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Basal insulin or longacting GLP-1 receptor agonists—making the right choice
Comment
There is general agreement that the optimum treatment of type 2 diabetes should allow most patients to achieve glycaemia as close to normal as feasible, while at the same time avoiding weight gain, hypoglycaemia, and other adverse effects of treatments.1,2 Although insulin treatment is typically required when glycaemic control is insufficient despite use of several oral hypoglycaemia drugs, it can cause substantial weight gain,3 whereas glucagon-like peptide-1 (GLP-1) receptor agonists typically cause weight loss.4 Insulin treatment is also associated with hypoglycaemia, which occurs less often with GLP-1 receptor agonists,5 with the proviso that concurrent use of these drugs with a sulfonylurea increases the likelihood of hypoglycaemia.6 Thus, the use GLP-1 receptor agonists rather than insulin could be attractive to many patients with type 2 diabetes and their clinicians. In The Lancet Diabetes & Endocrinology, Michaela Diamant and coworkers report the 3-year results of the DURATION-3 study of 456 patients with type 2 diabetes and suboptimum glycaemic control (HbA1c 7·1–11·0% [54–97 mmol/mol]) who were randomly assigned to once-weekly exenatide or once-daily insulin glargine (henceforth, glargine).7 All participants were receiving metformin, and 30% were also receiving a sulfonylurea. As in the 26-week core trial,8 the 233 patients who received at least one dose of exenatide had a greater least-squares mean change in HbA1c (–1·01% [SE 0·07]) than did the 223 patients who received glargine (–0·81% [0·07]; least-squares mean difference –0·20%, SE 0·10, 95% CI –0·39 to –0·02; p=0·03). The exposureadjusted rate of overall hypoglycaemia was lower in the exenatide group (0·3 events per patient per year) than in the glargine group (0·9 events per patient per year). Additionally, bodyweight decreased in the exenatide group (least-squares mean change –2·49 kg [SE 0·28]) but increased in the glargine group (2·01 kg [0·28]; least-squares mean difference –4·51 kg, SD 0·37, 95% CI –5·23 to –3·79; p<0·001). However, frequency of gastrointestinal adverse events was increased in patients given exenatide—eg, 36 (15%) of 233 patients given exenatide had nausea, compared with five (2%) of 223 given glargine. In the first 26 weeks,
12 patients (5%) given exenatide were withdrawn because of adverse events versus two (1%) given glargine,8 and the difference was maintained in the subsequent 130 weeks, when 22 patients (9%) given exenatide and five (2%) given glargine were withdrawn.7 Therefore, tolerability still seems to be an issue5 with longacting GLP-1 receptor agonists such as exenatide. Can exenatide be thought of as better than glargine? Diamant and colleagues7 report that 116 patients (50%) given exenatide achieved and sustained HbA1c control (<7·0%; <53 mmol/mol) compared with 96 (43%) given glargine. Not surprisingly, patients who did not achieve control had slightly higher baseline HbA1c (mean 8·5% [SD 1·1] in the glargine group and 8·6% [1·0] in the exenatide group) than did patients who did achieve control (8·2% [1·1] and 7·9% [0·8]). For patients receiving exenatide who did not achieve control, mean fasting serum glucose concentration increased to 8·89 mmol/L (SE 2·42) at week 156—clearly, these patients might have benefited from the addition of basal insulin to their treatment regimen. To understand why more than half the individuals given glargine did not achieve HbA1c control is complex. The insulin titration algorithm was used to adjust insulin doses to achieve target fasting glucose concentrations of 4·0–5·5 mmol/L,8 but the mean concentration after 156 weeks in patients given glargine who did not achieve HbA1c control was substantially higher at 7·53 mmol/L (SE 2·49).7 Diamant and colleagues recognise this issue, and express uncertainty about whether “increased doses would have been accepted by patients…or were precluded by hypoglycaemia”.7 Although sulfonylurea doses were reduced in a third of each group in response to hypoglycaemia, doses of concomitant oral glucoselowering therapies were increased in 47 patients (20%) assigned to exenatide versus 14 (6%) assigned to glargine. 27 patients (12%) in the exenatide group and 16 (7%) in the glargine group started taking other oral glucose-lowering therapies. Were the patients given glargine who did not achieve HbA1c control undertreated? By contrast with the “treat-to-target” idea,9 Diamant and colleagues7 discuss the fact that that many studies involving titration of glargine reach similar doses and
