Practical clinical guide: adding GLP-1 RAs to intensify type 2 diabetes therapy

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1 EARN 3 FREE CD OINTS diabetes Leader in digital CD for Southern African healthcare professionals ractical clinical guide: adding GL-1 RAs to intensify type 2 diabetes therapy atient selection guided by SEMDSA Guidelines and international approaches Introduction The availability of Glucagon-Like rotein-1 Receptor Agonists (GL-1 RAs) presents new therapeutic options for clinicians and patients with type 2 diabetes. These agents, of which currently only exenatide and liraglutide are available to the South African clinician, offer glycaemic efficacy without the unwanted effects of hypoglycaemia and weight gain. Available since late 25, increasing evidence of weight loss, blood pressure-lowering and cardiovascular benefits has resulted in careful evaluation of how to incorporate this relatively expensive, but effective therapy into daily clinical practice. The Society of Endocrinology, Metabolism and Diabetes of South Africa (SEMDSA) 217 type 2 diabetes Guidelines have proposed particular categories of patients for whom GL-1 RAs offer substantial advantages. 1 Recent international reviews 2,3 have also collated evidence from clinical trials and suggested patient groups that would benefit from GL-1 RAs added to basal insulin, as well as their addition to oral therapies. This report concentrates on the evidence for the use of GL-1 RAs to intensify therapy in selected patients already on basal insulin therapy using BIT (BIT = basal insulin combined with GL-1 RA); and contrasts this approach with basal insulin plus oral therapy and insulin aspart (referred to as Basal and Oral Therapy plus, BOTlus), 3 in the context of South African guidelines. KEY MESSAGES GL-1 RAs offer glycaemic efficacy without hypoglycaemia or weight gain Clinical consensus is emerging on practical usage of these anti-hyperglycaemic therapies and optimisation of their additional non-glycaemic benefits in selected patients. This report was made possible by an unrestricted educational sponsorship from Novo Nordisk. The content of the report is independent of the sponsor May 218 I 1

2 ractical clinical guide: adding GL-1 RAs to intensify type 2 diabetes therapy athophysiological background GL-1 RAs are able to enhance or normalise the so-called incretin effect in relation to a meal-induced glucose transfer from the intestine to the blood in type 2 diabetes. This is done by activating the GL-1 receptor on β-cells. In addition, the GL-1 RAs delay gastric emptying, enhance satiety related to gastric and cerebral signals, as well as suppress glucagon and its effects on gluconeogenesis. 1 Liraglutide has a moderate effect on gastric emptying during the early phase of a breakfast meal, but most of its prandial glucose-lowering effect is related to enhanced insulin secretion. 4 Its glucagon suppression does contribute to the postprandial glucose lowering effect. 5 In a randomised clinical trial comparing liraglutide with exenatide twice daily, liraglutide was superior with regard to number of patients reaching target HbA 1c (<7%) and its effect on fasting blood glucose, while exenatide was more effective after breakfast and dinner. 6 A comparison of available GL-1 RAs is provided in Table 1 1 (Extended release exenatide is not available in South Africa). Table 1: Comparison of available GL-receptor agonists* GL-1 receptor agonist: Exenatide Liraglutide Amino acid sequence similarity to native GL-1 53% 97% Half-life (t ½) 2.5 hrs hrs Starting dose 5ug BD for 4 weeks.6mg OD for 1 week Usual dose 1μg BD 1.2mg OD Max dose 1.8mg OD Route Subcutaneous Subcutaneous Timing of dose Within 6 min before morning and evening meal; not after a meal Any time of the day HbA 1c reduction (%) ~.8% 1.2mg:.8% 1.8mg: % Weight reduction (kg) kg kg Non-responders (no weight loss) ~ 25% ~ 25% Renal dose Do not use if egfr <3ml/min No dose adjustment required** Earn free CD oints Join our CD community at Adverse effects Diarrhoea (%) Nausea (%) Vomiting (%) *Extracted from JEMDSA 217; 22(1): Appendix 9.5: Drug review GL-1 receptor agonists **ost-marketing reports of acute kidney injury in patients with pre-existing kidney disease. Use with caution in patients with chronic kidney disease and start to earn today! 2 I May 218

