Properties of GLP-1 Agonists and Their Use in Type 2 Diabetes

DRUG POINTS n

Properties of GLP-1 agonists and their use in type 2 diabetes

STEVE CHAPLIN and STEPHEN BAIN

There are currently four KEY POINTS glucagon-like peptide-1 (GLP-1) receptor agonists n The GLP-1 receptor agonists dulaglutide, exenatide, liraglutide and lixisenatide licensed for use in the increase insulin secretion in a glucose-dependent manner and promote weight loss treatment of type 2 n All GLP-1 agonists are administered by subcutaneous injection diabetes in the UK: n Only dulaglutide is licensed as monotherapy; all are licensed as part of dual or dulaglutide, exenatide, triple therapy, including basal insulin, in the treatment of type 2 diabetes liraglutide and lixisenatide. n Dulaglutide and modified-release exenatide are administered once weekly Steve Chaplin gives an n NICE recommends GLP-1 agonists as part of triple therapy after tripal oral overview of their therapy has failed or is contraindicated and recommends targets for blood indications, mode of glucose levels and weight loss by six months administration and adverse n They have few drug interactions or contraindications effects, and Professor n Nausea, vomiting and diarrhoea are very common adverse effects Stephen Bain discusses n Lixisenatide is currently the least expensive GLP-1 agonist in primary care their current place in therapy. Furthermore, NICE states that their use beyond six months depends on achieving targets for improved glycaemic control STEVE CHAPLIN and weight loss. The Scottish Medicines Consortium (www.scottishmedicines.org. he glucagon-like peptide-1 (GLP-1) uk) has also appraised the GLP-1 agon- Treceptor agonists dulaglutide, exena- ists individually, with their use in NHS tide, liraglutide and lixisenatide activate Scotland mainly limited to third-line com- the glucagon-like peptide-1 receptor, bination therapy. increasing insulin secretion dependent on blood glucose levels, suppressing Administration glucagon secretion and slowing gastric Dulaglutide is administered once weekly. emptying. They also prevent weight gain Exenatide is available as a standard- or promote weight loss. release formulation for twice-daily injec- Dulaglutide is the only GLP-1 agon- tion (Byetta) and a modified-release ist licensed as monotherapy (when met- formulation with a once-weekly dosing formin is considered inappropriate due schedule (Bydureon); other GLP-1 agon- to intolerance or contraindications). All ists are administered once daily (see are licensed for the treatment of type 2 Table 1). diabetes as double or triple therapy, in All GLP-1 agonists are administered combination with oral antidiabetic agents by subcutaneous injection using a pre- and/or basal insulin. However, more lim- filled pen. Dulaglutide is also supplied ited indications are recommended in the as a prefilled syringe and once-weekly new NICE guideline on type 2 diabetes exenatide is supplied in a single-use (see Box 1) effectively limiting their use kit containing the powder for reconsti- to triple therapy only after triple oral tution with a syringe and solvent. This therapy with metformin and two other formulation contains exenatide in bio- drugs has failed or is contraindicated.1 degradable microspheres; with regular prescriber.co.uk Prescriber January 2016 z 43 n DRUG POINTS l GLP-1 agonists

In adults with type 2 diabetes, if triple therapy with metformin and two other oral drugs clinical experience, lixisenatide should is not effective, not tolerated or contraindicated, consider combination therapy with be used with caution in patients with metformin, a sulfonylurea and a GLP-1 agonist for adults with type 2 diabetes who: moderate renal impairment. No GLP-1 • have a BMI of 35 or higher* and specific psychological or other medical problems agonists are recommended for patients associated with obesity or with severe renal impairment (creatinine • have a BMI lower than 35 and: clearance <30ml per min). - for whom insulin therapy would have significant occupational implicationsor Contraindications include hyper- - weight loss would benefit other significant obesity-related co-morbidities. sensitivity. Twice-daily exenatide and lixisenatide contain metacresol, which may Only continue GLP-1 agonist therapy if the person with type 2 diabetes has had a cause allergic reactions. The GLP-1 agon- beneficial metabolic response (a reduction of at least 11mmol per mol (1.0%) in ists are not recommended for patients with severe gastrointestinal disease, eg HbA1c and a weight loss of at least 3 per cent of initial body weight in 6 months). inflammatory bowel disease, gastropar- Only offer a GLP-1 agonist in combination with insulin with specialist care advice and esis. Liraglutide should be used with cau- ongoing support from a consultant-led multidisciplinary team. tion in patients with thyroid disease in whom exacerbation of thyroid disorders *Adjust accordingly for people from black, Asian and other minority ethnic groups has been reported.

