Comment
resilience to ischaemia, and improve left ventricular function after ischaemia-reperfusion injury. Like cIMT, the effect of metformin on myocardial function and infarct size is also a surrogate endpoint for clinical outcome. Whether the primary endpoint of CAMERA or secondary endpoints such as HbA1c best represent cardiovascular outcome is unclear. The definitive evidence for the role of metformin in non-diabetic cardiovascular disease will have to be provided by large randomised clinical trials powered for cardiovascular outcomes such as the Glucose Lowering In Non-diabetic hyperglycaemia Trial (GLINT; ISRCTN34875079), in which 12 000 patients with high cardiovascular risk and dysglycaemia but without diabetes, will be assigned to metformin or placebo for 5 years. Until then, the role of metformin for improving cardiovascular outcomes has promise, but is still largely unproven.
CPHL and ICCH (principal) are investigators of the Glycometabolic Intervention as Adjunct to Primary Percutaneous Intervention in ST Elevation Myocardial Infarction trial (NCT01217307), of the effect of metformin on left ventricular function in patients without diabetes presenting with acute myocardial infarction. 1
2
3
4
5
6
7 8 9
Chris P H Lexis, *Iwan C C van der Horst Department of Cardiology (CPHL, ICCH), Hanzeplein 1, 9700 RB, PO Box 30001, Department of Critical Care (ICCH), University of Groningen, University Medical Center Groningen, Groningen, Netherlands [email protected]
10
Preiss D, Lloyd SM, Ford I, et al. Metformin for non-diabetic patients with coronary heart disease (the CAMERA study): a randomised controlled trial. Lancet Diabet & Endocrinol 2013; published online Nov 7. http://dx.doi. org/10.1016/S2213-8587(13)70152-9. Meaney E, Vela A, Samaniego V, et al. Metformin, arterial function, intima-media thickness and nitroxidation in metabolic syndrome: the mefisto study. Clin Exp Pharmacol Physiol 2008; 35: 895–903. Katakami N, Yamasaki Y, Hayaishi-Okano R, et al. Metformin or gliclazide, rather than glibenclamide, attenuate progression of carotid intima-media thickness in subjects with type 2 diabetes. Diabetalogia 2004; 47: 1906–13. Lundby Christensen L, Almdal T, Boesgaard T, et al; CIMT Trial Group. Study rationale and design of the CIMT trial: the Copenhagen Insulin and Metformin Therapy trial. Diabetes Obes Metab 2009; 11: 315–22. Stocker DJ, Taylor AJ, Langley RW, Jezior MR, Vigersky RA. A randomized trial of the effects of rosiglitazone and metformin on inflammation and subclinical atherosclerosis in patients with type 2 diabetes. Am Heart J 2007; 153: 445.e1–6. Yin M, van der Horst IC, van Melle JP, et al. Metformin improves cardiac function in a nondiabetic rat model of post-MI heart failure. Am J Physiol Heart Circ Physiol 2011; 301: H459–68. Bailey CJ. Metformin: effects on micro and macrovascular complications in type 2 diabetes. Cardiovasc Drugs Ther 2008; 22: 215–24. Cittadini A, Napoli R, Monti MG, et al. Metformin prevents the development of chronic heart failure in the SHHF rat model. Diabetes 2012; 61: 944–53. Kao J, Tobis J, McClelland RL, et al. Relation of metformin treatment to clinical events in diabetic patient undergoing percutaneous intervention. Am J Cardiol 2004; 93: 1347–50. Roussel R, Travert F, Pasquet B, et al. Metformin use and mortality among patients with diabetes and atherothrombosis. Arch Intern Med 2010; 170: 1892–99.