www.thelancet.com/diabetes-endocrinology Published online April 4, 2014 http://dx.doi.org/10.1016/S2213-8587(14)70036-1
Tony Craddock/Science Photo Library
Basal insulin or longacting GLP-1 receptor agonists—making the right choice
Lancet Diabetes Endocrinol 2014 Published Online April 4, 2014 http://dx.doi.org/10.1016/ S2213-8587(14)70036-1 See Online/Articles http://dx.doi.org/10.1016/ S2213-8587(14)70029-4
1
Comment
show similar poor achievement of fasting glucose targets. As shown by Diamant and colleagues,7 glargine effectively lowers fasting glucose concentrations and reduces prandial glucose throughout the day, but less effectively than exenatide does. Therefore, the correct interpretation of DURATION-3 could simply be that about half of patients taking metformin could benefit from both basal insulin and the longacting formulation of exenatide being added to their treatment regimen. Enrolment in DURATION-3 began 6 years ago. Since then, new ideas have been put forward about how to treat diabetes appropriately. Various agents that cause neither hypoglycaemia nor weight gain—eg, metformin, dipeptidyl peptidase-4 inhibitors, GLP-1 receptor agonists, sodium-glucose transporter-2 inhibitors, bile acid binding resins, α-glucosidase inhibitors, and the rapidly absorbed form of bromocriptine—are now available to treat diabetes.10 However, all these agents have potential side-effects and warnings. For now at least, basal insulin remains crucial for the optimum treatment of many patients, and the question of which agent is best is often asked. However, no one agent is better than others; optimum treatment approaches necessitate individualisation of treatment to appropriately fit the characteristics of the individual patient with diabetes. The question of how to use several agents in a cost-effective and affordable way to treat the hundreds of millions of people who will develop diabetes in the coming decades is one that is yet to be answered.
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Zachary T Bloomgarden Mount Sinai School of Medicine, New York, NY 10028, USA [email protected] I am a paid consultant for BMS, Astra-Zeneca, Jansen, Merck, Novartis, Boehringer Ingelheim, NovoNordisk, and Santarus. I have received fees for speaking for Janssen, Merck, Boehringer Ingelheim, NovoNordisk, and Santarus. I own shares of Baxter International, CVS Caremark, Roche Holdings, St Jude Medical, and Novartis. 1 2
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Garber AJ, Abrahamson MJ, Barzilay JI, et al. AACE comprehensive diabetes management algorithm 2013. Endocr Pract 2013; 19: 327–36. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2012; 35: 1364–79. Morgan CL, Jenkins-Jones S, Evans M, Barnett AH, Poole CD, Currie CJ. Weight change in people with type 2 diabetes: secular trends and the impact of alternative antihyperglycaemic drugs. Diabetes Obes Metab 2012; 14: 424–32. Gross JL, Kramer CK, Leitão CB, et al, for the Diabetes and Endocrinology Meta-Analysis Group (DEMA). Effect of antihyperglycemic agents added to metformin and a sulfonylurea on glycemic control and weight gain in type 2 diabetes: a network meta-analysis. Ann Intern Med 2011; 154: 672–79. Abdul-Ghani MA, Williams K, Kanat M, Altuntas Y, DeFronzo RA. Insulin vs GLP-1 analogues in poorly controlled type 2 diabetic subjects on oral therapy: a meta-analysis. J Endocrinol Invest 2013; 36: 168–73. Esposito K, Mosca C, Brancario C, Chiodini P, Ceriello A, Giugliano D. GLP-1 receptor agonists and HBA1c target of <7% in type 2 diabetes: meta-analysis of randomized controlled trials. Curr Med Res Opin 2011; 27: 1519–28. Diamant M, Van Gaal L, Guerci B, et al. Exenatide once weekly versus insulin glargine for type 2 diabetes (DURATION-3): 3-year results of an open-label randomised trial. Lancet Diabetes Endocrinol 2014; published online April 4. http://dx.doi.org/10.1016/S2213-8587(14)70029-4. Diamant M, Van Gaal L, Stranks S, et al. Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): an open-label randomised trial. Lancet 2010; 375: 2234–43. Riddle MC, Rosenstock J, Gerich J, on behalf of the Insulin Glargine 4002 Study Investigators. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 2003; 26: 3080–86. Garber AJ, Abrahamson MJ, Barzilay JI, et al. AACE comprehensive diabetes management algorithm 2013. Endocr Pract 2013; 19: 327–36.
