The prevalence of type-2 diabetes is increasing at

Non-insulin injectable therapy The prevalence of type-2 diabetes is rapidly increasing with up to a quarter of people over 60 years of age affected it. To reduce the risk of the associated microvascular and macrovascular complications, national guidelines for glycaemic control recommend HbA1c targets of between 6.5 7 5%. In recent years two novel GLP 1 receptor agonists exenatide and liraglutide have become available for clinical use. These drugs work via the incretin system and are licensed for the treatment of people with type-2 diabetes. These agents are administered as a fixed dose subcutaneous injection. The use of these agents is supported NICE guidelines as an alternative to insulin treatment in persons who have HbA1c levels of greater than 7.5% and a BMI greater than 35. Dr Vinay Eligar Department of Diabetes, Singleton hospital, Sketty Lane, Swansea Dr Richard Chudleigh Department of Diabetes, Singleton hospital, Sketty Lane, Swansea *email: Richard.Chudleigh3@wales.nhs.uk The prevalence of type-2 diabetes is increasing at an alarming rate. 1 Current estimates suggest that 2030 the worldwide prevalence will be 366 million. It is the older age group who are especially at risk of type-2 diabetes. In Europe and the US the prevalence of diabetes in patients over 60 years of age is between 15% and 23%. 2,3 Type-2 diabetes with its associated complications causes significant morbidity and mortality. Patients are at risk of both microvascular and macrovascular complications. Elderly patients newly diagnosed with type-2 diabetes have especially high rates of these complications. 4 Currently, agencies such as NICE 5 and the American Diabetes Association (ADA) 6 set HbA1c targets of between 6.5% and 7.5%. The ADA has suggested HbA1c of less than 7.0% as a target for glycaemic control. The UK Prospective Diabetes Study (UKPDS) 7 showed a in microvascular complications in subjects treated with intensive glycaemic control from diagnosis of type-2 diabetes. The Steno-2 study of patients with type-2 diabetes and microalbumnuria demonstrated a 50% in cardiovascular and microvascular complications with intensive multifactorial intervention over 7.8 years. 8 The achievement of target HbA1c depends on adherence to dietary and lifestyle measures as well as pharmacological interventions. In the elderly patient this pharmacological therapy must also be individualised to account for comorbidity, long-term prognosis and social factors. Pharmacotherapy has traditionally ranged from insulin sensitisers (metformin and thiazolidinediones) or insulin secretogogues (sulphonylureas) to insulin, with insulin being reserved for those not meeting targets with oral agents. Although insulin is effective in achieving glycaemic control there are associated risks of hypoglycaemia and also weight gain. In elderly patients limiting the adverse consequences of hypoglycaemia is an important consideration. There can also be reluctance to use treatment that causes weight gain in this group. The recent availability of incretin hormones has given healthcare professionals an alternative choice to insulin therapy and is likely to revolutionise the pharmacological management of type-2 diabetes. Currently, exenatide (Byetta) and liraglutide (Victoza) are the only synthetic analogues of glucagon like polypeptide-1 (GLP-1) available. These agents are injectable and come as a fixed dose preparation, which are slowly titrated. Exenatide is administered twice daily while liraglutide is a once-daily treatment. These agents have been shown to improve glycaemic control and promote weight loss. Pharmacology/method of action The incretin hormones are released from gastrointestinal L and K cells, in response to the ingestion of food. They stimulate glucose dependent insulin release from β-cells and inhibit glucagon release. 9 Circulating levels increase rapidly in the postprandial period and exert their main effect delayed gastric emptying, slower nutrient absorption and early satiety. These effects all promote weight loss. Glucagon-Like Polypeptide-1 (GLP-1) and Gastric Inhibitory Peptide (GIP) are the two molecules recognised to have incretin effect. Endogenous GLP- GM2 Midlife and Beyond 2011 April 11