Box 1. New NICE guideline on type 2 diabetes in adults (NG28): recommendations relating Drug interactions to the use of GLP-1 agonists1 There is an increased risk of hypo administration steady state levels are can then resume the normal once weekly glycaemia when a GLP-1 agonist is added achieved after six to seven weeks and schedule. The day of weekly administra- to treatment with a sulfonylurea, the levels persist for 10 weeks after stop- tion can be changed as long as the last dose of which may need to be reduced. ping treatment. dose was administered at least three For a similar reason, the dose of basal Daily GLP-1 agonists should be days previously. insulin may need to be adjusted when administered at the same time each day. dulaglutide, twice-daily exenatide, lira- Liraglutide may be injected irrespective Precautions glutide or lixisenatide are added, but this of meal times but twice-daily exenatide Experience in patients over 75 years old recommendation is not made for weekly and lixisenatide should be given within is limited but no recommendations for exenatide. Sitagliptin may increase the an hour before a meal and, in the case of dose adjustment are made for people hypoglycaemic effect of dulaglutide. exenatide, the doses should be at least aged 65 years or older. Dose escala- Interactions with other oral antidiabetic six hours apart. tion of twice-daily exenatide from 5 to drugs are less well documented. Modified-release exenatide should be 10µg should “proceed conservatively” in Because they delay gastric emptying, injected on the same day each week, at patients over 70 years old. The starting the GLP-1 agonists modify the absorp- any time of day, with or without meals. dose of dulaglutide should be 0.75mg tion of some drugs. This is not normally The day of weekly administration can weekly in those aged over 75 years. clinically significant but an increase in be changed provided the next dose is No dose adjustment for hepatic international normalised ratio (INR) has administered at least one day (24 hours) impairment is recommended with dula- been reported with warfarin and (with the later. If a dose is missed, it should be glutide, exenatide or lixisenatide. There exception of dulaglutide) increased mon- administered as soon as is practical. For is too little experience with liraglutide itoring is recommended. the next injection, patients can return to to make a recommendation in patients usual injection day but only one injection with hepatic impairment but, like other Pregnancy and breastfeeding should be administered in a 24-hour per- agents in this class, it is predominantly Reproductive toxicity in animal studies iod. Blood glucose levels may be tran- eliminated renally and no problems are has been reported with all GLP-1 agon- siently increased in patients switching anticipated. ists and they are contraindicated during from twice daily to weekly exenatide; this No dose adjustment is recommended pregnancy. Women of childbearing age usually resolves within two weeks. for patients with mild renal impairment must use contraception during treat- Dulaglutide should normally be (creatinine clearance 50–80ml per ment. There is little experience of their administered on the same day (regard- min). In patients with moderate renal use by women who are breastfeeding and less of meals) but if a dose is missed, it impairment, dose escalation of twice- treatment is not recommended. can be administered as soon as possible daily exenatide should proceed con- provided there are at least three days servatively, and weekly exenatide is not Adverse effects until the next scheduled dose. If there recommended due to lack of clinical Gastrointestinal disorders such as nau- is less time, the missed dose should experience. However, there is no contra- sea, vomiting and diarrhoea are very be skipped and the next dose should be indication for liraglutide or weekly dula- commonly reported with GLP-1 agonists, administered as scheduled. The patient glutide in these patients. Due to lack of with nausea affecting 20–30 per cent of

