Correspondence
Incidence of hypoglycaemia (%)
35 30 25 20 15 10 5 0 No sulfonylurea, no linagliptin
Sulfonylurea, no linagliptin
Linagliptin, no sulfonylurea
Sulfonylurea and linagliptin
Figure: Incidence of hypoglycaemia by treatment received Data are from reference 1.
but in the results section, it seems that only one patient discontinued because of side-effects. I declare that I have no conflicts of interest.
Rahman Shah [email protected] Departement of Cardiology, University of Tennessee, Memphis, TN 38104, USA 1
2
Barnett AH, Huisman H, Jones R, von Eynatten M, Patel S, Woerle HJ. Linagliptin for patients aged 70 years or older with type 2 diabetes inadequately controlled with common antidiabetes treatments: a randomised, double-blind, placebo-controlled trial. Lancet 2013; 382: 1413–23. Sibbald B, Roland M. Understanding controlled trials. Why are randomised controlled trials important? BMJ 1998; 316: 201.
Anthony Barnett and colleagues1 recently reported the results of a trial comparing linagliptin with placebo in elderly patients with type 2 diabetes. They note that the higher incidence of hypoglycaemia with linagliptin, although not statistically significant, was mainly recorded in patients receiving sulfonylureas; hypoglycaemia was much the same between groups in patients not receiving sulfonylureas. The authors conclude that hypoglycaemia in patients receiving linagliptin is driven by sulfonylureas. However, it could similarly be argued that an excess of hypoglycaemia in patients receiving sulfonylureas is driven by linagliptin, because this excess is observed when both drugs are associated. This can be seen in Barnett and colleagues’ figure 5,1 and more easily if we present the same data as shown in our figure. www.thelancet.com Vol 383 January 25, 2014
It is expected that drugs stimulating insulin secretion induce hypoglycaemia and that giving two of these drugs increases the risk. Barnett and colleagues’1 safety results confirm that giving both linagliptin and sulfonylureas has an increased risk of hypoglycaemia that should be considered carefully in elderly patients. This finding should not be minimised because of statistical interpretation, but should be emphasised because it is of clinical importance. FS is a consultant for YOLARx Consultants. NM has received honoraria from Pfizer, Servier, Pierre Fabre, Roche, Merck Serono, Novartis, AstraZeneca, Abbott, Axcan, Bristol-Myers Squibb, Celgene, Cephalon, Vivatec, Lundbeck, GlaxoSmithKline, Leo Pharma, Helsinn Healthcare, Orion, Genevrier, Takeda, Sanofi, and Johnson and Johnson. AP declares that he has no conflicts of interest.
*Francesco Salvo, Nicholas Moore, Antoine Pariente [email protected] Université Bordeaux Segalen, Bordeaux 33076, France 1
Barnett AH, Huisman H, Jones R, von Eynatten M, Patel S, Woerle HJ. Linagliptin for patients aged 70 years or older with type 2 diabetes inadequately controlled with common antidiabetes treatments: a randomised, double-blind, placebo-controlled trial. Lancet 2013; 382: 1413–23.
Authors’ reply We read with interest the Comment by Alan Sinclair and John Morley,1 and the Correspondences from Tomohide Yamada, Rahman Shah, and Francesco Salvo and colleagues on our Article2 describing a randomised study of linagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, in
elderly patients (≥70 years) with type 2 diabetes. Although we largely agree with Sinclair and Morley’s comments, we would like to offer the following observations. They challenge the necessity of lowering glycated haemoglobin A 1c (HbA 1c) levels towards 7·0% and indicate that such attempts might lead to harmful overall outcomes in elderly patients. This argument reflects the current debate regarding the appropriate target for glycaemic control in older adults. There is general consensus that hyperglycaemia leading to symptoms or risk of acute hyperglycaemic complications should be avoided in all patients. Beyond this concept, however, the scarcity of clinical studies in elderly patients means that guideline recommendations remain vague. Thus, recommendations are based on individualised assessments of the likely benefit to risk profile of the intervention. These assessments should consider factors such as succeptibility to hypoglycaemia, ability to self-manage, presence or absence of other disorders, cognitive status, and life expectancy of the patient.3 Recent evidence, however, has linked hyperglycaemia to an increased risk of dementia,4 an observation that might argue against generally higher targets for HbA1c in elderly people. Moreover, the general concern about stricter HbA1c control is largely based on studies that used glucose-lowering drugs with relatively high risk of hypoglycaemia. Thus, hypoglycaemia might outweigh the benefits of intensive glycaemic control, particularly in patients of older age and frail.5 This illustrates the dilemma of poor health outcomes with either hyperglycaemia or hypoglycaemia in older adults with diabetes. This burden, however, might be alleviated by using pharmacotherapies that could improve glycaemic control with low risk of hypoglycaemia or other adverse effects. We thus concur with Sinclair and Morley that 307
