- Email: [email protected]
An alternative combination therapy for type 2 diabetes?
Comment
many trials. Palmer and colleagues’ findings will be helpful for designing future trials, including appropriate selection of patients, choice of antihypertensive regimen, and meaningful definitions of adverse outcomes. The Kidney Disease Improving Global Outcomes (KDIGO) classification and staging of acute kidney injury could serve as a guide for defining this adverse event in future research.13 Emerging treatments for hyperkalaemia are likely to improve the safety profile of RAAS blockers.14 About 350 million people in the world have diabetes.15 A substantial proportion of these individuals will develop end-stage kidney failure, which underscores the need for preventive treatments.3 Screening for albuminuria and prompt initiation of lifestyle and pharmacological interventions is likely to prevent progression of chronic kidney disease and cardiovascular disease.3 Addition of dual ACE inhibitor and ARB treatment to this multifactorial management approach—if confirmed to be efficacious and cost effective—might further improve patients’ outcomes in regions of the world where careful selection of patients and close monitoring are possible.
1
2
3
4 5 6
7 8 9 10
11 12
13 14
*Tazeen Hasan Jafar, Pryseley Nkouibert Assam Health Services and Systems Research (THJ) and Centre for Quantitative Medicine (PNA), Duke-NUS Graduate Medical School, Singapore 169857 [email protected]
15
Brancati FL, Whelton PK, Randall BL, Neaton JD, Stamler J, Klag MJ. Risk of end-stage renal disease in diabetes mellitus: a prospective cohort study of men screened for MRFIT. JAMA 1997; 278: 2069–74. Fox CS, Matsushita K, Woodward M, et al, for the Chronic Kidney Disease Prognosis Consortium. Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis. Lancet 2012; 380: 1662–73. Gansevoort RT, Correa-Rotter R, Hemmelgarn BR, et al. Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention. Lancet 2013; 382: 339–52. Fried LF, Emanuele N, Zhang JH, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med 2013; 369: 1892–903. Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358: 1547–59. Palmer SC, Mavridis D, Navarese E, et al. Comparative efficacy and safety of blood pressure-lowering agents in adults with diabetes and kidney disease: a network meta-analysis. Lancet 2015; 385: 2047–56. Gurley SB, Coffman TM. The renin-angiotensin system and diabetic nephropathy. Semin Nephrol 2007; 27: 144–52. Raebel MA, Ross C, Xu S, et al. Diabetes and drug-associated hyperkalemia: effect of potassium monitoring. J Gen Intern Med 2010; 25: 326–33. Anderson S, Eldadah B, Halter JB, et al. Acute kidney injury in older adults. J Am Soc Nephrol 2011; 22: 28–38. Chertow GM, Burdick E, Honour M, Bonventre JV, Bates DW. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol 2005; 16: 3365–70. Foley RN, Collins AJ. The USRDS: what you need to know about what it can and can’t tell us about ESRD. Clin J Am Soc Nephrol 2013; 8: 845–51. Inker LA, Levey AS, Pandya K, Stoycheff N, Okparavero A, Greene T. Early change in proteinuria as a surrogate end point for kidney disease progression: an individual patient meta-analysis. Am J Kidney Dis 2014; 64: 74–85. Thomas ME, Blaine C, Dawnay A, et al. The definition of acute kidney injury and its use in practice. Kidney Int 2015; 87: 62–73. Ingelfinger JR. A new era for the treatment of hyperkalemia? N Engl J Med 2015; 372: 275–77. Danaei G, Finucane MM, Lu Y, et al, on behalf of the Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group (Blood Glucose). National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2·7 million participants. Lancet 2011; 378: 31–40.
We declare no competing interests.
An alternative combination therapy for type 2 diabetes? See Articles page 2057
2020
In The Lancet, Lawrence Blonde and colleagues1 present data from a randomised controlled trial of the latest glucagon-like peptide-1 (GLP-1) receptor agonist. Dulaglutide has few known discriminating features compared with the other long-acting GLP-1 receptor agonists on the market with full diurnal GLP-1 activity.2,3 Yet, in the present trial, Blonde and colleagues have turned things upside down and tested this drug as an antihyperglycaemic backbone to pre-prandial shortacting insulin and metformin treatment in patients with type 2 diabetes. This combination of a GLP-1 receptor agonist and insulin has, until now, not been formally tested against the last resort of treatment intensification in patients with type 2 diabetes—namely, long-acting (basal) insulin and mealtime insulin.
