Exenatide (Byetta) for type 2 diabetes mellitus

• First injectable synthetic analogue of glucagon-like peptide 1
  Exenatide has a different mechanism of action to that of other antidiabetes drugs.
• Inject subcutaneously twice daily before meals
  Give within the hour before the morning and evening meals. Do not give after a meal.
• PBS listed for dual or triple therapy
  Exenatide is not approved for use as monotherapy or in combination with antidiabetes drugs other than metformin and/or a sulfonylurea.
• Improves glycaemic control with metformin and/or a sulfonylurea
  Exenatide reduces glycated haemoglobin levels (HbA_1c) to a similar extent as insulin (glargine, aspart).
• No data on diabetes-related complications and mortality
  Clinical trials have only measured HbA_1c levels as a surrogate for clinical outcomes.
• Long-term effect on weight is unknown
  Exenatide is associated with weight loss, but there are no data on whether this affects clinical outcomes or is maintained in the long term.
• Gastrointestinal adverse effects are common
  Nausea, vomiting and diarrhoea are 2–3 times more likely with exenatide compared with insulin or placebo.
• Long-term safety profile yet to be established
  There have been rare postmarketing reports of acute pancreatitis and altered kidney function with exenatide.

What is known about this drug

Adding exenatide to metformin or a sulfonylurea reduced HbA_1c by about 1.0% compared with placebo. Similar reductions in HbA_1c were achieved when either exenatide or insulin (glargine, aspart) were used as part of triple therapy. Nausea and vomiting are common and usually improve with continued therapy.

Areas of uncertainty

There are no data on exenatide's effect on diabetes-related complications, mortality or long-term weight. The long-term safety profile of exenatide is yet to be established: be alert for acute pancreatitis or altered kidney function.

What does NPS MedicineWise say?

Exenatide is an option for people who need dual or triple therapy. However, insulin is usually preferred because there are clinical outcome data, it has extensive experience of use and an established long-term safety profile.

Authority required (streamlined)

Dual therapy in combination with either metformin or a sulfonylurea for people with type 2 diabetes whose glycated haemoglobin (HbA_1c) is > 7% despite use of metformin or a sulfonylurea, and for whom the combination of metformin and a sulfonylurea is contraindicated or not tolerated.

Triple therapy in combination with metformin and a sulfonylurea, for people with type 2 diabetes whose HbA_1c is > 7% despite maximally tolerated doses of metformin and a sulfonylurea.

The date of the HbA_1c measurement* (within the last 4 months) is required except when the person is transferring from a PBS-subsidised thiazolidinedione ('glitazone') or dipeptidyl peptide-4 inhibitor ('gliptin') to exenatide.

From 1 October 2015 the PBS listing of exenatide twice daily is extended to allow triple therapy with exenatide in combination with insulin and metformin (unless contraindicated or not tolerated) for the treatment of type 2 diabetes mellitus. For more information see the October 2015 brief item Exenatide triple therapy, an option for type 2 diabetes add-on treatment.

*Blood glucose monitoring may be accepted in some situations. Refer to www.pbs.gov.au for details.

The Pharmaceutical Benefits Advisory Committee (PBAC) recommended exenatide for listing on a cost-minimisation basis — that is, similar efficacy and cost — compared with a combination of rosiglitazone and insulin glargine. The equi-effective doses for the purposes of setting the listing price for dual therapy were exenatide 9.35 micrograms twice a day equivalent to insulin glargine 27.30 international units/day. For triple therapy these were exenatide 10 micrograms twice daily equivalent to rosiglitazone 8 mg once daily, and exenatide 9.07 micrograms twice daily equivalent to insulin glargine 24.93 international units/day. Special pricing arrangements apply.¹ The PBAC also recommended that the listings allow people to switch from a glitazone or a gliptin to exenatide without the need for an HbA_1c of > 7%. Although there is limited evidence to support switching between these drugs, the PBAC considered it unreasonable for people to require a loss of diabetes control in order to qualify for an alternative drug.

Exenatide is the first injectable synthetic analogue of the incretin hormone glucagon-like peptide 1 (GLP-1). Exenatide is an 'incretin mimetic': it mimics the action of GLP-1. Incretin mimetics increase glucose-dependent insulin secretion, suppress inappropriate glucagon secretion, delay gastric emptying (which reduces the rate of glucose absorption) and reduce appetite.^2,3

The action of incretin mimetics is different from that of 'incretin enhancers', such as the gliptins, which inhibit the breakdown of incretins. For more information about the pharmacological action of gliptins, refer to the NPS RADAR review Dipeptidyl peptidase-4 inhibitors ('gliptins') for type 2 diabetes mellitus.⁴

Exenatide is a treatment option for people with type 2 diabetes mellitus who require:

• dual therapy but for whom a combination of metformin and a sulfonylurea is contraindicated or not tolerated, or
• triple therapy for people who are already taking metformin and a sulfonylurea.

Exenatide is given as a subcutaneous injection twice a day (see Dosing issues). It is used in combination with metformin and/or a sulfonylurea.