Correspondence
Science Source/Science Photo Library
future research into management of elderly patients with diabetes should consider the specific needs of this population and identify safe and efficacious treatment options. Similarly, we agree with Yamada that physicians should carefully consider the benefits and risks of treatments in elderly patients and base treatment decisions on individualised goals. Shah challenges our conclusion on the overall safety profile of linagliptin. However, few patients had drug-related adverse events, or serious adverse events, or had to discontinue due to adverse events; and the small differences between the linagliptin and placebo groups might have been due to chance. Given that the overall incidence of adverse events in this vulnerable patient population was almost identical in each treatment group, we believe that our interpretation of linagliptin’s tolerability profile is consistent with the data presented. We also believe that the safety results support a positive benefit to risk profile for linagliptin in elderly patients with type 2 diabetes. With regard to discontinuations in the linagliptin group, eight patients discontinued because of adverse events but only in one patient was the adverse event considered to be drug-related by the investigator responsible—as described in the Article. We agree with Salvo and colleagues that the combination of linagliptin with a sulfonylurea might increase the risk of hypoglycaemia. This contrasts with the lack of increase in risk when linagliptin is combined with glucose-lowering drugs not acting as insulin secretagogues, or used as monotherapy. In fact, this same event applies to all incretinbased therapies, probably because of a pharmacodynamic interaction whereby sulfonylureas uncouple glucose-dependence from the insulinotropic action of glucagonlike peptide-1 (GLP1).6 Hence, the prescribing information for all incretin 308
therapies—including DPP4 inhibitors and GLP1 receptor agonists—states that reducing the dosage of any concomitant sulfonylurea should be considered to reduce the risk of hypoglycaemia. In our opinion, sulfonylureas must only be used with great caution in the elderly, particularly in those with concomitant renal impairment, because of the inherent risk of hypoglycaemia. The finding that hypoglycaemia rates with linagliptin were no greater than those with placebo in the absence of sulfonylurea strongly suggests that DPP4 inhibitors should be used as alternatives to sulfonylureas in older adults rather than in combination with sulfonylureas. Of note, sulfonylurea-induced hypoglycaemia is one of the main causes of emergency hospital admissions for iatrogenic adverse events in this vulnerable population.7 AHB has received honoraria for lectures and advisory work from Boehringer Ingelheim (manufacturer of linagliptin), MSD, Novartis, Bristol-Myers Squibb, AstraZeneca, Takeda, Eli Lilly, Novo Nordisk, and Sanofi-Aventis. MvE, SP, and H-JW are employees of Boehringer Ingelheim. We thank Giles Brooke (Envision Scientific Solutions, Horsham, UK), supported financially by Boehringer Ingelheim, for writing assistance.
*Anthony H Barnett, Maximilian von Eynatten, Sanjay Patel, Hans-Juergen Woerle [email protected] Diabetes Centre, Heart of England NHS Foundation Trust, and University of Birmingham, Birmingham, B9 5SS, UK (AHB); Boehringer Ingelheim, Ingelheim, Germany (MvE, H-JW); and Boehringer Ingelheim, Bracknell, UK (SP) 1 2
3
4
Sinclair A, Morley J. Frailty and diabetes. Lancet 2013; 382: 1386-87. Barnett AH, Huisman H, Jones R, von Eynatten M, Patel S, Woerle HJ. Linagliptin for patients aged 70 years or older with type 2 diabetes inadequately controlled with common antidiabetes treatments: a randomised, double-blind, placebo-controlled trial. Lancet 2013; 382: 1413–23. Sinclair AJ, Paolisso G, Castro M, Bourdel-Marchasson I, Gadsby R, Rodriguez Manas L. European Diabetes Working Party for Older People 2011 clinical guidelines for type 2 diabetes mellitus. Executive summary. Diabetes Metab 2011; 37: S27–38. Crane PK, Walker R, Hubbard RA, et al. Glucose levels and risk of dementia. N Engl J Med 2013; 369: 540–48.