The results are particularly interesting because the improvements in several safety and efficacy outcomes reported with dulaglutide (0·75 mg or 1·5 mg once weekly) plus mealtime insulin lispro (three times daily) were significantly greater than those with titrated insulin glargine (once daily) plus mealtime insulin lispro (three times daily). Recruited patients were already receiving insulin (up to two times a day) suggesting that most had deficits in insulin secretory capacity. Irrespective of these deficits, dulaglutide was effective. In our opinion, the glucagonostatic effect4,5 might be an important contributor to the retained efficacy of GLP-1 receptor agonists also in the later stages of type 2 diabetes. Unfortunately, an absence of glucagon data in Blonde and colleagues’ study1 www.thelancet.com Vol 385 May 23, 2015
precludes any appraisal of the contribution of glucagon suppression in this trial. 884 patients were randomly assigned to receive dulaglutide 1·5 mg (n=295) or 0·75 mg (n=293), or insulin glargine (n=296). In terms of the trial’s primary endpoint, dulaglutide 1·5 mg (as approved for add-on therapy) or 0·75 mg, plus insulin lispro, lowered glycated haemoglobin A1c (HbA1c) slightly more than did insulin glargine plus insulin lispro (–1·64% [95% CI –1·78 to –1·50], –17·93 mmol/mol [–19·44 to –16·42]; and –1·59% [–1·73 to –1·45], –17·38 mmol/mol [–18·89 to –15·87], respectively; vs –1·41% [–1·55 to –1·27], –15·41 mmol/ mol [–16·92 to –13·90]) after 26 weeks (below the predetermined clinically relevant non-inferiority margin of 0·4%). At 52 weeks, 9% more patients in the high-dose dulaglutide group than the glargine group achieved the HbA1c target of less than 7·0% (<53 mmol/mol): 161 (59%) patients in the high-dose dulaglutide group versus 138 (49%) patients in the insulin glargine group. Thus, 11 patients would have to be treated for 1 year with dulaglutide instead of insulin glargine for one additional patient to reach an HbA1c target of less than 7·0%. Not surprisingly, in the dulaglutide group, the mean total dose of insulin was lower, but insulin lispro doses were about 30% higher. Insulin lispro doses were about 90 units per day, which could explain why the effect of dulaglutide on weight reduction was less pronounced than in other trials.3,6–9 Nonetheless, compared with patients given insulin glargine, who had a mean weight gain of about 3·5 kg at 52 weeks, the weight neutrality of dulaglutide could be of importance to weight-conscious patients. Dulaglutide treatment was safe compared with insulin glargine. Patients in the dulaglutide groups had more adverse events than did those in the glargine groups, mainly the gastrointestinal side-effects that are well known from other GLP-1 receptor agonists. However, dulaglutide had fewer serious adverse events, mainly because of fewer occurrences of severe hypoglycaemia. In the high-dose dulaglutide group, ten (3%) patients had severe hypoglycaemia (defined as requiring assistance from others) versus 15 (5%) patients in the glargine group. Thus, 59 patients would have to be treated for 1 year with dulaglutide instead of glargine to prevent one case of severe hypoglycaemia. The finding of a lower event rate of total (any type) hypoglycaemia with dulaglutide versus glargine was mostly driven by rather large differences in nocturnal hypoglycaemia after both www.thelancet.com Vol 385 May 23, 2015
Ian Hooton/Science Photo Library
Comment