A quarter of a century after the discovery of incretin hormones and their impaired regulation of insulin and glucagon secretion in type 2 diabetes,1 specific treatments to improve the diminished incretin effect have become widely available for glycaemic control in type 2 diabetes. Incretin treatments consist of either oral DPP-4 inhibitors, which decrease the clearance of secreted incretins GLP-1 and GIP, or injectable analogues of GLP-1. Relative freedom from hypoglycaemia, an absence of weight gain, and additivity in glucose control in combination with metformin have largely driven the increasing acceptance of these drugs.2,3 Despite the proliferation of many new drugs for diabetes management, low persistence and adherence of patients to these drugs remain key drivers of residual hyperglycaemia in this population. Increasing complexity of therapeutic interventions is one key www.thelancet.com/diabetes-endocrinology Vol 2 February 2014
reason for low adherence.4 For this reason, the use of combination treatments for managing type 2 diabetes is increasingly common, since reducing the number of tablets per day by combining two agents into a single tablet reduces complexity of treatment for the patient.3 Because the once daily DPP-4 inhibitors can be used in combination with long-acting metformin preparations, this combination effectively reduces the pill burden for many patients, especially those with early, asymptomatic type 2 diabetes, in which many patients believe their therapies to be somewhat optional. Another strategy to increase adherence and persistence is to reduce the frequency of medication administration. Thus, once-daily medications seem preferable to those that must be administered twice or three-times daily. Recently, once weekly drugs have begun to make an appearance in the
Photo Researchers Inc/Science Photo Library
The importance of incretin therapies for managing type 2 diabetes
Published Online November 1, 2013 http://dx.doi.org/10.1016/ S2213-8587(13)70157-8 See Articles page 125
95
Comment
marketplace, following on from the success enjoyed by bisphosphonates when longer-acting drugs were developed that enabled progressively longer dosing intervals, thereby reducing the burden of medication dosing to less frequent intervals. The substantial burden of restricted posture, as well as limits on liquid and food intake imposed when dosing these medications, undoubtedly contributed to the success of long-acting preparations of these drugs.5 As the bisphosphanate class has progressed, we have seen the development of products that can be administered at intervals widening from once daily to once weekly and now monthly or longer. A similar approach has been applied to the injectable GLP-1 analogues, including exenatide.Owing to its somewhat short half-life, this drug must be injected at least twice daily to be effective. Adherence issues, particularly with the second injection of the day, limited utility and adherence of exenatide. The creation of a long-acting (once weekly) form of exenatide (Bydureon) had been developed to address this issue.6 Whether or not weekly intervals will be successful commercially remains to be determined. In a parallel series of developmental efforts, longacting DPP-4 inhibitors are currently in trials by several companies. The hypothesis underlying these efforts is again that once-weekly administration will have superior adherence and persistence compared with once-daily dosing of drugs in the same class. Unfortunately, unlike for bisphosphonates or injectable compounds, no data exist from which to infer that daily usage of the DPP-4 inhibitors is impeded by tolerability or administration issues. Accordingly, the article by Nobuya Inagaki and colleagues7 in The Lancet Diabetes & Endocrinology investigates the dosing characteristics of a once-weekly DPP-4 inhibitor, SYR472.7 The study presents adequate dose-finding results for the efficacy of this drug in a population of Japanese patients, with least square mean changes in HbA1c concentration from baseline of 0·35% (SE 0·068) for the placebo group, –0·37% (0·068) for the 12·5 mg group of SYR-472, –0·32% (0·070) for the 25 mg group, –0·42% (0·070) for the 50 mg group, –0·54% (0·068) for the 100 mg group, and –0·55% (0·069) for the 200 mg group. Since the glycaemic benefits of DPP-4 inhibitors are generally related to the residual inhibition of the enzyme at the end of the dosing interval, weekly drugs 96
must retain enzyme inhibition activity at the end of 1 week. The study by Inagaki and colleagues was done exclusively in a Japanese population, a population that has previously been shown to have drug hypersensitivities that often require dose reductions— eg, with the injectable GLP-1 analogue liraglutide. The efficacy of these doses and suitability of weekly administration might require further investigation in patients of other ethnicities before any general conclusions can be drawn. Another concern remains regarding the fundamental concept of drug utility being improved by weekly administration—especially in drugs that have few adverse effects and uncomplicated administration, such as with the DPP-4 inhibitors. Whether or not efficacy of a drug with few burdens of administration is improved by weekly administration as compared with daily administration remains unproven. Similarly, the issues of adherence and persistence are not addressed in this study, and will probably require further study before such weekly drugs are deemed acceptable. Of perhaps greater significance is the frequent pairing of these inhibitors with metformin, which must be taken at least once daily. Replacement of a once-daily drug with two drugs, one a once daily and the other a once weekly, renders the utility of a weekly DPP-4 inhibitor somewhat moot. Regardless of the concerns listed here, various weekly DPP-4 inhibitors will probably be developed for the world marketplace and they are likely to be used. As the number of patients with type 2 diabetes escalates annually worldwide, and as the number of therapeutic drugs multiplies, a cohort of patients will be found for each new drug and each new administration requirement. The only open questions are how large each cohort will be and whether there will be reimbursement for every new innovation in the diabetes arena. Alan J Garber Department of Medicine, Biochemistry and Molecular Biology, and Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA [email protected] I have been a consultant for Merck, Novonordisk, Santarus, and Janssen Pharmaceuticals. 1
Nauck M, Stockmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 diabetes. Diabetelogia 1986; 29: 46–52.