Table 1: Pivotal exenatide studies Study Number and antidiabetic agents Duration and exenatide dose Comparator drug Hba1c exenatide Hba1c comparator weight exenatide weight comparator drug Hypoglycaemia exenatide vs. comparator drug De Fronzo et al.2005 18 272 MET 30 wks 5 or 10 µg BID SC Placebo -0.4% to -0.78% +0.8% -1.6 kg to -2.8 kg -0.3 kg 5% vs 5% Kendall et al.2005 733 MET+SU 30 wks 5 or 10 µg BID SC Placebo -0.6% to -0.8% +0.2% -1.6 kg -0.9 kg 23% vs 13% Zinmann et al 2007 20 233 TZD±MET 16 wks 10 µg BID SC Placebo -0.89% +0.09% -1.75 kg -0.24 kg 11% vs 7% 1 displays a very short circulating half-life of two minutes due to rapid renal clearance and NH2-terminal degradation the enzyme Dipeptidyl peptidase-4 (DPP-4). The synthetic analogues of GLP-1 or Glucagon-Like Polypeptide-1 Receptor agonists (GLP- 1R agonists) are resistant to DPP-4 enzyme breakdown and prolong stimulation of the β-cell. 10 Exogenous GLP-1R agonists administration can enhance insulin secretion and lower plasma glucose effectively. 11,12 Due to their mode of action the most commonly encountered adverse effect of these agents are nausea and vomiting occurring in up to 23% of patients. This is often transient and dose dependent. Other adverse effects include mild hypoglycaemia, dyspepsia, diarrhoea, constipation, malaise and generalised oedema. 13 Hypoglycaemia was more commonly noted when prescribed in association with sulphonylurea therapy 14 hence in dose of these agents is recommended when co-prescribed with GLP-1 receptor agonists. More serious adverse events such as pancreatitis and renal failure have been reported. However, a review of 30 cases of pancreatitis reported in patients on exenatide showed that 90% had other factors that could predispose to pancreatitis. 15 In the cases of renal failure reported 16 often other factors such as plasma volume contraction secondary to nausea and vomiting or reduced fluid intake were contributing to the problem. There is no evidence that exenatide is directly nephrotoxic. Supportive therapy, stopping nephrotoxic drugs, including exenatide should reverse renal failure. 17 Clinical evidence Exenatide Exenatide was the first GLP-1R agonist released to the market. It was introduced in the US in 2005 and Europe in 2007. Clinical studies have demonstrated glucose-lowering effect with s in HbA1c and significantly less hypoglycaemia. 18,19,20 Significant weight loss has also been demonstrated. The twice daily dosing of exenatide resulted in a mean in HbA1c of 1.5% after 30 weeks. 18,19 Larger s have been reported with once weekly formulation, which is not yet licensed for clinical use. 21,22 weight loss of -3.6 kg 30 weeks 18-20 and -5.3 kg at 3.5 years was evident in pivotal clinical trials. 23 Much larger s were noted in individual patients, whose baseline HbA1c and weight was much higher. Patients on exenatide treatment also reported fewer episodes of hypoglycaemia (up to 17%), when compared with patients treated with insulin glargine or aspart. Hypoglycaemic events were lower in patients treated with metformin as adjuvant therapy compared with patients on insulin or sulphonylureas. Apart from above desired effects, exenatide has also shown improvements in cardiovascular risk factors 12

Table 2: Pivotal liraglutide studies Trial (duration) Liraglutide+ drug Drugs compared Number of subjects HbA1c % change Weight (kg) change LEAD-1 (26 weeks Liraglutide+glimepiride Rosiglitazone 4 mg placebo 114-1.08-1.13-0.44 +0.23 +0.32-0.23 +2.11-0.10 LEAD-2 Liraglutide+metformin 27 Glimepiride 4 mg placebo 114-0.97-1.0-0.98 +0.09-2.58-2.79 +0.95-1.51 LEAD-3 (52 weeks) Liraglutide only 28 Glimepiride 8 mg 234 234 234-0.84-1.14-0.51-2.05-2.45 +1.12 LEAD-4 Liraglutide+metformin +rosiglitazone 29 Placebo 178 178 177-1.48-1.48-0.54-1.02-2.02 +0.60 LEAD-5 Liraglutide+metformin +glimepiride 30 Glargine placebo 207 219 96-1.33-1.09-0.24-1.81 +1.62-0.42 LEAD-6 Liraglutide+metformin ±sulphonylurea 31 Exenatide 10μg 233 231-1.12-0.79-3.24-2.87 23, 24 such as, blood pressure and lipid profile. Exenatide is administered twice daily as a subcutaneous (SC) injection in dose of 5 or 10 μg within one hour before the two major meals of the day, which should be eaten at least six hours apart. Initial dose is 5 μg twice a day for one month and increased to 10 μg if nausea is not a limiting factor. The drug is delivered via pen device, which delivers 60 fixed doses, so each pen lasts for one month. Exenatide is not used in type-1 diabetes and is contraindicated in renal impairment. Liraglutide Liraglutide is the first acylated analogue of human GLP-1 and shares 97% sequence homology to native GLP-1. 25 It was licensed in Europe in July 2009 and introduced to the US and Japan in January 2010. It is highly protein bound that makes it long acting with a half life of 13 hours and hence is used conveniently as a once daily preparation. The clinical effects of liraglutide have been investigated in the LEAD (Liraglutide Effect and Action in Diabetes) series of phase III studies, which included over 4000 patients with type-2 diabetes. 26-31 Liraglutide demonstrated effective of HbA1c and weight when used alone and in combination with other available oral agents. The net were similar at 1.2 mg and 1.8 mg dose, hence NICE guidelines have not recommended the highest dose. It is started at 0.6 mg SC OD for initial one month and increased to 1.2 mg SC OD. It is delivered via pen device with fixed dose. It is licensed for use as combination either with metformin and sulphonylurea or thiazolidinediones as part of a triple therapy regime. The LEAD 6 trial demonstrated that liraglutide produced a greater in HbA1c when compared to exenatide. Liraglutide achieved greater s in fasting blood glucose, however exenatide had better glucose lowering effect in the post-prandial period. 14