26 and 52 weeks. Blonde and colleagues1 also report safety endpoints of uncertain importance, such as slightly lowered systolic blood pressure at the expense of minor increases in heart rate; increases in circulating pancreatic enzymes, but with no events of adjudicated pancreatitis or pancreatic cancer; and slightly fewer cardiovascular events in the high-dose (n=5) and low-dose (n=6) dulaglutide groups compared with glargine (n=12). A limitation of Blonde and colleagues’ trial1 is the distance from the real-life situation. Thus, the exclusion of treatments other than metformin (roughly 75% of patients were receiving metformin), and abrupt intensification to insulin lispro three times a day to reach mean HbA1c values of about 6·5% (48 mmol/mol) after 13 weeks treatment, would, in many patients, probably not confer a positive risk–benefit balance and would thus be in conflict with present guidelines that advocate treatment individualisation and focus on avoidance of hypoglycaemia. This overtreatment is shown by the finding that about 80% of patients in all treatment groups had documented symptomatic hypoglycaemia at 26 weeks. Another limitation was the allowance of bedtime insulin glargine titration, which made blinding impossible. Actually, bedtime administration of glargine might have a marginally inferior risk–benefit balance compared with morning administration.10 Patients in the glargine group also had substantially lower mean nocturnal concentrations of plasma glucose than did those in the high-dose and low-dose dulaglutide groups (–2·36 vs –1·84 and –1·73 mmol/L, respectively). Thus, in view of the high rate of nocturnal hypoglycaemia, the bedtime glargine dosing was likely to have been 2021
Comment
too aggressive for some patients. The investigators could have addressed the effect of the trial design on hypoglycaemic events in more detail. A position statement on management of hyperglycaemia in patients with type 2 diabetes from the American Diabetes Association and the European Association for the Study of Diabetes11 recommends GLP-1 receptor agonists or mealtime insulin equally as add-on therapy to basal insulin, in patients with poor glucose control despite triple combination antidiabetic treatment. In such patients, many physicians would probably have tried a GLP-1 receptor agonist before beginning insulin therapy. Blonde and colleagues’ trial1 could raise the question of whether mealtime insulin should be initiated instead of basal insulin in a patient already receiving a GLP-1 receptor agonist. As indicated in the guideline,11 the combination of a long-acting GLP1 receptor agonist and basal insulin is a sound treatment option. The effectiveness of that combination was shown in a trial comparing the long-acting GLP-1 receptor agonist albiglutide with pre-meal insulin lispro in patients also treated with insulin glargine.12 That trial showed a much lower incidence of documented symptomatic hypoglycaemia with albiglutide (ie, 16%) than that reported by Blonde and colleagues, but also a substantially smaller reduction in HbA1c (–0·8%). The combination of dulaglutide with insulin glargine (or placebo) is being investigated in the ongoing AWARD-9 trial (ClinicalTrials.gov, number NCT02152371). Clearly, patient convenience is better with once-daily basal insulin than with thrice-daily mealtime insulin injections. Nevertheless, on the basis of the report by Blonde and colleagues,1 a long-acting GLP-1 receptor agonist combined with prandial insulin could be regarded as a treatment option for some patients. How the addition of prandial versus basal insulin to a long-acting GLP-1 receptor agonist directly compares in future trials will be interesting to see. Overall, the trial by Blonde and colleagues was done well. Bearing in mind the caveats
discussed, the results are of great clinical and academic interest by providing a novel perspective on treatment intensification in patients with type 2 diabetes. *Signe H Østoft, Mikkel Christensen Center for Diabetes Research, Department of Medicine, Gentofte Hospital (SHØ, MC) and Department of Clinical Pharmacology, Bispebjerg Hospital (MC), University of Copenhagen, Hellerup 2900, Denmark [email protected] We declare no competing interests. 1
2 3
4
5
6
7
8
9
10
11
12