Exenatide improves glycaemic control in combination with metformin and/or a sulfonylurea. It is not approved by the Therapeutic Goods Administration (TGA) or PBS listed for monotherapy or for use in combination with acarbose, a gliptin, a glitazone, insulin or repaglinide.

Other options for dual or triple therapy include insulin or an oral antidiabetes drug (Table 1). Insulin is usually the preferred option, as there are data on its effect on diabetes-related complications and mortality, it has extensive experience of use and an established long-term safety profile.

Table 1.
Other antidiabetes drugs for dual or triple therapy^†

† Repaglinide is not listed on the PBS: refer to www.pbs.gov.au for details about PBS restrictions for other drugs.

Other factors may influence the choice of antidiabetes drug, including dosage form (oral or injectable), frequency of administration, what other drugs can be co-prescribed, titrated versus fixed dose, and potential adverse effects such as weight gain and hypoglycaemia.

There are no data on the effects of exenatide on diabetes-related complications or mortality. Clinical trials have been small (n = 150–733), relatively short (16–82 weeks) and have measured HbA_1c levels as a surrogate for clinical outcomes. Some trial data suggest that exenatide may not affect lipids.⁵ Exenatide's effects on blood pressure and cardiovascular events are unknown.

In contrast, some other antidiabetes drugs have known effects on clinical outcomes. Metformin reduces the incidence of diabetes-related complications and mortality.⁶ Sulfonylureas and insulin have been shown to reduce the incidence of microvascular complications.⁷

Exenatide reduces HbA_1c levels with metformin and/or a sulfonylurea

Two trials have assessed the efficacy of exenatide as dual therapy with either metformin or a sulfonylurea.^8–11 Exenatide 10 micrograms twice a day reduced HbA_1c by about 1.0% after 30 weeks compared with placebo. The proportion of people who achieved an HbA_1c ≤ 7% (34–40%, compared with placebo 8–11%) was maintained over the following year in unblinded extension trials.^8,10

Exenatide has been compared with placebo and insulin (glargine, aspart) for use as triple therapy (with metformin and a sulfonylurea).^12–14 Reductions in HbA_1c were comparable between exenatide and insulin (average insulin dose studied was about 25 units daily) and a similar proportion in each treatment group achieved an HbA_1c ≤ 7% (Table 2). However, more people receiving exenatide stopped treatment, mostly because of gastrointestinal adverse effects (see Safety issues).

Table 2.
Exenatide compared with insulin (glargine, aspart) as triple therapy with metformin and a sulfonylurea^‡13,14

‡ Sulfonylureas used in the 26-week trial were not reported¹³

Long-term effect on weight is not known

Exenatide is associated with weight loss and thus may be a useful option for people who are overweight. However, whether weight loss with exenatide improves clinical outcomes, or is maintained in the long term, is currently unknown.

In trials of up to 30 weeks, people who had exenatide added to their oral therapy lost an average of 1.4 kg more than those who received oral therapy alone.⁵ Weight loss continued during the following year, although this observation came from uncontrolled unblinded extension studies (n = 150, n = 401).^9,11 Weight loss also occurred with exenatide (2.3 kg loss) compared with insulin glargine (1.8 kg gain) in a 26-week trial; similarly, in a 52-week trial, exenatide led to a 2.5 kg weight loss compared with a 2.9 kg gain with insulin aspart.^13,14

The effect on weight loss should be interpreted cautiously: no trial has studied weight loss with exenatide as a primary outcome, and the available data are limited to 1 year of unblinded treatment.

Common adverse effects with exenatide include gastrointestinal adverse effects (nausea, vomiting, diarrhoea, dyspepsia, gastro-oesophageal reflux disease and abdominal pain), headache, dizziness, jitteriness and injection-site reactions. Hypoglycaemia may also occur, mainly when exenatide is used with a sulfonylurea.²

Pancreatitis, allergic reactions and altered kidney function have been reported rarely with exenatide.^2,15 Avoid exenatide in people with severe renal impairment or end-stage kidney disease.^15,16 Be cautious about starting or increasing the dose of exenatide in people with moderate renal impairment (creatinine clearance 30–50 mL/minute). ¹⁶

Do not use exenatide in pregnant women or women planning to become pregnant (ADEC Category C).² Avoid in breastfeeding women, as there are no data on its use in lactation.²

Report suspected adverse reactions to the TGA online or by using the 'Blue Card' distributed three times a year with Australian Prescriber. For information about reporting adverse reactions, see the TGA website.

Nausea and vomiting are common and usually improve with continued therapy

A meta-analysis of trials found that about one in two people experienced nausea, and about one in five experienced vomiting when exenatide was added to oral therapy.⁵ People receiving exenatide were about three times more likely to experience nausea or vomiting and twice as likely to experience diarrhoea than those using placebo or insulin.⁵ Nausea and vomiting usually improve with continued therapy. ²

Hypoglycaemia mostly occurs in combination with a sulfonylurea

The risk of hypoglycaemia appears to increase with exenatide when it is combined with a sulfonylurea.⁵ In one trial 36% of people experienced hypoglycaemia when exenatide 10 micrograms was added to a sulfonylurea (incidence for a sulfonylurea alone: 3%).¹⁰ In another trial 28% of people experienced hypoglycaemia when exenatide 10 micrograms was added to metformin with a sulfonylurea (metformin with sulfonylurea alone: 13%).¹² In contrast, there was no increased risk of hypoglycaemia when exenatide was added to metformin, compared with placebo or insulin, unless used as triple therapy.