44 z Prescriber January 2016 prescriber.co.uk GLP-1 agonists l DRUG POINTS n

GLP-1 agonist Dosage Timing Basic NHS price NIC per item per month (2014/15)2

dulaglutide 0.75mg weekly as Any time of day, not £73.25 for both doses - monotherapy within 3 days of the next scheduled dose 1.5mg weekly as add-on therapy

exenatide 5μg twice daily for at least one Within 60 minutes £68.24 for both doses Daily £82.35 month, increased to 10μg twice before the morning and daily if required evening meals

2mg once weekly Same day each week £73.36 Weekly £78.78

liraglutide Initially 0.6mg once daily, Same time each day, £39.24 – £117.72 £100.98 increasing to 1.2mg daily after independent of meals at least one week and to 1.8mg daily after at least one further week

lixisenatide 10μg once daily for 2 weeks Within 60 minutes £57.93 £60.28 then 20μg once daily before the same meal each day

Table 1. Dosage regimens and cost of GLP-1 agonists; NIC – net ingredient cost patients (13 per cent with the lower dose patients experience rapid weight loss statistics show that the actual cost of dulaglutide), becoming less frequent (>1.5kg per week); this is not stated with per item dispensed in primary care in and milder with continued treatment. other GLP-1 agonists. England is higher than the basic price Patients should be warned of the risk of GLP-1 agonists have rarely been would suggest, but is lowest for lixi- dehydration if affected. associated with acute pancreatitis. senatide (see Table 1). Dulaglutide was Other common adverse effects Patients should be informed of the char- introduced too recently to be included in include dyspepsia, abdominal distension acteristic symptoms of acute pancreatitis these statistics. and discomfort, and decreased appetite. and treatment should be discontinued if The incidence of treatment discontinua- this is suspected. Declaration of interests tion due to adverse events, largely due to None to declare. gastrointestinal events, is 6–8 per cent Costs within six months. The manufacturer of The basic NHS costs are broadly similar Steve Chaplin is a pharmacist who exenatide reports that 3–5 per cent of for all the GLP-1 agonists. Prescribing specialises in writing on therapeutics

Place in therapy insulin are simplicity of use, low risk of reduction in body weight. The new NICE 1 STEPHEN BAIN hypoglycaemia and weight loss. guidance (NG28) continues to promote Exenatide, as twice daily Byetta, was these limitations for all GLP-1 agonists There are now four different GLP-1 recep- included in the NICE clinical guideline and has made their prescribing more tor agonists licensed for use in the UK, (CG87) published in 2009 and modified- limited, in that their use now appears and another, albiglutide, is available in release exenatide (Bydureon) and lira- to be sanctioned only after triple oral Europe but has not yet been launched glutide NICE single technology apprais- therapy has failed or is contraindicated. in the UK. The first drug in this class als followed. All were approved for use Moreover, they are absent from the met- (exenatide) was launched in the UK in triple therapy combinations, typically formin-intolerant algorithm, presumably in 2007, and since then the class has with metformin and a sulfonylurea, and on the basis of “lack of evidence base” proved popular, especially in a secondary had “stopping rules”. These were more rather than any genuine concern that they care setting, as an alternative to insulin stringent than rules applied to the glip- act differently in this setting. initiation in patients with suboptimal gly- tin class and required a 1 per cent (11 Contrary to the original NICE guid- caemic control on maximal oral antigly- mmol per mol) HbA1c reduction over six ance, GLP-1 agonists were commonly caemic therapy. The benefits over basal months, in combination with a 3 per cent used in combination with insulin (>30 prescriber.co.uk Prescriber January 2016 z 45 n DRUG POINTS l GLP-1 agonists