Blonde L, Jendle J, Gross J, et al. Once-weekly dulaglutide versus bedtime insulin glargine, both in combination with prandial insulin lispro, in patients with type 2 diabetes (AWARD-4): a randomised, open-label, phase 3, non-inferiority study. Lancet 2015; 385: 2057–66. Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol 2012; 8: 728–42. Naver SV, Jimenez-Solem E, Christensen M, Andersen JT, Knop FK. Dulaglutide: a novel once-weekly glucagon-like peptide-1 receptor agonist. Clin Investig 2014; 4: 729–43. Kielgast U, Krarup T, Holst JJ, Madsbad S. Four weeks of treatment with liraglutide reduces insulin dose without loss of glycemic control in type 1 diabetic patients with and without residual beta-cell function. Diabetes Care 2011; 34: 1463–68. Hare KJ, Vilsbøll T, Asmar M, Deacon CF, Knop FK, Holst JJ. The glucagonostatic and insulinotropic effects of glucagon-like peptide 1 contribute equally to its glucose-lowering action. Diabetes 2010; 59: 1765–70. Umpierrez G, Tofé Povedano S, Pérez Manghi F, Shurzinske L, Pechtner V. Efficacy and safety of dulaglutide monotherapy versus metformin in type 2 diabetes in a randomized controlled trial (AWARD-3). Diabetes Care 2014; 37: 2168–76. Wysham C, Blevins T, Arakaki R, et al. Efficacy and safety of dulaglutide added onto pioglitazone and metformin versus exenatide in type 2 diabetes in a randomized controlled trial (AWARD-1). Diabetes Care 2014; 37: 2159–67. Nauck M, Weinstock RS, Umpierrez GE, Guerci B, Skrivanek Z, Milicevic Z. Efficacy and safety of dulaglutide versus sitagliptin after 52 weeks in type 2 diabetes in a randomized controlled trial (AWARD-5). Diabetes Care 2014; 37: 2149–58. Dungan KM, Povedano ST, Forst T, et al. Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial. Lancet 2014; 384: 1349–57. Fritsche A, Schweitzer MA, Häring H-U; the 4001 Study Group. Glimepiride combined with morning insulin glargine, bedtime neutral protamine hagedorn insulin, or bedtime insulin glargine in patients with type 2 diabetes: a randomized, controlled trial. Ann Intern Med 2003; 138: 952–59. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2015; 58: 429–42. Rosenstock J, Fonseca VA, Gross JL, et al. Advancing basal insulin replacement in type 2 diabetes inadequately controlled with insulin glargine plus oral agents: a comparison of adding albiglutide, a weekly GLP-1 receptor agonist, versus thrice-daily prandial insulin lispro. Diabetes Care 2014; 37: 2317–25.
DPP-4 inhibitors and risk of heart failure EXAMINEd Published Online March 10, 2015 http://dx.doi.org/10.1016/ S0140-6736(15)60037-X See Articles page 2067
2022
In The Lancet, Faiez Zannad and colleagues1 report on heart failure and mortality outcomes in patients taking alogliptin in a post-hoc analysis of the EXAMINE trial. This report has been eagerly awaited because, in October,
2013, two randomised, placebo-controlled trials, SAVOR TIMI 532 and EXAMINE,3 which assessed blood-glucose lowering with DPP-4 inhibitors, one with saxagliptin and one with alogliptin, reported cardiovascular outcomes. www.thelancet.com Vol 385 May 23, 2015
many trials. Palmer and colleagues’ findings will be helpful for designing future trials, including appropriate selection of patients, choice of antihypertensive regimen, and meaningful definitions of adverse outcomes. The Kidney Disease Improving Global Outcomes (KDIGO) classification and staging of acute kidney injury could serve as a guide for defining this adverse event in future research.13 Emerging treatments for hyperkalaemia are likely to improve the safety profile of RAAS blockers.14 About 350 million people in the world have diabetes.15 A substantial proportion of these individuals will develop end-stage kidney failure, which underscores the need for preventive treatments.3 Screening for albuminuria and prompt initiation of lifestyle and pharmacological interventions is likely to prevent progression of chronic kidney disease and cardiovascular disease.3 Addition of dual ACE inhibitor and ARB treatment to this multifactorial management approach—if confirmed to be efficacious and cost effective—might further improve patients’ outcomes in regions of the world where careful selection of patients and close monitoring are possible.