5
6
7
Skyler JS, Bergenstal R, Bonow RO, et al. Intensive glycemic 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 American College of Cardiology Foundation and the American Heart Association. Diabetes Care 2009; 32: 187–92. de Heer J, Holst JJ. Sulfonylurea compounds uncouple the glucose dependence of the insulinotropic effect of glucagon-like peptide 1. Diabetes 2007; 56: 438–43. Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med 2011; 365: 2002–12.
Department of Error Kuppermann N, Holmes JF, Dayan PS, et al, for the Pediatric Emergency Care Applied Research Network (PECARN). Identification of children at very low risk of clinically-important brain injuries after head trauma: a prospective cohort study. Lancet 2009; 374: 1160–70—In this Article (Oct 3) an error in construction of the final analytical database led to the incorrect classification of the mechanism of injury as moderate, rather than severe, for 394 of 42 412 patients. This error had minor effects on the severity of injury mechanism sections of tables 1, 2, and 3, figures 2 and 3, and data within the Summary and main text. Additionally, the order of variables in the decision tree for patients 2 years or older changed slightly—in particular, the mechanism of injury and basilar skull fracture decision nodes switched order in the rule. None of the children with a clinically important traumatic brain injury (ciTBI) had their classifications affected by this data error. Thus, the sensitivities of the rules presented, and other important details, such as numbers and descriptions of the children with ciTBIs who were incorrectly classified, remain unchanged, as does the conclusion that CT can be omitted in children at low risk of ciTBI. Additionally, figure 3 has slight numerical changes that do not affect the interpretation of the rules. These corrections have been made to the online version as of Jan 24, 2014. Smolen JS, Emery P, Fleischmann R, et al. Adjustment of therapy in rheumatoid arthritis on the basis of achievement of stable low disease activity with adalimumab plus methotrexate or methotrexate alone: the randomised controlled OPTIMA trial. Lancet 2014; 383: 321–32—In figure 2 of this Article (published online first on Oct 26, 2013), the y axis values of parts (C), (E), and (F) were incorrect—the correct values were 0, 20, 40, 60, 80, and 100. This correction has been made to the printed Article, and to the online version as of Jan 24, 2014.
www.thelancet.com Vol 383 January 25, 2014
Incidence of hypoglycaemia (%)
35 30 25 20 15 10 5 0 No sulfonylurea, no linagliptin
Sulfonylurea, no linagliptin
Linagliptin, no sulfonylurea
Sulfonylurea and linagliptin
Figure: Incidence of hypoglycaemia by treatment received Data are from reference 1.
but in the results section, it seems that only one patient discontinued because of side-effects. I declare that I have no conflicts of interest.
Rahman Shah [email protected] Departement of Cardiology, University of Tennessee, Memphis, TN 38104, USA 1
2
Barnett AH, Huisman H, Jones R, von Eynatten M, Patel S, Woerle HJ. Linagliptin for patients aged 70 years or older with type 2 diabetes inadequately controlled with common antidiabetes treatments: a randomised, double-blind, placebo-controlled trial. Lancet 2013; 382: 1413–23. Sibbald B, Roland M. Understanding controlled trials. Why are randomised controlled trials important? BMJ 1998; 316: 201.
Anthony Barnett and colleagues1 recently reported the results of a trial comparing linagliptin with placebo in elderly patients with type 2 diabetes. They note that the higher incidence of hypoglycaemia with linagliptin, although not statistically significant, was mainly recorded in patients receiving sulfonylureas; hypoglycaemia was much the same between groups in patients not receiving sulfonylureas. The authors conclude that hypoglycaemia in patients receiving linagliptin is driven by sulfonylureas. However, it could similarly be argued that an excess of hypoglycaemia in patients receiving sulfonylureas is driven by linagliptin, because this excess is observed when both drugs are associated. This can be seen in Barnett and colleagues’ figure 5,1 and more easily if we present the same data as shown in our figure. www.thelancet.com Vol 383 January 25, 2014
It is expected that drugs stimulating insulin secretion induce hypoglycaemia and that giving two of these drugs increases the risk. Barnett and colleagues’1 safety results confirm that giving both linagliptin and sulfonylureas has an increased risk of hypoglycaemia that should be considered carefully in elderly patients. This finding should not be minimised because of statistical interpretation, but should be emphasised because it is of clinical importance. FS is a consultant for YOLARx Consultants. NM has received honoraria from Pfizer, Servier, Pierre Fabre, Roche, Merck Serono, Novartis, AstraZeneca, Abbott, Axcan, Bristol-Myers Squibb, Celgene, Cephalon, Vivatec, Lundbeck, GlaxoSmithKline, Leo Pharma, Helsinn Healthcare, Orion, Genevrier, Takeda, Sanofi, and Johnson and Johnson. AP declares that he has no conflicts of interest.