www.thelancet.com/diabetes-endocrinology Published online April 4, 2014 http://dx.doi.org/10.1016/S2213-8587(14)70036-1
There is general agreement that the optimum treatment of type 2 diabetes should allow most patients to achieve glycaemia as close to normal as feasible, while at the same time avoiding weight gain, hypoglycaemia, and other adverse effects of treatments.1,2 Although insulin treatment is typically required when glycaemic control is insufficient despite use of several oral hypoglycaemia drugs, it can cause substantial weight gain,3 whereas glucagon-like peptide-1 (GLP-1) receptor agonists typically cause weight loss.4 Insulin treatment is also associated with hypoglycaemia, which occurs less often with GLP-1 receptor agonists,5 with the proviso that concurrent use of these drugs with a sulfonylurea increases the likelihood of hypoglycaemia.6 Thus, the use GLP-1 receptor agonists rather than insulin could be attractive to many patients with type 2 diabetes and their clinicians. In The Lancet Diabetes & Endocrinology, Michaela Diamant and coworkers report the 3-year results of the DURATION-3 study of 456 patients with type 2 diabetes and suboptimum glycaemic control (HbA1c 7·1–11·0% [54–97 mmol/mol]) who were randomly assigned to once-weekly exenatide or once-daily insulin glargine (henceforth, glargine).7 All participants were receiving metformin, and 30% were also receiving a sulfonylurea. As in the 26-week core trial,8 the 233 patients who received at least one dose of exenatide had a greater least-squares mean change in HbA1c (–1·01% [SE 0·07]) than did the 223 patients who received glargine (–0·81% [0·07]; least-squares mean difference –0·20%, SE 0·10, 95% CI –0·39 to –0·02; p=0·03). The exposureadjusted rate of overall hypoglycaemia was lower in the exenatide group (0·3 events per patient per year) than in the glargine group (0·9 events per patient per year). Additionally, bodyweight decreased in the exenatide group (least-squares mean change –2·49 kg [SE 0·28]) but increased in the glargine group (2·01 kg [0·28]; least-squares mean difference –4·51 kg, SD 0·37, 95% CI –5·23 to –3·79; p<0·001). However, frequency of gastrointestinal adverse events was increased in patients given exenatide—eg, 36 (15%) of 233 patients given exenatide had nausea, compared with five (2%) of 223 given glargine. In the first 26 weeks,
12 patients (5%) given exenatide were withdrawn because of adverse events versus two (1%) given glargine,8 and the difference was maintained in the subsequent 130 weeks, when 22 patients (9%) given exenatide and five (2%) given glargine were withdrawn.7 Therefore, tolerability still seems to be an issue5 with longacting GLP-1 receptor agonists such as exenatide. Can exenatide be thought of as better than glargine? Diamant and colleagues7 report that 116 patients (50%) given exenatide achieved and sustained HbA1c control (<7·0%; <53 mmol/mol) compared with 96 (43%) given glargine. Not surprisingly, patients who did not achieve control had slightly higher baseline HbA1c (mean 8·5% [SD 1·1] in the glargine group and 8·6% [1·0] in the exenatide group) than did patients who did achieve control (8·2% [1·1] and 7·9% [0·8]). For patients receiving exenatide who did not achieve control, mean fasting serum glucose concentration increased to 8·89 mmol/L (SE 2·42) at week 156—clearly, these patients might have benefited from the addition of basal insulin to their treatment regimen. To understand why more than half the individuals given glargine did not achieve HbA1c control is complex. The insulin titration algorithm was used to adjust insulin doses to achieve target fasting glucose concentrations of 4·0–5·5 mmol/L,8 but the mean concentration after 156 weeks in patients given glargine who did not achieve HbA1c control was substantially higher at 7·53 mmol/L (SE 2·49).7 Diamant and colleagues recognise this issue, and express uncertainty about whether “increased doses would have been accepted by patients…or were precluded by hypoglycaemia”.7 Although sulfonylurea doses were reduced in a third of each group in response to hypoglycaemia, doses of concomitant oral glucoselowering therapies were increased in 47 patients (20%) assigned to exenatide versus 14 (6%) assigned to glargine. 27 patients (12%) in the exenatide group and 16 (7%) in the glargine group started taking other oral glucose-lowering therapies. Were the patients given glargine who did not achieve HbA1c control undertreated? By contrast with the “treat-to-target” idea,9 Diamant and colleagues7 discuss the fact that that many studies involving titration of glargine reach similar doses and