1
2
3
4 5 6
7 8 9 10
11 12
13 14
*Tazeen Hasan Jafar, Pryseley Nkouibert Assam Health Services and Systems Research (THJ) and Centre for Quantitative Medicine (PNA), Duke-NUS Graduate Medical School, Singapore 169857 [email protected]
15
Brancati FL, Whelton PK, Randall BL, Neaton JD, Stamler J, Klag MJ. Risk of end-stage renal disease in diabetes mellitus: a prospective cohort study of men screened for MRFIT. JAMA 1997; 278: 2069–74. Fox CS, Matsushita K, Woodward M, et al, for the Chronic Kidney Disease Prognosis Consortium. Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis. Lancet 2012; 380: 1662–73. Gansevoort RT, Correa-Rotter R, Hemmelgarn BR, et al. Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention. Lancet 2013; 382: 339–52. Fried LF, Emanuele N, Zhang JH, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med 2013; 369: 1892–903. Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358: 1547–59. Palmer SC, Mavridis D, Navarese E, et al. Comparative efficacy and safety of blood pressure-lowering agents in adults with diabetes and kidney disease: a network meta-analysis. Lancet 2015; 385: 2047–56. Gurley SB, Coffman TM. The renin-angiotensin system and diabetic nephropathy. Semin Nephrol 2007; 27: 144–52. Raebel MA, Ross C, Xu S, et al. Diabetes and drug-associated hyperkalemia: effect of potassium monitoring. J Gen Intern Med 2010; 25: 326–33. Anderson S, Eldadah B, Halter JB, et al. Acute kidney injury in older adults. J Am Soc Nephrol 2011; 22: 28–38. Chertow GM, Burdick E, Honour M, Bonventre JV, Bates DW. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol 2005; 16: 3365–70. Foley RN, Collins AJ. The USRDS: what you need to know about what it can and can’t tell us about ESRD. Clin J Am Soc Nephrol 2013; 8: 845–51. Inker LA, Levey AS, Pandya K, Stoycheff N, Okparavero A, Greene T. Early change in proteinuria as a surrogate end point for kidney disease progression: an individual patient meta-analysis. Am J Kidney Dis 2014; 64: 74–85. Thomas ME, Blaine C, Dawnay A, et al. The definition of acute kidney injury and its use in practice. Kidney Int 2015; 87: 62–73. Ingelfinger JR. A new era for the treatment of hyperkalemia? N Engl J Med 2015; 372: 275–77. Danaei G, Finucane MM, Lu Y, et al, on behalf of the Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group (Blood Glucose). National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2·7 million participants. Lancet 2011; 378: 31–40.
We declare no competing interests.
An alternative combination therapy for type 2 diabetes? See Articles page 2057
2020
In The Lancet, Lawrence Blonde and colleagues1 present data from a randomised controlled trial of the latest glucagon-like peptide-1 (GLP-1) receptor agonist. Dulaglutide has few known discriminating features compared with the other long-acting GLP-1 receptor agonists on the market with full diurnal GLP-1 activity.2,3 Yet, in the present trial, Blonde and colleagues have turned things upside down and tested this drug as an antihyperglycaemic backbone to pre-prandial shortacting insulin and metformin treatment in patients with type 2 diabetes. This combination of a GLP-1 receptor agonist and insulin has, until now, not been formally tested against the last resort of treatment intensification in patients with type 2 diabetes—namely, long-acting (basal) insulin and mealtime insulin.
The results are particularly interesting because the improvements in several safety and efficacy outcomes reported with dulaglutide (0·75 mg or 1·5 mg once weekly) plus mealtime insulin lispro (three times daily) were significantly greater than those with titrated insulin glargine (once daily) plus mealtime insulin lispro (three times daily). Recruited patients were already receiving insulin (up to two times a day) suggesting that most had deficits in insulin secretory capacity. Irrespective of these deficits, dulaglutide was effective. In our opinion, the glucagonostatic effect4,5 might be an important contributor to the retained efficacy of GLP-1 receptor agonists also in the later stages of type 2 diabetes. Unfortunately, an absence of glucagon data in Blonde and colleagues’ study1 www.thelancet.com Vol 385 May 23, 2015
