results were less successful than the paper implied;

this study raises issues about commercial bias in study design, interpretation and reporting by the pharmaceutical sponsors.”

Comparison 5 – addition of GLP-1 analogue to metformin monotherapy

DeFronzo and colleagues (2005) carried out a three-armed trial (the Exenatide 112 trial), in 336 patients, aged 19 to 78 years (mean 53 years), who had had diabetes for an average of about 6 years, in 82 sites in the United States. Baseline mean BMI was 34 and mean HbA1c 8.2%. The three arms were metformin plus one of placebo, exenatide 10 ug BID, and exenatide 5 ug BID. Only the standard dose of 10 ug BID is included here.

HbA1c results

These are shown in Table 4 below.

Table 4. HbAc1 results for GLP-1 trials.

Table 4

HbAc1 results for GLP-1 trials.

The trials show that in those whose control is not good enough on dual therapy, addition of exenatide improved HbA1c by about 1% (Kendall 200558 and Zinman 200759).

In the Kendall (2005)58 trial, the changes in HbA1c at 30 weeks were greater in those whose baseline level was higher.

Exenatide 5ugExenatide 10ugPlaceboSignificance
Baseline A1c <9% (read from graph Fig 2C)−0.40−0.550.35Compared with placebo P<0.0001)
Baseline A1c ≥9 (read from graph Fig 2C)−0.95−1.400Compared with placebo (P=< 0.0002)

When exenatide is compared with various insulin regimens, the results are similar, suggesting non-inferiority, though the issue of non-optimisation of the insulin treatment remains an issue.

Hypoglycaemia

Table 5 shows the frequency of hypoglycaemia.

Table 5. Frequency of hypoglycaemic events in GLP-1 trials.

Table 5

Frequency of hypoglycaemic events in GLP-1 trials.

Definitions of hypoglycaemia used in the included trials.

  • Barnett 2007 defined it as any sign or symptom due to hypoglycaemia, or a serum glucose concentration under 3.3 mmol/l. So asymptomatic hypos were included.
  • Davis 2007 included any episode in which a patient felt they were experiencing a sign or symptom of hypoglycaemia, or a blood glucose under 3.4 mmol/l, irrespective of whether any symptoms were associated.
  • De Fronzo 2005 based recording on symptoms which were confirmed by a plasma glucose under 3.3 mmol/l.
  • Heine 2005 included both symptomatic episodes and biochemical ones.
  • Kendall 2005 used symptoms that “may have been documented by a plasma glucose under 3.33 mmol/l”.
  • Nauck 2007 included both symptomatic episodes and instances of blood glucose under 3.4 mmol/l during self-monitoring, whether or not the monitored episode was associated with any symptoms.
  • Zinman 2007 also defined hypoglycaemia as either symptoms or self-monitoring readings.

As expected, the frequency of hypoglycaemia varied amongst studies. Severe hypoglycaemia was uncommon. There were no severe hypos in the Nauck 2007 and Zinman 2007 trials, and only one in the Kendall 2005 study.

In Barnett 2007, three patients experienced 8 episodes of severe hypoglycemia during insulin glargine treatment, whereas there were no episodes of severe hypoglycaemia during exenatide treatment.

Also exenatide-treated patients had significantly lower mean rates of overall hypoglycemia (P = 0.039) and nocturnal hypoglycemia (P < 0.001) compared with insulin glargine-treated patients. There were also no significant differences in rates of daytime hypoglycemia between exenatide and insulin glargine treatment

In the Davis 2007 trial, most hypoglycaemia occurred during daytime. Of the 13 exenatide patients who reported hypoglycaemia, 10 were also taking a sulphonylurea. Overall hypoglycaemia rates were higher in those with good control (exenatide 2.5 events per patient year; insulin 1.2 events per patient year).

In the Heine 2005 trial, the overall frequencies of hypoglycaemia were similar, but nocturnal hypoglycaemia was less frequent in those on exenatide. In those who achieved good control (HbA1c of 7% or less at week 26), 61% of the exenatide group and 68% of the glargine group reported at least one symptomatic hypoglycaemic episode, and 21% of those on exenatide and 43% of those on glargine reported at least one episode of nocturnal hypoglycaemia.