*Francesco Salvo, Nicholas Moore, Antoine Pariente [email protected] Université Bordeaux Segalen, Bordeaux 33076, France 1
Barnett AH, Huisman H, Jones R, von Eynatten M, Patel S, Woerle HJ. Linagliptin for patients aged 70 years or older with type 2 diabetes inadequately controlled with common antidiabetes treatments: a randomised, double-blind, placebo-controlled trial. Lancet 2013; 382: 1413–23.
Authors’ reply We read with interest the Comment by Alan Sinclair and John Morley,1 and the Correspondences from Tomohide Yamada, Rahman Shah, and Francesco Salvo and colleagues on our Article2 describing a randomised study of linagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, in
elderly patients (≥70 years) with type 2 diabetes. Although we largely agree with Sinclair and Morley’s comments, we would like to offer the following observations. They challenge the necessity of lowering glycated haemoglobin A 1c (HbA 1c) levels towards 7·0% and indicate that such attempts might lead to harmful overall outcomes in elderly patients. This argument reflects the current debate regarding the appropriate target for glycaemic control in older adults. There is general consensus that hyperglycaemia leading to symptoms or risk of acute hyperglycaemic complications should be avoided in all patients. Beyond this concept, however, the scarcity of clinical studies in elderly patients means that guideline recommendations remain vague. Thus, recommendations are based on individualised assessments of the likely benefit to risk profile of the intervention. These assessments should consider factors such as succeptibility to hypoglycaemia, ability to self-manage, presence or absence of other disorders, cognitive status, and life expectancy of the patient.3 Recent evidence, however, has linked hyperglycaemia to an increased risk of dementia,4 an observation that might argue against generally higher targets for HbA1c in elderly people. Moreover, the general concern about stricter HbA1c control is largely based on studies that used glucose-lowering drugs with relatively high risk of hypoglycaemia. Thus, hypoglycaemia might outweigh the benefits of intensive glycaemic control, particularly in patients of older age and frail.5 This illustrates the dilemma of poor health outcomes with either hyperglycaemia or hypoglycaemia in older adults with diabetes. This burden, however, might be alleviated by using pharmacotherapies that could improve glycaemic control with low risk of hypoglycaemia or other adverse effects. We thus concur with Sinclair and Morley that 307
Correspondence
Science Source/Science Photo Library
future research into management of elderly patients with diabetes should consider the specific needs of this population and identify safe and efficacious treatment options. Similarly, we agree with Yamada that physicians should carefully consider the benefits and risks of treatments in elderly patients and base treatment decisions on individualised goals. Shah challenges our conclusion on the overall safety profile of linagliptin. However, few patients had drug-related adverse events, or serious adverse events, or had to discontinue due to adverse events; and the small differences between the linagliptin and placebo groups might have been due to chance. Given that the overall incidence of adverse events in this vulnerable patient population was almost identical in each treatment group, we believe that our interpretation of linagliptin’s tolerability profile is consistent with the data presented. We also believe that the safety results support a positive benefit to risk profile for linagliptin in elderly patients with type 2 diabetes. With regard to discontinuations in the linagliptin group, eight patients discontinued because of adverse events but only in one patient was the adverse event considered to be drug-related by the investigator responsible—as described in the Article. We agree with Salvo and colleagues that the combination of linagliptin with a sulfonylurea might increase the risk of hypoglycaemia. This contrasts with the lack of increase in risk when linagliptin is combined with glucose-lowering drugs not acting as insulin secretagogues, or used as monotherapy. In fact, this same event applies to all incretinbased therapies, probably because of a pharmacodynamic interaction whereby sulfonylureas uncouple glucose-dependence from the insulinotropic action of glucagonlike peptide-1 (GLP1).6 Hence, the prescribing information for all incretin 308
therapies—including DPP4 inhibitors and GLP1 receptor agonists—states that reducing the dosage of any concomitant sulfonylurea should be considered to reduce the risk of hypoglycaemia. In our opinion, sulfonylureas must only be used with great caution in the elderly, particularly in those with concomitant renal impairment, because of the inherent risk of hypoglycaemia. The finding that hypoglycaemia rates with linagliptin were no greater than those with placebo in the absence of sulfonylurea strongly suggests that DPP4 inhibitors should be used as alternatives to sulfonylureas in older adults rather than in combination with sulfonylureas. Of note, sulfonylurea-induced hypoglycaemia is one of the main causes of emergency hospital admissions for iatrogenic adverse events in this vulnerable population.7 AHB has received honoraria for lectures and advisory work from Boehringer Ingelheim (manufacturer of linagliptin), MSD, Novartis, Bristol-Myers Squibb, AstraZeneca, Takeda, Eli Lilly, Novo Nordisk, and Sanofi-Aventis. MvE, SP, and H-JW are employees of Boehringer Ingelheim. We thank Giles Brooke (Envision Scientific Solutions, Horsham, UK), supported financially by Boehringer Ingelheim, for writing assistance.