precludes any appraisal of the contribution of glucagon suppression in this trial. 884 patients were randomly assigned to receive dulaglutide 1·5 mg (n=295) or 0·75 mg (n=293), or insulin glargine (n=296). In terms of the trial’s primary endpoint, dulaglutide 1·5 mg (as approved for add-on therapy) or 0·75 mg, plus insulin lispro, lowered glycated haemoglobin A1c (HbA1c) slightly more than did insulin glargine plus insulin lispro (–1·64% [95% CI –1·78 to –1·50], –17·93 mmol/mol [–19·44 to –16·42]; and –1·59% [–1·73 to –1·45], –17·38 mmol/mol [–18·89 to –15·87], respectively; vs –1·41% [–1·55 to –1·27], –15·41 mmol/ mol [–16·92 to –13·90]) after 26 weeks (below the predetermined clinically relevant non-inferiority margin of 0·4%). At 52 weeks, 9% more patients in the high-dose dulaglutide group than the glargine group achieved the HbA1c target of less than 7·0% (<53 mmol/mol): 161 (59%) patients in the high-dose dulaglutide group versus 138 (49%) patients in the insulin glargine group. Thus, 11 patients would have to be treated for 1 year with dulaglutide instead of insulin glargine for one additional patient to reach an HbA1c target of less than 7·0%. Not surprisingly, in the dulaglutide group, the mean total dose of insulin was lower, but insulin lispro doses were about 30% higher. Insulin lispro doses were about 90 units per day, which could explain why the effect of dulaglutide on weight reduction was less pronounced than in other trials.3,6–9 Nonetheless, compared with patients given insulin glargine, who had a mean weight gain of about 3·5 kg at 52 weeks, the weight neutrality of dulaglutide could be of importance to weight-conscious patients. Dulaglutide treatment was safe compared with insulin glargine. Patients in the dulaglutide groups had more adverse events than did those in the glargine groups, mainly the gastrointestinal side-effects that are well known from other GLP-1 receptor agonists. However, dulaglutide had fewer serious adverse events, mainly because of fewer occurrences of severe hypoglycaemia. In the high-dose dulaglutide group, ten (3%) patients had severe hypoglycaemia (defined as requiring assistance from others) versus 15 (5%) patients in the glargine group. Thus, 59 patients would have to be treated for 1 year with dulaglutide instead of glargine to prevent one case of severe hypoglycaemia. The finding of a lower event rate of total (any type) hypoglycaemia with dulaglutide versus glargine was mostly driven by rather large differences in nocturnal hypoglycaemia after both www.thelancet.com Vol 385 May 23, 2015
Ian Hooton/Science Photo Library
Comment
26 and 52 weeks. Blonde and colleagues1 also report safety endpoints of uncertain importance, such as slightly lowered systolic blood pressure at the expense of minor increases in heart rate; increases in circulating pancreatic enzymes, but with no events of adjudicated pancreatitis or pancreatic cancer; and slightly fewer cardiovascular events in the high-dose (n=5) and low-dose (n=6) dulaglutide groups compared with glargine (n=12). A limitation of Blonde and colleagues’ trial1 is the distance from the real-life situation. Thus, the exclusion of treatments other than metformin (roughly 75% of patients were receiving metformin), and abrupt intensification to insulin lispro three times a day to reach mean HbA1c values of about 6·5% (48 mmol/mol) after 13 weeks treatment, would, in many patients, probably not confer a positive risk–benefit balance and would thus be in conflict with present guidelines that advocate treatment individualisation and focus on avoidance of hypoglycaemia. This overtreatment is shown by the finding that about 80% of patients in all treatment groups had documented symptomatic hypoglycaemia at 26 weeks. Another limitation was the allowance of bedtime insulin glargine titration, which made blinding impossible. Actually, bedtime administration of glargine might have a marginally inferior risk–benefit balance compared with morning administration.10 Patients in the glargine group also had substantially lower mean nocturnal concentrations of plasma glucose than did those in the high-dose and low-dose dulaglutide groups (–2·36 vs –1·84 and –1·73 mmol/L, respectively). Thus, in view of the high rate of nocturnal hypoglycaemia, the bedtime glargine dosing was likely to have been 2021
Comment
too aggressive for some patients. The investigators could have addressed the effect of the trial design on hypoglycaemic events in more detail. A position statement on management of hyperglycaemia in patients with type 2 diabetes from the American Diabetes Association and the European Association for the Study of Diabetes11 recommends GLP-1 receptor agonists or mealtime insulin equally as add-on therapy to basal insulin, in patients with poor glucose control despite triple combination antidiabetic treatment. In such patients, many physicians would probably have tried a GLP-1 receptor agonist before beginning insulin therapy. Blonde and colleagues’ trial1 could raise the question of whether mealtime insulin should be initiated instead of basal insulin in a patient already receiving a GLP-1 receptor agonist. As indicated in the guideline,11 the combination of a long-acting GLP1 receptor agonist and basal