There was no significant difference in the degree of weight loss observed. 31 Combination treatment with insulin Currently GLP-1R agonists are not licensed for use in combination with insulin. However, some specialists have used this off license combination in specific circumstances and have reported encouraging early results. The addition of exenatide to insulin-based therapy has been reported to produce s in HbA1c, weight, and prandial insulin requirements. 13 A study presented at the European Association for the Study of Diabetes in September 2010, compared the combination of exenatide and insulin glargine with a group treated with a placebo and insulin glargine group. The exenatide group had a greater improvement HbA1c level and modest weight loss with no increase in hypoglycaemia. 32 Once weekly formulations Currently there are several novel agents with a longer half life under evaluation in clinical trials. These include once weekly exenatide (Exenatide QW), Taspoglutide, Albiglutide and AVE0010. 33 36 These agents have shown improvements in glycaemic control and have promoted weight loss. Exenatide QW, has shown improved glycaemic control compared to twice-daily exenatide with a lower incidence of adverse-effects. 37 Clinical trials have demonstrated improvement in cardiovascular risk factors with s in systolic blood pressure and improved lipid parameters. It also preserves β-cell mass and function probably due to sustained stimulation. FDA is awaiting thorough QT study data before deciding on approval. Arrival of these newer agents will widen the choice of GLP-1 analogues available. Clinical guidelines NICE guidelines NICE guidance 5,37 which following a recent update are applicable to exenatide and liraglutide, state xx

that GLP-1 receptor agonists can be considered as part of a triple therapy regime in combination with metformin and sulphonylurea or metformin and thiazolidinedione if blood glucose control is inadequate with HbA1c >7.5% if the following criteria are met. Body mass index (BMI) 35 kg/m 2 and specific psychological or medical problems associated with high body weight, or BMI <35 kg/m 2, and therapy with insulin would have significant occupational implications or weight loss would benefit other significant obesity related comorbidities. The guideline also states that The GLP-1R agonists are to be continued only if HbA1c drops 1% and body weight reduces 3% after six months. Conclusion The GLP 1 receptor agonists provide an important new therapeutic option for use in the obese patient with type-2 diabetes. They provide an alternative option to insulin treatment, especially when further weight gain is a concern. The major advantages are reduced risks of hypoglycaemia, fixed dose regimes and easy to use pen devices. Studies thus far have included patients between the ages of 18 and 76 years. No studies have specifically addressed the elderly age group. Caution should be exercised in those with evidence of renal impairment or gastrointestinal problems. Conflict of interest: none declared References 1. Zimmer P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature. 2001; 414: 782 87. 2. Cowie CC, Rust KF; Ford ES, et al. Full accounting of diabetes and pre-diabetes in the U.S. population in 1988-1994 and 2005-2006. Diabetes Care 2009; 32(2): 287 94 3. Report: Prevalence of diabetes in western board area, Northern Ireland. Brendan Bonner, Investing for Health Partnership, August 2006. 4. Bethel MA, Sloan FA, Belsky D, Feinglos MN. Longitudinal incidence and prevalence of adverse outcomes of diabetes mellitus in elderly patients. Arch Intern Med 2007; 167 (9): 921 27 5. National Institute for Health and Clinical Excellence. Type 2 diabetes; the management of type 2 diabetes, NICE clinical guideline 87. London: NICE, 2009. www. nice.org.uk Accessed 12/04/11 6. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care 2009; 32(1): S13 S61 7. Stratton IM, Adler AI, Neil HAW, et al. Association of glycaemia with mac- rovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000; 321: 405 12 8. Gæde P, Vedel P, Larsen N, et al. Multifactorial Intervention and Cardiovascular Disease in Patients with Type 2 Diabetes. N Engl J Med 2003; 348: 383 93 9. Kjems LL. The influence of GLP-1 on glucose-stimulated insulin secretion: effects on B-cell sensitivity in type 2 and nondiabetic subjects. Diabetes 2003; 52: 380 86 10 Drucker DJ, Sherman SI, Gorelick FS, et al. Incretinbased therapies for the treatment of type 2 diabetes: evaluation of the risks and benefits. Diabetes Care 2010; 33(2): 428-33 11. Nauck MA. Preserved incretin activity of glucagonlike peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest. 1993; 91: 301-7 12. Kolterman OG, Buse JB, Fineman MS, et al. Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab 2003; 88: 3082 89 13. Nancy M. Yoon, Melissa K. Cavaghan, Rocco L. Brunelle, Paris Roach. Exenatide added to insulin therapy: A retrospective review of clinical practice over two years in an academic endocrinology outpatient setting: Clinical Therapeutics 2009; 31(7): 1511 23 14. Marre M, Shaw J, Brändle M, et al. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with Type 2 diabetes (LEAD-1 SU). Diabet Med. 2009; 26(3): 268 78 15. Ahmad SR, Swann J. Exenatide and rare adverse events. NEJM 2008; 358:1970 71 16. Weise WJ, Sivanandy MS, et al. Exenatide-Associated Ischemic Renal Failure; Diabetes care 2009; 32(2) 17. Amylin Pharmaceuticals, Inc. http://www.etta. GM2 Midlife and Beyond 2011 April 17

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