3 ractical clinical guide: adding GL-1 RAs to intensify type 2 diabetes therapy ractical approach to the use of GL-1 RAs A useful clinical diagram (Figure 1) aids the discussion of the use of GL-1 RAs for particular type 2 diabetes patients. 3 This diagram is discussed in the context of the SEMDSA recommendations in each category (Table 2). arameter/treatment BOTlus Favoured BIT Favoured Obesity with NAFLD/ Intended weight loss No/None overweight/no overweight/yes severe/yes Hypoglycemia risk low high Age young old Micro- and macrovascular diseases many/severe none Liver dysfunction Renal function revious pancreatitis/ risk of pancreatitis Gastrointestinal symptoms severe none GFR < 3 ml/min/m 2 GFR 5 8 ml/min/m 2 normal yes/high not sure no/low often rare never Figure 1: BOTlus (Basal, Oral Therapy + Aspart) vs. BIT (Basal + Incretin Therapy) A clinical decision guide Amended from: Scholz GH and Fleischmann H. Basal insulin combined incretin mimetic therapy with glucagon-like protein 1 receptor agonists: a practical guide to decision making. Ther Adv Endocrinol Metab 214; 5(5) Table 2: SEMDSA recommendations 1 At step 2: Dual therapy Metformin plus GL-1 RA In established cardiovascular disease as an alternative option (not as routine use) At step 3: Triple therapy In Complex therapy: In selected (obese and hypoglycaemia-prone) patients, as a third glucose lowering drug As a preferred option with either basal insulin or oral agents May 218 I 3

4 ractical clinical guide: adding GL-1 RAs to intensify type 2 diabetes therapy atient groups In obesity or intended weight loss GL-1 RAs are particularly useful in type 2 diabetes-related obesity with visceral fat accumulation and non-alcoholic fatty liver disease (NAFLD) because of this phenotype s association with insulin resistance, accelerated gluconeogenesis, hypertension, inflammation and risk for cardiovascular events. 7 In a recent review of 21 trials using GL-1 RAs, 8 GL-1 RAs were associated with greater weight loss than control groups (weighted mean difference -2.9kg, 95% confidence interval -3.6 to -2.2kg). A study of insulin-naïve, obese type 2 diabetes patients uncontrolled on metformin ± sulphonylurea, treated with liraglutide 1.8mg for 12 weeks and then randomised to add-on insulin detemir to achieve a year s treatment and compared to the non-insulin detemir control group, is important for obese type 2 diabetes patients. 9 The 3.5kg mean weight loss achieved with 12 weeks of GL-1 RA added to therapy was maintained at 52 weeks of added insulin detemir therapy. Hypoglycaemic events were very low (.23 minor events/patient year, no major events). Glycaemic control was improved from 8.3% to 7.6% in the GL-1 RA added group. Earn free CD oints Join our CD community at atients at high risk of hypoglycaemia Many patients have conditions that increase the risk of hypoglycaemia, including renal failure, autonomic neuropathy, adrenocortical insufficiency and mental disorders such as depression, anxiety, dementia or affective disorders. Hypoglycaemia, including silent hypoglycaemic episodes, is associated with increased cardiovascular morbidity and mortality. Severe hypoglycaemia is a strong predictor of cardiovascular morbidity and mortality and should be avoided this is particularly pertinent in those with pre-existing cardiovascular disease. 1 According to their mode of action, GL-1 RAs do not enhance the risk of hypoglycaemia and are particularly useful in these patients. The question of whether to use intensification with a short-acting insulin as BOTlus therapy or using BIT therapy was addressed by a recent study of 177 type 2 diabetes patients requiring intensification of basal insulin therapy (Liraglutide add-on study) 11 (Figure 2). The rate of hypoglycaemia was 8.15 episodes per patient year of exposure on BOTlus and 1. episodes on BIT therapy respectively. Hypoglycaemia was significantly lower by 87% in the insulin degludec plus liraglutide group with an estimated risk ratio of.13 (95%CI.8-.21), as compared to insulin degludec plus a single daily dose of insulin aspart. Also, nocturnal hypoglycaemia was 86% lower with the addition of a GL-1 RA as compared to the addition of insulin aspart. There was significantly greater weight loss (-2.8kg) in the BIT group versus a gain of.9kg in the BOTlus therapy group. The HbA 1c reduction was also significantly better with the BIT (-.74%) as compared to the insulin aspart group (minus.39%). This efficacy favours the use of liraglutide in patients who are obese with a certain higher risk of hypoglycaemia, or in patients who have to avoid hypoglycaemic episodes because of pre-existing cardiovascular disease or professional circumstances. and start to earn today! 4 I May 218

5 ractical clinical guide: adding GL-1 RAs to intensify type 2 diabetes therapy SMBG (mmol/l) HbA1c (%) HbA1c (mmol/mol) SMBG (mg/dl) FG (mmol/l) Time (weeks) Time (weeks) Change in weight from baseline FG (mg/dl) Change in weight from baseline re BF 9 mins after BF re lunch 9 mins after lunch re dinner 9 mins after dinner Bedtime 4. am re BF Figure 2: Comparison of the addition of a GL-1 RA compared to insulin aspart Aged patients The age-related risk of increased hypoglycaemia with added-insulin therapy must be considered, especially in patients older than 8 years, as visits to the emergency department frequently lead to hospitalisation in the older patient (>64 years of age). 12 There are however no data on the benefit of BIT therapy in the age group older than 8 years, but clinical usage studies have shown a preference for this approach in the young old (65-79 year group). 13 Because of the higher associated risk with the use of short-acting insulin added to basal insulin, the older age group should enjoy the benefit of the GL-1 RAs, but special attention must be paid to gastrointestinal side-effects, renal effects and comorbidity-related unintended weight loss. atients with micro- and macrovascular disease Vascular disease such as acute coronary syndromes (ACSs) frequently predicates diabetes diagnosis. The presence of established cardiovascular disease influences the choice of anti-hyperglycaemia strategies because of safety and the need for further protection. Accumulating evidence of GL-1 RAs cardiovascular benefits favours their use in those patients with micro- and macrovascular disease. May 218 I 5