Trial protocols halved the sulfonylurea dose in people who had hypoglycaemia while using exenatide with a sulfonylurea.^10,12–14 Consider reducing the dose of sulfonylurea when adding exenatide.¹⁵

Risk of hypoglycaemia appears similar to that with insulin

Trials found a similar incidence of self-reported hypoglycaemia between exenatide and insulin (glargine, aspart) at the insulin doses studied (average about 25 units daily).^13,14 However, the comparative risk in people who frequently experience severe episodes of hypoglycaemia is unknown, because those who had more than three recent severe episodes were excluded from trials. The risk of hypoglycaemia for exenatide compared with other insulins (e.g. isophane) and escalating insulin doses is also unknown.

Development of anti-exenatide antibodies is common

Exenatide is derived from a non-mammalian source — from the venom of the Gila monster lizard (Heloderma suspectum) — and may be recognised as an antigen by the human immune system.^17,18 Up to 50% of people in clinical trials developed anti-exenatide antibodies^{8,10,12–14,19}, but only about 3% of these people had no apparent glycaemic response to exenatide.¹⁷ Consider alternative antidiabetic therapy for people in whom exenatide therapy does not reduce HbA_1c.²⁰

Stop exenatide and check serum amylase level if severe abdominal pain occurs

Be alert for pancreatitis in anyone taking exenatide who complains of persistent, severe unexplained abdominal pain (with or without nausea and/or vomiting). Stop exenatide (and any other suspect drugs)¹⁵ and check amylase. Consider other antidiabetic drugs for people with a history of pancreatitis (avoid gliptins: for more information refer to the NPS RADAR review of gliptins⁴).²¹

Postmarketing reports of acute pancreatitis, including fatal haemorrhagic or necrotising pancreatitis, have occurred with exenatide in the US, UK, Europe and Australia.^21–24 A causal association has not been confirmed and some of these cases may have involved other risk factors such as concomitant use of other suspect drugs, obesity, gallstones, severe hypertriglyceridaemia and alcohol use.

Do not restart exenatide if pancreatitis is confirmed.²¹ Recurrence of pancreatitis has been reported after restarting exenatide.^23,25

Be alert for changes in kidney function

Look out for signs and symptoms including increased serum creatinine, changes in urine (such as colour, frequency and amount), unexplained swelling in the extremities, increased blood pressure, lethargy or changes in appetite and/or digestion.¹⁶

There have been postmarketing reports of altered kidney function (including acute renal failure, increased serum creatinine concentration) in the US, the UK and Europe.^16,23,26 A causal association has not been confirmed and some of these cases occurred in people with pre-existing kidney disease or in people with risk factors such as other diseases (e.g. hypertension, heart failure) or using other drugs (e.g. nonsteroidal anti-inflammatory drugs, diuretics). Some cases reported nausea, vomiting and diarrhoea, which may have contributed to the development of altered kidney function.

Start with a subcutaneous injection of 5 micrograms twice a day for at least a month. Give within 1 hour before the morning and evening meals (or before two main meals at least 6 hours apart). Do not inject after a meal. If an injection is missed, continue with the next scheduled injection.¹⁵

If the initial dose is tolerated, after 1 month the dose can be increased to 10 micrograms twice a day.¹⁵ Stop exenatide if improved glycaemic control is not achieved after 3–4 months of therapy.

When adding exenatide to a sulfonylurea, consider reducing the dose of sulfonylurea to reduce the risk of hypoglycaemia (see Safety issues).¹⁵ The dose of metformin does not need to be modified in combination with exenatide.

Provide patients or carers with instructions on how to inject and dispose of exenatide, including the timing of the dose (not after meals).

Nausea, vomiting and diarrhoea commonly occur with exenatide. Inform patients or carers that the initial dose titration aims to improve tolerability to gastrointestinal adverse effects.

Exenatide delays stomach emptying, which can slow the absorption of oral medicines. Advise on what medicines should be taken separately from exenatide (at least 1 hour before or 4 hours after an injection) to prevent the medicine from causing gastric irritation or having a delayed effect.

Recommend that patients promptly seek medical attention if they experience persistent or severe unexplained abdominal pain (with or without nausea and/or vomiting) or changes in urine (such as colour, frequency and amount) or dehydration.

Discuss the Byetta Consumer Medicine Information (CMI) leaflet with the patient.

Medicine Update

An NPS Medicine Update leaflet on exenatide is available for consumers. Medicine Update helps consumers to ask the right questions about new medicines, and helps them compare the potential benefits and harms of a new medicine with those of other medicines.

Updated 1 October 2015 to reflect extension of the PBS listing to include triple therapy in combination with insulin and metformin (see PBS listing for details).

Updated 1 March 2012 to reflect addition of 'streamlined' to authority PBS listing. Evidence since the original release date has not been reviewed.
First released November 2010.