www.thelancet.com/diabetes-endocrinology Vol 2 February 2014
Comment
2 3
4
5
Inzucchi S, Bergenstal R, Buse J, et al. Management of hyperglycemia in type 2 diabetes: a patient centered approach. Diabetes Care 2012; 35: 1364–79. Garber A, Abrahamson M, Barzilay J, et al. American Association Of Clinical Endocrinologists’ comprehensive diabetes management algorithm 2013 consensus statement. Endocr Pract 2013; 19: 327–35. Garcia-Perez L, Alvarez M, Dilla T, Gil-Guillen V, Orozco-Beltran D. Adherence to therapies in patients with type 2 diabetes. Diabetes Ther 2013; published online Aug 30. http://dx.doi.org/10.1007/s13300-0130034-y. Cooper C. Beyond daily dosing: clinical experience. Bone 2006; 38: S13–17.
6
7
Painter N, Morello C, Singh R, McBane S. An evidence based and practical approach to using Bydureon in patients with type 2 diabetes. J Amer Board Fam Med 2013; 26: 203–10. Inagaki N, Onouchi H, Sano H, Funao N, Kuroda S, Kaku K. SYR-472, a novel once-weekly dipeptidyl peptidase-4 (DPP-4) inhibitor, in type 2 diabetes mellitus: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2013; published online Nov 1. http://dx.doi. org/10.1016/S2213-8587(13)70149-9.
The goal of carbohydrate counting in the management of type 1 diabetes is to match insulin dose to food intake to permit flexibility in food choices without adversely affecting metabolic control and health outcomes.1 In The Lancet Diabetes and Endocrinology, the meta-analysis of carbohydrate counting research in type 1 diabetes by Kirstine Bell and colleagues2 identified some evidence to recommend carbohydrate counting over alternate advice or so-called usual care in adults with type 1 diabetes. Although the meta-analysis of the seven randomised trials that met the inclusion criteria identified no overall significant improvement in HbA1c concentration with carbohydrate counting versus control or usual care (–0·35%, p=0·096), restricting the analysis to the five trials in adults, which used a parallel design, identified a –0·64% improvement in HbA1c in favour of carbohydrate counting (p
resilience to ischaemia, and improve left ventricular function after ischaemia-reperfusion injury. Like cIMT, the effect of metformin on myocardial function and infarct size is also a surrogate endpoint for clinical outcome. Whether the primary endpoint of CAMERA or secondary endpoints such as HbA1c best represent cardiovascular outcome is unclear. The definitive evidence for the role of metformin in non-diabetic cardiovascular disease will have to be provided by large randomised clinical trials powered for cardiovascular outcomes such as the Glucose Lowering In Non-diabetic hyperglycaemia Trial (GLINT; ISRCTN34875079), in which 12 000 patients with high cardiovascular risk and dysglycaemia but without diabetes, will be assigned to metformin or placebo for 5 years. Until then, the role of metformin for improving cardiovascular outcomes has promise, but is still largely unproven.
CPHL and ICCH (principal) are investigators of the Glycometabolic Intervention as Adjunct to Primary Percutaneous Intervention in ST Elevation Myocardial Infarction trial (NCT01217307), of the effect of metformin on left ventricular function in patients without diabetes presenting with acute myocardial infarction. 1
2
3
4
5
6
7 8 9
Chris P H Lexis, *Iwan C C van der Horst Department of Cardiology (CPHL, ICCH), Hanzeplein 1, 9700 RB, PO Box 30001, Department of Critical Care (ICCH), University of Groningen, University Medical Center Groningen, Groningen, Netherlands [email protected]
10
Preiss D, Lloyd SM, Ford I, et al. Metformin for non-diabetic patients with coronary heart disease (the CAMERA study): a randomised controlled trial. Lancet Diabet & Endocrinol 2013; published online Nov 7. http://dx.doi. org/10.1016/S2213-8587(13)70152-9. Meaney E, Vela A, Samaniego V, et al. Metformin, arterial function, intima-media thickness and nitroxidation in metabolic syndrome: the mefisto study. Clin Exp Pharmacol Physiol 2008; 35: 895–903. Katakami N, Yamasaki Y, Hayaishi-Okano R, et al. Metformin or gliclazide, rather than glibenclamide, attenuate progression of carotid intima-media thickness in subjects with type 2 diabetes. Diabetalogia 2004; 47: 1906–13. Lundby Christensen L, Almdal T, Boesgaard T, et al; CIMT Trial Group. Study rationale and design of the CIMT trial: the Copenhagen Insulin and Metformin Therapy trial. Diabetes Obes Metab 2009; 11: 315–22. Stocker DJ, Taylor AJ, Langley RW, Jezior MR, Vigersky RA. A randomized trial of the effects of rosiglitazone and metformin on inflammation and subclinical atherosclerosis in patients with type 2 diabetes. Am Heart J 2007; 153: 445.e1–6. Yin M, van der Horst IC, van Melle JP, et al. Metformin improves cardiac