6 ractical clinical guide: adding GL-1 RAs to intensify type 2 diabetes therapy Caution in renal and hepatic failure Renal failure must be taken into account because of the reduced degradation of insulin and the associated risk of hypoglycaemia, which is dependent on renal function. Insulin is, however, indicated in renal failure when other antidiabetic medications fail or are contra-indicated. In the case of renal or hepatic failure, BOTlus is the preferred option, rather than the use of liraglutide. It should be noted that liraglutide should not be used at creatinine clearance (CrCl) of <6ml/min. Caution in pancreatic and gastrointestinal dysfunction Earn free CD oints Are you a member of Southern Africa s leading digital Continuing rofessional Development website earning FREE CD points with access to best practice content? Only a few clicks and you can register to start earning today Visit For all Southern African healthcare professionals Find us at DeNovo There is no restriction in the use of insulin and BOTlus in patients with pancreatic or gastrointestinal dysfunction. Nevertheless, in the former, a reduced glucagon response and changes in digestion have to be considered; and in the latter, an unpredictable resorption of References: SEMDSA Guideline Committee. SEMDSA 217 Guidelines for the Management of Type 2 diabetes mellitus. JEMDSA 217; 22(1): S1-S Trautmann ME and Vora J. Use of glucagon-like peptide-1 receptor agonists among individuals on basal insulin requiring treatment intensification. Diabet Med 218; doi:1.1111/dme Scholz GH and Fleischmann H. Basal insulin combined incretin mimetic therapy with glucagon-like protein 1 receptor agonists: a practical guide to decision making. Ther Adv Endocrinol Metab 214; 5(5): doi: / Flint A, Kapitza C, Hindsberger C, et al. The once-daily GL-1 analogue liraglutide improves postprandial glucose levels in type 2 diabetes patients. Adv Ther 211; 28(3): doi: 1.17/s x. 5. Matsumoto S, Yamazaki M, Kadono M, et al. Effects of liraglutide on postprandial insulin and glucagon responses in Japanese patients with type 2 diabetes. J Clin Biochem Nutr 213; 53(1): doi: / jcbn Buse JB, Rosenstock J, Sesti G, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 29; 374(9683): doi: 1.116/S (9) Lee MJ, Wu Y, Fried SK. Adipose tissue heterogeneity: implication of depot difference in adipose tissue for obesity complications. Mol Aspects Med 213; 34(1): doi: 1.116/j.mam nutrients. Although safety concerns are now largely diminished, GL-1 RAs alone or in BIT are not recommended for use in patients with previous or current dysfunctions of the pancreas, stomach and gut. 8. Vilsboll T, Christensen M, Gluud LL, et al. Effects of glucagon-like peptide-1 receptor agonists on weight loss: systemic review and meta-analyses of randomised controlled trials. BMJ 212; 344: d Rosenstock J, Rodbard HW, Bain SC, et al. One-year sustained glycaemic control and weight reduction in T2DM after addition of liraglutide to metformin followed by insulin detemir according to HbA 1c target. J Diabetes Complications 213; 27: Skyler JS, Bergenstal R, Bonow RO, et al. Intensive glycaemic control and the prevention of cardiovascular events: Implications of the ACCORD, ADVANCE and VA Diabetes trials: a position statement of the American Diabetes Association and a scientific statement of the ACC Foundation and the American Heart Association. Diabetes Care 29; 32(1): doi: / dc Mathieu C, Rodbard HW, Cariou B, et al. A comparison of adding liraglutide versus a single daily dose of insulin aspart to insulin degludec in subjects with type 2 diabetes (VICTOZA ADD-ON). Diabetes Obes and Metab 214; 16: Geller AI, Shehab N, Lovegrove MC, et al. National estimates of insulin-related hypoglycaemia and errors leading to emergency department visits and hospitalisations. JAMA Intern Med 214; 174(5): doi: 1.11/jamainternmed Thompson A, Vande Griend J, Linnebur SA, et al. Evaluation of type 2 diabetes mellitus medication management and control in older adults. Consult harm 213; 28: Disclaimer The views and opinions expressed in the article are those of the presenters and do not necessarily reflect those of the publisher or its sponsor. In all clinical instances, medical practitioners are referred to the product insert documentation as approved by relevant control authorities. ublished by denovo Medica Reg: 212/216456/7 7 Arlington Street, Everglen, Cape Town, 755 Tel: (21) I info@denovomedica.com 6 I May 218