per cent in the Association of British sodium glucose co-transporter 2 4. Zinman B, et al. Empagliflozin, cardiovascu- Clinical Diabetologists (ABCD) audits (SGLT2) inhibitors (canagliflozin, dapa lar outcomes and mortality in type 2 diabetes. of exenatide and liraglutide),3 despite gliflozin, empagliflozin), with similar N Engl J Med 2015;373:2117–28. initially having no licensed indica- weight benefits (and positive cardiovas- tion. Now the licenses exist for this cular safety data for empagliflozin4) may Declaration of interests combination and we now have the slow this progression. Professor Bain has received grants and first fixed-ratio combination of basal honoraria from Eli Lilly, Novo Nordisk, insulin and GLP-1 agonist, which has References AstraZeneca and Sanofi. restricted approval for use in both 1. NICE. Type 2 diabetes in adults: Scotland and Wales (insulin degludec/ Management. NG28. December 2015. Stephen Bain is professor of med- liraglutide (Xultophy)). 2. Health and Social Care Information Centre. icine (diabetes), Institute of Life The use of GLP-1 agonists seems Prescription Cost Analysis 2014. April 2015. Science, Swansea University and set to increase in clinical practice 3. Available at: http://www.diabetologists- Honorary Consultant Physician, AMBU although the availability of three oral abcd.org.uk/research_and_audit.htm HealthBoard, Wales POEMs SBP of 120mmHg instead of 140mmHg in nondiabetic, high-risk elderly leads to significant benefits and some harms (SPRINT) Clinical question: versus standard blood-pressure control. 140mmHg group were converted from Is there a net benefit to a systolic blood N Engl J Med 2015;373(22):2103-116. their usual drug to an equivalent in the pressure target of 120mmHg compared formulary. Drugs were added from the with 140mmHg in patients without dia- Study design: Randomised controlled formulary as needed to achieve blood betes who are at high risk of cardiovas- trial (single-blinded). Funding: pressure targets. The average number cular disease? Government. Setting: Outpatient (any). of agents used in the 120mmHg group Allocation: Uncertain. was 2.7, with 32 per cent of patients Bottom line: requiring three drugs and 24 per cent of In this group of older patients (mean age Synopsis: patients requiring four or more drugs. In = 68 years) who do not have diabetes Previous trials of more aggressive blood the 140mmHg group, the average num- but are at high risk of cardiovascular dis- pressure targets in high-risk patients ber of medications was 1.8, only 17 per ease, a more aggressive systolic blood have either shown no benefit, or in some cent of patients required three drugs, pressure target of 120mmHg instead cases a benefit limited to only one of and 7 per cent required four or more. of 140mmHg led to benefits (lower all- many possible clinical outcomes, eg Analysis was by intention to treat, cause mortality, lower cardiovascular haemorrhagic stroke only. This study and the mean blood pressures achieved mortality, less heart failure), but also identified patients 50 years and older in the two groups were 121mmHg and some harms (more serious episodes with a baseline systolic blood pressure 136mmHg. Although the study origi- of hypotension, electrolyte abnormal- between 130mmHg and 180mmHg and nally planned a five-year follow-up, it ity, syncope, and acute kidney injury). no history of diabetes mellitus or stroke. was halted after 3.3 years on the basis Patients in the intensive therapy group All were at increased risk of cardiovascu- of positive findings in an interim analy- took an average of one additional drug lar complications sis. The intensive treatment group was to achieve this target. The decision Of 14 692 patients screened for less likely to die from any cause (3.3 per to pursue this more aggressive target eligibility, 9361 were randomised to cent vs 4.5 per cent; p = 0.003; num- should be guided by how well the patient either a systolic blood pressure target ber needed to treat [NNT] = 83 over 3.3 fits the profile of patients in this study, of 120mmHg or 140mmHg. The mean years), less likely to die from a cardio- ie no diabetes, older than 50 years, high age of participants was 68 years, 56 vascular cause (0.8 per cent vs 1.4 per risk of cardiovascular disease) and how per cent were current or former smok- cent; p = 0.005; NNT = 167 over 3.3 well the additional therapy is tolerated. ers. The protocol for the 120mmHg years), and less likely to develop heart (LOE = 1b) group specified beginning with two- or failure (1.3 per cent vs 2.1 per cent; p three-drug therapy with a combination = 0.002; NNT = 125 over 3.3 years). Reference: of a thiazide diuretic, an ACE inhibitor There were no significant differences in The SPRINT Research Group, Wright JT or angiotensin-receptor blocker, and/or the likelihood of myocardial infarction, Jr, et al. A randomized trial of intensive a calcium-channel blocker; those in the acute coronary syndrome or stroke.

46 z Prescriber January 2016 prescriber.co.uk