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% (
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% (