Although the nocturnal hypoglycaemia rate in the Nauck 2007 study was significantly lower in the exenatide group (see table), this was no longer statistically significant once adjusted for baseline HbA1c. Once the sulphonylurea doses were reduced, hypoglycaemia rates fell from 27 to 6 events per patient year.

Weight

Most studies reported weight loss with exenatide treatment. Results are shown in Table 6

Table 6. Weight changes in GLP-1 trials.

Table 6

Weight changes in GLP-1 trials.

Does nausea cause the weight loss?

Maggs and colleagues (2005)64 carried out an analysis of patients in three trials (Buse 200456, De Fronzo 200565 and Kendall 200558) to see if the weight loss with exenatide was related to the nausea. Severe nausea was found in only 4%. They found little correlation between nausea and weight loss (or HbA1c). In the extension studies (to 52 weeks), the majority of patients had very little nausea, but lost the same amount of weight as the more nauseated subgroups.

Heine and colleagues53 found that although the magnitude of weight reduction tended to be greater in patients taking exenatide who experienced longer durations of nausea, patients who did not report any episodes of nausea during the trial (n = 120) still demonstrated a mean weight change of −1.9 kg (CI, −2.5 to −1.4 kg)

Adverse events other than hypoglycaemia

Table 7 shows the most frequent side-effects.

Table 7. Most frequent side-effects in GLP-1 trials.

Table 7

Most frequent side-effects in GLP-1 trials.

The most striking finding is the high frequency of nausea with exenatide, with vomiting not uncommon. However the number who had to stop exenatide because of side-effects was much lower. Most nausea was mild, and the frequency decreased over time. For example, Heine and colleagues reported that 55% of patients reported nausea in the first eight weeks, but only 13% did so in the last 8 weeks. However 18 patients from the exenatide group withdrew because of nausea (compared to one in the insulin group). Heine and colleagues reported the frequency of mild, moderate and severe nausea to be 33%, 20% and 5% respectively.

Kendall and colleagues also reported that the frequency of nausea diminished over time, and only 4% had to withdraw because of it.

Zinman and colleagues reported that 9% of the exenatide group withdrew because of nausea, but that most nausea was mild (44%) or moderate (41%) and that it declined over time.

Cardiovascular risk factors

Three trials reported lipid and blood pressure data.

DeFronzo 2005 reported that exenatide treatment was not associated with an increased incidence of cardiovascular, hepatic, or renal adverse events. Also no changes in plasma lipids, laboratory safety parameters, heart rate, blood pressure, or electrocardiogram variables were observed between treatment arms.

Nauck and colleagues reported that HDL was higher, by 0.04mmol/l, with insulins, but that blood pressure fell with exenatide (systolic by 5 mm/Hg and diastolic by 2mm) but did not change with insulin.

Zinman and colleagues found no significant differences in lipids and blood pressure.

Other outcomes

Patient reported outcomes from the Barnett 2007 trial were reported by Secnik and colleagues in a poster presented at IDF in 2006.66 Responses to the health outcome intruments the Psychological General Well-Being Index (PGWB), Diabetes Symptom Checklist-Revised (DSC-R), EuroQol instrument score (EQ-5D), Treatment Flexibility Scale (TFS), and Hypoglycaemia Fear Survey (HFS) were examined. No statistically significant between-group differences between twice daily exenatide and glargine were found on any of these measured health outcomes.

Secnik Boye and colleagues (2006)67 reported some patient reported outcomes from the Heine trial, including EQ5D, the vitality scale of the SF-36, the Diabetes Symptom checklist, and the Diabetes Treatment Satisfaction Questionnaire. No differences were found, suggesting that the greater number of injections with exenatide (twice daily versus once for glargine), and the frequent (at least initially) nausea was not enough to affect overall satisfaction, perhaps because those were balanced by weight loss on exenatide (on average, 2.3 kg) versus gain on insulin (mean 1.8kg).

An abstract from the Nauck 206 trial by Yurgin and colleagues (2006)68 also reported EQ5D and SF36 data, stating that the exenatide group showed some improvement whereas the biphasic aspart group showed no change.

Lower dose exenatide

The standard dose of exenatide is 10 μg BID, but there are some results on 5 μg BID from two of the trials (Table 8).

Table 8. Comparison of low dose and standard dose results.

Table 8

Comparison of low dose and standard dose results.

Hence those who can tolerate the starting dose but not the full one, still get some benefit. (NB the cost appears to be the same, so the benefit/cost ratio is higher).