insulin is a sound treatment option. The effectiveness of that combination was shown in a trial comparing the long-acting GLP-1 receptor agonist albiglutide with pre-meal insulin lispro in patients also treated with insulin glargine.12 That trial showed a much lower incidence of documented symptomatic hypoglycaemia with albiglutide (ie, 16%) than that reported by Blonde and colleagues, but also a substantially smaller reduction in HbA1c (–0·8%). The combination of dulaglutide with insulin glargine (or placebo) is being investigated in the ongoing AWARD-9 trial (ClinicalTrials.gov, number NCT02152371). Clearly, patient convenience is better with once-daily basal insulin than with thrice-daily mealtime insulin injections. Nevertheless, on the basis of the report by Blonde and colleagues,1 a long-acting GLP-1 receptor agonist combined with prandial insulin could be regarded as a treatment option for some patients. How the addition of prandial versus basal insulin to a long-acting GLP-1 receptor agonist directly compares in future trials will be interesting to see. Overall, the trial by Blonde and colleagues was done well. Bearing in mind the caveats
discussed, the results are of great clinical and academic interest by providing a novel perspective on treatment intensification in patients with type 2 diabetes. *Signe H Østoft, Mikkel Christensen Center for Diabetes Research, Department of Medicine, Gentofte Hospital (SHØ, MC) and Department of Clinical Pharmacology, Bispebjerg Hospital (MC), University of Copenhagen, Hellerup 2900, Denmark [email protected] We declare no competing interests. 1
2 3
4
5
6
7
8
9
10
11
12
Blonde L, Jendle J, Gross J, et al. Once-weekly dulaglutide versus bedtime insulin glargine, both in combination with prandial insulin lispro, in patients with type 2 diabetes (AWARD-4): a randomised, open-label, phase 3, non-inferiority study. Lancet 2015; 385: 2057–66. Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol 2012; 8: 728–42. Naver SV, Jimenez-Solem E, Christensen M, Andersen JT, Knop FK. Dulaglutide: a novel once-weekly glucagon-like peptide-1 receptor agonist. Clin Investig 2014; 4: 729–43. Kielgast U, Krarup T, Holst JJ, Madsbad S. Four weeks of treatment with liraglutide reduces insulin dose without loss of glycemic control in type 1 diabetic patients with and without residual beta-cell function. Diabetes Care 2011; 34: 1463–68. Hare KJ, Vilsbøll T, Asmar M, Deacon CF, Knop FK, Holst JJ. The glucagonostatic and insulinotropic effects of glucagon-like peptide 1 contribute equally to its glucose-lowering action. Diabetes 2010; 59: 1765–70. Umpierrez G, Tofé Povedano S, Pérez Manghi F, Shurzinske L, Pechtner V. Efficacy and safety of dulaglutide monotherapy versus metformin in type 2 diabetes in a randomized controlled trial (AWARD-3). Diabetes Care 2014; 37: 2168–76. Wysham C, Blevins T, Arakaki R, et al. Efficacy and safety of dulaglutide added onto pioglitazone and metformin versus exenatide in type 2 diabetes in a randomized controlled trial (AWARD-1). Diabetes Care 2014; 37: 2159–67. Nauck M, Weinstock RS, Umpierrez GE, Guerci B, Skrivanek Z, Milicevic Z. Efficacy and safety of dulaglutide versus sitagliptin after 52 weeks in type 2 diabetes in a randomized controlled trial (AWARD-5). Diabetes Care 2014; 37: 2149–58. Dungan KM, Povedano ST, Forst T, et al. Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial. Lancet 2014; 384: 1349–57. Fritsche A, Schweitzer MA, Häring H-U; the 4001 Study Group. Glimepiride combined with morning insulin glargine, bedtime neutral protamine hagedorn insulin, or bedtime insulin glargine in patients with type 2 diabetes: a randomized, controlled trial. Ann Intern Med 2003; 138: 952–59. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2015; 58: 429–42. Rosenstock J, Fonseca VA, Gross JL, et al. Advancing basal insulin replacement in type 2 diabetes inadequately controlled with insulin glargine plus oral agents: a comparison of adding albiglutide, a weekly GLP-1 receptor agonist, versus thrice-daily prandial insulin lispro. Diabetes Care 2014; 37: 2317–25.
DPP-4 inhibitors and risk of heart failure EXAMINEd Published Online March 10, 2015 http://dx.doi.org/10.1016/ S0140-6736(15)60037-X See Articles page 2067
2022
In The Lancet, Faiez Zannad and colleagues1 report on heart failure and mortality outcomes in patients taking alogliptin in a post-hoc analysis of the EXAMINE trial. This report has been eagerly awaited because, in October,
2013, two randomised, placebo-controlled trials, SAVOR TIMI 532 and EXAMINE,3 which assessed blood-glucose lowering with DPP-4 inhibitors, one with saxagliptin and one with alogliptin, reported cardiovascular outcomes. www.thelancet.com Vol 385 May 23, 2015