function in a nondiabetic rat model of post-MI heart failure. Am J Physiol Heart Circ Physiol 2011; 301: H459–68. Bailey CJ. Metformin: effects on micro and macrovascular complications in type 2 diabetes. Cardiovasc Drugs Ther 2008; 22: 215–24. Cittadini A, Napoli R, Monti MG, et al. Metformin prevents the development of chronic heart failure in the SHHF rat model. Diabetes 2012; 61: 944–53. Kao J, Tobis J, McClelland RL, et al. Relation of metformin treatment to clinical events in diabetic patient undergoing percutaneous intervention. Am J Cardiol 2004; 93: 1347–50. Roussel R, Travert F, Pasquet B, et al. Metformin use and mortality among patients with diabetes and atherothrombosis. Arch Intern Med 2010; 170: 1892–99.
A quarter of a century after the discovery of incretin hormones and their impaired regulation of insulin and glucagon secretion in type 2 diabetes,1 specific treatments to improve the diminished incretin effect have become widely available for glycaemic control in type 2 diabetes. Incretin treatments consist of either oral DPP-4 inhibitors, which decrease the clearance of secreted incretins GLP-1 and GIP, or injectable analogues of GLP-1. Relative freedom from hypoglycaemia, an absence of weight gain, and additivity in glucose control in combination with metformin have largely driven the increasing acceptance of these drugs.2,3 Despite the proliferation of many new drugs for diabetes management, low persistence and adherence of patients to these drugs remain key drivers of residual hyperglycaemia in this population. Increasing complexity of therapeutic interventions is one key www.thelancet.com/diabetes-endocrinology Vol 2 February 2014
reason for low adherence.4 For this reason, the use of combination treatments for managing type 2 diabetes is increasingly common, since reducing the number of tablets per day by combining two agents into a single tablet reduces complexity of treatment for the patient.3 Because the once daily DPP-4 inhibitors can be used in combination with long-acting metformin preparations, this combination effectively reduces the pill burden for many patients, especially those with early, asymptomatic type 2 diabetes, in which many patients believe their therapies to be somewhat optional. Another strategy to increase adherence and persistence is to reduce the frequency of medication administration. Thus, once-daily medications seem preferable to those that must be administered twice or three-times daily. Recently, once weekly drugs have begun to make an appearance in the
Photo Researchers Inc/Science Photo Library
The importance of incretin therapies for managing type 2 diabetes
Published Online November 1, 2013 http://dx.doi.org/10.1016/ S2213-8587(13)70157-8 See Articles page 125
95
Comment
marketplace, following on from the success enjoyed by bisphosphonates when longer-acting drugs were developed that enabled progressively longer dosing intervals, thereby reducing the burden of medication dosing to less frequent intervals. The substantial burden of restricted posture, as well as limits on liquid and food intake imposed when dosing these medications, undoubtedly contributed to the success of long-acting preparations of these drugs.5 As the bisphosphanate class has progressed, we have seen the development of products that can be administered at intervals widening from once daily to once weekly and now monthly or longer. A similar approach has been applied to the injectable GLP-1 analogues, including exenatide.Owing to its somewhat short half-life, this drug must be injected at least twice daily to be effective. Adherence issues, particularly with the second injection of the day, limited utility and adherence of exenatide. The creation of a long-acting (once weekly) form of exenatide (Bydureon) had been developed to address this issue.6 Whether or not weekly intervals will be successful commercially remains to be determined. In a parallel series of developmental efforts, longacting DPP-4 inhibitors are currently in trials by several companies. The hypothesis underlying these efforts is again that once-weekly administration will have superior adherence and persistence compared with once-daily dosing of drugs in the same class. Unfortunately, unlike for bisphosphonates or injectable compounds, no data exist from which to infer that daily usage of the DPP-4 inhibitors is impeded by tolerability or administration issues. Accordingly, the article by Nobuya Inagaki and colleagues7 in The Lancet Diabetes & Endocrinology investigates the dosing characteristics of a once-weekly DPP-4 inhibitor, SYR472.7 The study presents adequate dose-finding results for the efficacy of this drug in a population of Japanese patients, with least square mean changes in HbA1c concentration from baseline of 0·35% (SE 0·068) for the placebo group, –0·37% (0·068) for the 12·5 mg group of SYR-472, –0·32% (0·070) for the 25 mg group, –0·42% (0·070) for the 50 mg group, –0·54% (0·068) for the 100 mg group, and –0·55% (0·069) for the 200 mg group. Since the glycaemic benefits of DPP-4 inhibitors are generally related to the residual inhibition of the enzyme at the end of the dosing interval, weekly drugs 96