*Anthony H Barnett, Maximilian von Eynatten, Sanjay Patel, Hans-Juergen Woerle [email protected] Diabetes Centre, Heart of England NHS Foundation Trust, and University of Birmingham, Birmingham, B9 5SS, UK (AHB); Boehringer Ingelheim, Ingelheim, Germany (MvE, H-JW); and Boehringer Ingelheim, Bracknell, UK (SP) 1 2
3
4
Sinclair A, Morley J. Frailty and diabetes. Lancet 2013; 382: 1386-87. Barnett AH, Huisman H, Jones R, von Eynatten M, Patel S, Woerle HJ. Linagliptin for patients aged 70 years or older with type 2 diabetes inadequately controlled with common antidiabetes treatments: a randomised, double-blind, placebo-controlled trial. Lancet 2013; 382: 1413–23. Sinclair AJ, Paolisso G, Castro M, Bourdel-Marchasson I, Gadsby R, Rodriguez Manas L. European Diabetes Working Party for Older People 2011 clinical guidelines for type 2 diabetes mellitus. Executive summary. Diabetes Metab 2011; 37: S27–38. Crane PK, Walker R, Hubbard RA, et al. Glucose levels and risk of dementia. N Engl J Med 2013; 369: 540–48.
5
6
7
Skyler JS, Bergenstal R, Bonow RO, et al. Intensive glycemic 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 American College of Cardiology Foundation and the American Heart Association. Diabetes Care 2009; 32: 187–92. de Heer J, Holst JJ. Sulfonylurea compounds uncouple the glucose dependence of the insulinotropic effect of glucagon-like peptide 1. Diabetes 2007; 56: 438–43. Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med 2011; 365: 2002–12.
Department of Error Kuppermann N, Holmes JF, Dayan PS, et al, for the Pediatric Emergency Care Applied Research Network (PECARN). Identification of children at very low risk of clinically-important brain injuries after head trauma: a prospective cohort study. Lancet 2009; 374: 1160–70—In this Article (Oct 3) an error in construction of the final analytical database led to the incorrect classification of the mechanism of injury as moderate, rather than severe, for 394 of 42 412 patients. This error had minor effects on the severity of injury mechanism sections of tables 1, 2, and 3, figures 2 and 3, and data within the Summary and main text. Additionally, the order of variables in the decision tree for patients 2 years or older changed slightly—in particular, the mechanism of injury and basilar skull fracture decision nodes switched order in the rule. None of the children with a clinically important traumatic brain injury (ciTBI) had their classifications affected by this data error. Thus, the sensitivities of the rules presented, and other important details, such as numbers and descriptions of the children with ciTBIs who were incorrectly classified, remain unchanged, as does the conclusion that CT can be omitted in children at low risk of ciTBI. Additionally, figure 3 has slight numerical changes that do not affect the interpretation of the rules. These corrections have been made to the online version as of Jan 24, 2014. Smolen JS, Emery P, Fleischmann R, et al. Adjustment of therapy in rheumatoid arthritis on the basis of achievement of stable low disease activity with adalimumab plus methotrexate or methotrexate alone: the randomised controlled OPTIMA trial. Lancet 2014; 383: 321–32—In figure 2 of this Article (published online first on Oct 26, 2013), the y axis values of parts (C), (E), and (F) were incorrect—the correct values were 0, 20, 40, 60, 80, and 100. This correction has been made to the printed Article, and to the online version as of Jan 24, 2014.
www.thelancet.com Vol 383 January 25, 2014