www.thelancet.com/diabetes-endocrinology Published online April 4, 2014 http://dx.doi.org/10.1016/S2213-8587(14)70036-1
Tony Craddock/Science Photo Library
Basal insulin or longacting GLP-1 receptor agonists—making the right choice
Lancet Diabetes Endocrinol 2014 Published Online April 4, 2014 http://dx.doi.org/10.1016/ S2213-8587(14)70036-1 See Online/Articles http://dx.doi.org/10.1016/ S2213-8587(14)70029-4
1
Comment
show similar poor achievement of fasting glucose targets. As shown by Diamant and colleagues,7 glargine effectively lowers fasting glucose concentrations and reduces prandial glucose throughout the day, but less effectively than exenatide does. Therefore, the correct interpretation of DURATION-3 could simply be that about half of patients taking metformin could benefit from both basal insulin and the longacting formulation of exenatide being added to their treatment regimen. Enrolment in DURATION-3 began 6 years ago. Since then, new ideas have been put forward about how to treat diabetes appropriately. Various agents that cause neither hypoglycaemia nor weight gain—eg, metformin, dipeptidyl peptidase-4 inhibitors, GLP-1 receptor agonists, sodium-glucose transporter-2 inhibitors, bile acid binding resins, α-glucosidase inhibitors, and the rapidly absorbed form of bromocriptine—are now available to treat diabetes.10 However, all these agents have potential side-effects and warnings. For now at least, basal insulin remains crucial for the optimum treatment of many patients, and the question of which agent is best is often asked. However, no one agent is better than others; optimum treatment approaches necessitate individualisation of treatment to appropriately fit the characteristics of the individual patient with diabetes. The question of how to use several agents in a cost-effective and affordable way to treat the hundreds of millions of people who will develop diabetes in the coming decades is one that is yet to be answered.
2
Zachary T Bloomgarden Mount Sinai School of Medicine, New York, NY 10028, USA [email protected] I am a paid consultant for BMS, Astra-Zeneca, Jansen, Merck, Novartis, Boehringer Ingelheim, NovoNordisk, and Santarus. I have received fees for speaking for Janssen, Merck, Boehringer Ingelheim, NovoNordisk, and Santarus. I own shares of Baxter International, CVS Caremark, Roche Holdings, St Jude Medical, and Novartis. 1 2
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5
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Garber AJ, Abrahamson MJ, Barzilay JI, et al. AACE comprehensive diabetes management algorithm 2013. Endocr Pract 2013; 19: 327–36. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2012; 35: 1364–79. Morgan CL, Jenkins-Jones S, Evans M, Barnett AH, Poole CD, Currie CJ. Weight change in people with type 2 diabetes: secular trends and the impact of alternative antihyperglycaemic drugs. Diabetes Obes Metab 2012; 14: 424–32. Gross JL, Kramer CK, Leitão CB, et al, for the Diabetes and Endocrinology Meta-Analysis Group (DEMA). Effect of antihyperglycemic agents added to metformin and a sulfonylurea on glycemic control and weight gain in type 2 diabetes: a network meta-analysis. Ann Intern Med 2011; 154: 672–79. Abdul-Ghani MA, Williams K, Kanat M, Altuntas Y, DeFronzo RA. Insulin vs GLP-1 analogues in poorly controlled type 2 diabetic subjects on oral therapy: a meta-analysis. J Endocrinol Invest 2013; 36: 168–73. Esposito K, Mosca C, Brancario C, Chiodini P, Ceriello A, Giugliano D. GLP-1 receptor agonists and HBA1c target of <7% in type 2 diabetes: meta-analysis of randomized controlled trials. Curr Med Res Opin 2011; 27: 1519–28. Diamant M, Van Gaal L, Guerci B, et al. Exenatide once weekly versus insulin glargine for type 2 diabetes (DURATION-3): 3-year results of an open-label randomised trial. Lancet Diabetes Endocrinol 2014; published online April 4. http://dx.doi.org/10.1016/S2213-8587(14)70029-4. Diamant M, Van Gaal L, Stranks S, et al. Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): an open-label randomised trial. Lancet 2010; 375: 2234–43. Riddle MC, Rosenstock J, Gerich J, on behalf of the Insulin Glargine 4002 Study Investigators. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 2003; 26: 3080–86. Garber AJ, Abrahamson MJ, Barzilay JI, et al. AACE comprehensive diabetes management algorithm 2013. Endocr Pract 2013; 19: 327–36.
www.thelancet.com/diabetes-endocrinology Published online April 4, 2014 http://dx.doi.org/10.1016/S2213-8587(14)70036-1