must retain enzyme inhibition activity at the end of 1 week. The study by Inagaki and colleagues was done exclusively in a Japanese population, a population that has previously been shown to have drug hypersensitivities that often require dose reductions— eg, with the injectable GLP-1 analogue liraglutide. The efficacy of these doses and suitability of weekly administration might require further investigation in patients of other ethnicities before any general conclusions can be drawn. Another concern remains regarding the fundamental concept of drug utility being improved by weekly administration—especially in drugs that have few adverse effects and uncomplicated administration, such as with the DPP-4 inhibitors. Whether or not efficacy of a drug with few burdens of administration is improved by weekly administration as compared with daily administration remains unproven. Similarly, the issues of adherence and persistence are not addressed in this study, and will probably require further study before such weekly drugs are deemed acceptable. Of perhaps greater significance is the frequent pairing of these inhibitors with metformin, which must be taken at least once daily. Replacement of a once-daily drug with two drugs, one a once daily and the other a once weekly, renders the utility of a weekly DPP-4 inhibitor somewhat moot. Regardless of the concerns listed here, various weekly DPP-4 inhibitors will probably be developed for the world marketplace and they are likely to be used. As the number of patients with type 2 diabetes escalates annually worldwide, and as the number of therapeutic drugs multiplies, a cohort of patients will be found for each new drug and each new administration requirement. The only open questions are how large each cohort will be and whether there will be reimbursement for every new innovation in the diabetes arena. Alan J Garber Department of Medicine, Biochemistry and Molecular Biology, and Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA [email protected] I have been a consultant for Merck, Novonordisk, Santarus, and Janssen Pharmaceuticals. 1
Nauck M, Stockmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 diabetes. Diabetelogia 1986; 29: 46–52.
www.thelancet.com/diabetes-endocrinology Vol 2 February 2014
Comment
2 3
4
5
Inzucchi S, Bergenstal R, Buse J, et al. Management of hyperglycemia in type 2 diabetes: a patient centered approach. Diabetes Care 2012; 35: 1364–79. Garber A, Abrahamson M, Barzilay J, et al. American Association Of Clinical Endocrinologists’ comprehensive diabetes management algorithm 2013 consensus statement. Endocr Pract 2013; 19: 327–35. Garcia-Perez L, Alvarez M, Dilla T, Gil-Guillen V, Orozco-Beltran D. Adherence to therapies in patients with type 2 diabetes. Diabetes Ther 2013; published online Aug 30. http://dx.doi.org/10.1007/s13300-0130034-y. Cooper C. Beyond daily dosing: clinical experience. Bone 2006; 38: S13–17.
6
7
Painter N, Morello C, Singh R, McBane S. An evidence based and practical approach to using Bydureon in patients with type 2 diabetes. J Amer Board Fam Med 2013; 26: 203–10. Inagaki N, Onouchi H, Sano H, Funao N, Kuroda S, Kaku K. SYR-472, a novel once-weekly dipeptidyl peptidase-4 (DPP-4) inhibitor, in type 2 diabetes mellitus: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2013; published online Nov 1. http://dx.doi. org/10.1016/S2213-8587(13)70149-9.
The goal of carbohydrate counting in the management of type 1 diabetes is to match insulin dose to food intake to permit flexibility in food choices without adversely affecting metabolic control and health outcomes.1 In The Lancet Diabetes and Endocrinology, the meta-analysis of carbohydrate counting research in type 1 diabetes by Kirstine Bell and colleagues2 identified some evidence to recommend carbohydrate counting over alternate advice or so-called usual care in adults with type 1 diabetes. Although the meta-analysis of the seven randomised trials that met the inclusion criteria identified no overall significant improvement in HbA1c concentration with carbohydrate counting versus control or usual care (–0·35%, p=0·096), restricting the analysis to the five trials in adults, which used a parallel design, identified a –0·64% improvement in HbA1c in favour of carbohydrate counting (p