Follow-up studies - open label extensions

Klonoff and colleagues (2008)42 report results in people who had been on exenatide for at least three years. The participants were from the three 30-week studies (Buse 200456, De Fronzo 2005 65 and Kendall 200558) only one of which met our inclusion criteria for this review. However the pooled open label follow-up can provide useful data on duration of efficacy, and side-effects.

The withdrawal rate was high. Of 527 eligible patients, 310 withdrew. The reasons for withdrawal included adverse events (11%), poor control (3%), and patient or investigator decision (41% - reasons not given).

Weight loss was maintained amongst the 41% (217) who stayed in the follow-up study. The mean weight loss at 3 years was 5.3kg. 84% of patients lost weight. Reductions in HbA1c were also sustained (but this may be because those in whom it rose again left the study). Total cholesterol fell by 5% and triglycerides by 12%, presumably because of the weight loss, because there was a correlation between weight loss and cardiovascular risk factors.

The most frequent adverse effect (in 59%) was nausea, usually mild. Next came hypoglycaemia, but only in those treated with a sulphonylurea. Upper respiratory infections were common (36%) but the significance of that cannot be assessed without a control group. There were no serious side-effects other than a few severe hypoglycaemic episodes. So exenatide appears safe, but the high drop-out rate reduces the value of the study.

Results from routine care

Rather different results were found in routine care by Wolfe and King (2007).69 Two hundred consecutive exenatide-treated patients included 56 treated for 12 months. The nadir of weight occurred at 6 months. Few details are given of later weight loss in this ADA conference abstract, but the suggestion is that there was a plateau after six months.

Loh and Clement (ADA poster 2007)70 reported a small follow-up study of 30 patients with type 2 diabetes treated with exenatide, some in addition of oral antidiabetic drugs (OADs), others in addition to insulin. At one year, there was weight loss (mean 2 kg; p=0.0033) but no significant reduction in HbA1c overall. Maximum weight loss occurred by 7 months, with most patients regaining weight over months 7 to 12. Half the patients had stopped exenatide by 12 months, because of therapeutic failure or side-effects. Loh and Clement conclude that in the “real world”, exenatide may not give as good results as seen in trials.

Yoon and colleagues in a conference abstract (ADA 2008), reported use of exenatide added to insulin. In a case series of 226 patients who started exenatide, 34 (15%) stopped within 3 months due to adverse effects.71 Another 78 discontinued it later, mainly due to side effects or lack of efficacy. The final analysis of those who had used it for more than a year (116) showed weight loss of 6 kg, and a 20% reduction in insulin dosage. Eleven patients with an initial mean insulin dose of 17 units per day were able to stop insulin.

Another study from routine care, reported by Bhushan and colleagues at the ADA 2008 conference,72 followed 201 patients for 16 weeks; all received exenatide in addition to previous treatment (details of which not given). Weight loss was seen in 69%, and averaged about 2 kg. Total cholesterol fell by 6 mg/dl. Blood pressure was unchanged.

It seems logical that exenatide be combined with insulin, although this is not a currently licensed indication. In an abstract from the recent European Association for the Study of Diabetes conference, Govindan and colleagues73 presented a small case series from Wolverhampton, of 27 obese patients (mean BMI 43 at baseline) who were already on insulin but poorly controlled (mean HbA1c 8.8%). About half had nausea on exenatide, but only three had to stop it. The mean weight fell from 128 kg to 115 kg after three months; BMI from 43 to 40; and insulin dose from a mean of 170 units/day to 36 units/day. The average insulin dose reduction comes about because ten patients could stop it altogether, although mean HbA1c did not improve much (by only 0.3%; NS). Longer follow-up might show greater benefit, and it suggests that trials of combined exenatide and insulin therapy are justified.

Also from the EASD conference, Wintle and colleagues (from Amylin and Lilly)74 presented data from diabetic care records from the General Electric database, on 2086 patients treated with exenatide for six months or more. Patients had previously been on metformin, sulphonylurea or glitazone monotherapy (about 30%), or on dual therapy (38%) or triple therapy (34%), but were not well controlled (mean HbA1c 8.4% and BMI 38.5).

Exenatide reduced HbA1c by 0.9% in those who had been on monotherapy, but by less (0.5 to 0.8%) in those who had been on combination treatment.

Kendall and colleages (Amylin and Lilly)75 reported a pooled analysis of two years of exenatide treatment. Patients were split into three groups according to pattern of weight loss – one group which lost none (they gained about 1 kg – but since their HbA1c fell by over 1%, they were presumably taking the exenatide, suggesting that compliance was not the issue); a second group (34%) which lost weight quite quickly (about 4 kg by week 12); and a third group (46%) which lost as much weight as the second group, but who did so more slowly. Groups 2 and 3 lost on average 6 kg by two years.

In the group which did not lose weight, HbA1c fell by about 1.2% but started rising again in the second year, to a drop of about 0.7% (from graph). In groups 2 and 3, the fall in HbA1c of about 1.5% was more sustained – about 1.5% reduction at 52 weeks and 1.3% at 104 weeks.

This finding might have implications if NICE recommended a stopping rule for exenatide, since it could be stopped in those in whom it was least effective (no weight loss), thereby improving the cost-effectiveness.

Exenatide LAR

The exenatide LAR formulation has been studied in a 15 week phase II trial (Kim 2007) in patients with type 2 diabetes.47 The trial reported that a 2 mg dose of exenatide LAR showed a reduction in HbA1c of 1.4% (relative to placebo) which the authors say is approximately twice as great as that seen with twice daily injections of conventional exenatide. Preliminary results have suggested that the LAR formulation is also better tolerated than the original formulation, with less nausea, and (in the 2mg form) is associated with greater weight loss; however patient numbers were small. Results from other trials are awaited. The Amylin websit 45 reports an unpublished 30-week RCT of long-acting exenatide versus twice daily Byetta, and states that “results showed that exenatide once weekly demonstrated powerful glucose efficacy, complemented by striking weight loss.”

This trial is presumably the DURATION trial, recently described in two abstracts. ADA abstract Drucker and colleagues reported the 30 week results in brief.76 They showed that once weekly exenatide reduced HbA1c slightly more than twice daily; 1.9% versus 1.5%. Seventy seven percent of the once weekly group achieved HbA1c less than 7.0%, compared to 61% for the twice daily. The trial recruited 295 patients who were poorly controlled (mean HbA1c 8.3%), but most were on no oral drugs (15%) or monotherapy (45%). Only the 40% on two oral agents are relevant to this review.

However, the trial clearly suggests that the future lies with once weekly exenatide. No details on cost are yet available, but some economies would be expected compared to twice daily injections.

The second abstract is from EASD77 and is a 22-week open label follow-up of 241 of the DURATION patients by Buse and colleagues (the same team as Drucker and colleagues). Much of the abstract is about the patients who switched from twice daily to weekly, but the 52 week HbA1c results in the original once weekly group are reported in brief as being sustained – reduction at 52 weeks of 2% (1.9% at 30 weeks).

GLP-1 agonists and beta-cell function

Rodent studies have reported that liraglutide can increase beta-cell mass.

Gallwitz (2006)78 has reviewed some of the animal and in vitro studies. The animal studies are mainly in rats, with a couple in mice. The evidence suggests that beta-cell growth is stimulated and that apoptosis is reduced. In isolated human islets, GLP-1 expands beta-cell mass. However he found no evidence regarding beta-cell mass in humans.

Xu and colleagues79 reported that in rats made diabetic by partial pancreatectomy, exenatide treatment improved diabetic control, and that this was related to an increase in beta-cell mass (assessed histologically). Interestingly, the improved control was seen even after exenatide was stopped after 10 days. Gedulin and colleagues80 also reported an increase in beta-cell mass in rats after exenatide treatment.

Tourrel and colleagues81 treated newborn rats made diabetic with streptoxozotocin with exenatide and again noted an increase in betal cell mass, which persisted (though the beta-cells were less responsive to glucose).

If these findings are confirmed in humans, that would be of great importance, because it would suggest that the progressive nature of type 2 diabetes4,5 could be halted. Barnett (2007) 38 and Holst (2008) 82 both note that if the GLP-1 analogues could increase beta-cell mass, there would be an argument for treatment early in the disease, before too many beta-cells had been lost.

However there are few data on the effect in humans – some very short experiments on islet cells in vitro, reviewed by Wajchenberg83, who concludes that there is as yet no clinical evidence that the GLP-1 analogues protect beta-cells.

Bunck and colleagues,84 in an ADA abstract from their RCT of exenatide versus glargine85 reported that the beneficial effects seen on exenatide were not sustained – 5 weeks after stopping exenatide all the improvements had gone, which may suggest that beta-cell function was not improved.

Further research is required, ideally with some means of determining at an early stage (2–3 years?) whether beta-cell mass is maintained in humans with type 2 diabetes.

Discussion

Barnett (2007) 38 comments that:

“The appeal of exenatide therapy is that it provides glycaemic control with concomitant weight loss (as opposed to rapid or short-acting insulins which tend to cause weight gain), and, when not used with a drug that increases circulating insulin levels, does not cause hypoglycaemia.”

The evidence to date shows that the GLP-1 analogues can provide a useful improvement in glucose control when added to dual treatment with oral drugs, and that at least in the short term, they can be an alternative to starting insulin. How long this effect would last, is not known. If we assume that the disease will steadily progress, as shown in UKPDS 164, then some of the benefit will be lost since the beta-cells will no longer be there to be release insulin. Other benefits such as delayed gastric emptying may continue, which may help control post-prandial hyperglycaemia.

The glucose-dependent nature of the insulin release means that hypoglycaemia should be less of a problem, but the differences in the trials were not marked.

Weight loss is a useful feature in the trials, though perhaps seen less in routine care.

The drawbacks are the need for injections (twice daily with exenatide and once a day with liraglutide), the high rate of side-effects (especially nausea), and the cost.

Injecting a foreign peptide could lead to antibody formation, but Barnett (2007)38 notes that such antibodies were common by 30 weeks but did not appear to reduce efficacy.

A review by the well-respected Prescrire International group from France concluded that exenatide was an alternative to starting insulin in poorly controlled type 2 diabetes patients, but that there was no evidence as yet that it was better, and that given the much greater experience with insulin, that should be preferred.86

The German Institute for Quality and Efficiency in Health Care (Institut fur Qualitat und Wirtschaftlickeit im Gesundheitswesen or IQWiG) issued a report on exenatide in 2007.87 Their review of exenatide addressed two questions;

  • is it worthwhile to add exenatide to therapy with metformin and/or a sulphonylurea?
  • how does adding exenatide compare with other additional treatments?

The review identified five trials. These included the Kendall 2005, Nauck 2007, DeFronzo 2005 and Heine 2005 studies included in our TAR. The other one was Buse 2004,56 excluded from this TAR, because patients had failed on sulphonylurea monotherapy but not had metformin.

The IQWiG review concluded that;

  • the reduction in HbA1c was comparable for exenatide and insulin
  • no difference in the frequency of severe hypoglycaemia was shown in the trials against insulins
  • patients on exenatide lost weight, but those on insulin gained weight.
  • the long-term benefits or harms of exenatide are unclear.

Post-prandial hyperglycaemia

The slowing of gastric emptying by the incretin mimetics could in theory reduce post-prandial hyperglycaemia.

Acute pancreatitis

There have been recent concerns about acute pancreatitis in people treated with exenatide.88 The FDA had (as at end of 2006) reviewed 30 reports of acute pancreatitis in patients on exenatide. Nearly all had other possible reasons for pancreatitis, including gallstones and alcohol use. Nearly all improved after exenatide was stopped, and a few in whom it was started again had a recurrence of symptoms. However the improvement after the drug was stopped may be coincidental. The FDA has asked for a warning to be added to patient information, has arranged enhanced monitoring, but has not restricted use.89

The MHRA (Drug safety Update May 2008)90 has called for vigilance. It notes that by September 2007, there had been 89 reports of acute pancreatitis, with, curiously, 87 in the USA and two in Germany. One case has since been reported in the UK, after only 5 μg of the drug.

Summary

In patients with inadequate control, the addition of exenatide led to a fall in HbA1c of about 1.0%. In trial against insulins, the HbA1c results were comparable. There was less nocturnal hypoglycaemia with exenatide than with insulin. In trials against insulin, patients on exenatide lost weight whereas those on insulin gained weight. Nausea is very common, especially initially, but is not usually severe.

The need to inject exenatide twice daily may be a deterrent, but a long-acting once-weekly form is coming.

Copyright © 2009, National Institute for Health and Clinical Excellence.

All rights reserved. This material may be freely reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the express written permission of NICE.

Bookshelf ID: NBK61922
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