- Email: [email protected]
Liraglutide for weight loss in obese people
Correspondence
5
Kumar A, Zarychanski R, Pinto R, for the Canadian Critical Care Trials Group H1N1 Collaborative. Critically ill patients with 2009 influenza A(H1N1) infection in Canada. JAMA 2009; 302: 1872–79. Kahn JM, Asch RJ, Iwashyna TJ, et al. Physician attitudes toward regionalization of adult critical care: a national survey. Crit Care Med 2009; 37: 2149–54.
Authors’ reply In answer to Thilo Busch and colleagues, inhaled nitric oxide (iNO) was used to transport patients who were critically hypoxic or who developed recurrent hypoxia after weaning from extracorporeal membrane oxygenation (ECMO). We are not aware of any studies to show that iNO improves survival in adults. It remains to be seen whether an iNO-based algorithm would reduce the need for ECMO without compromising survival. We agree with Jayant Jainandunsing and Farouq Ismael that the molecular albumin recirculating system (MARS) was important in the ECMO group. MARS was not prohibited in the conventional group, but no centre elected to use it. It is possible that, by preventing death from respiratory failure, ECMO allowed patients to develop progressive multisystem and liver failure, which required MARS. We would like to clarify that sample-size adjustments were supported by the independent data monitoring committee on the basis of the primary endpoint of death or severe disability at 6 months. With the exception of data coordinating staff, who reported to the data monitoring committee, the trial team was unaware of the results of the study until after completion. In answer to Thomas Bein and colleagues, the incidence of serious adverse events in CESAR was about what we expect in our own normal institutional experience. Although CESAR patients received ECMO using roller pumps, they did not receive high anticoagulation. The evolution of newer extracorporeal systems such as interventional www.thelancet.com Vol 375 February 13, 2010
lung assist1 is interesting, but it is important to recognise their benefits and limitations—ie, interventional lung assist is a carbon dioxide removal device with a reported 10% incidence of leg ischaemia. We encourage workers to report their results to the Extracorporeal Life Support Organization. Finally, CESAR patients were significantly more hypoxic than those in the ARDS-Network study.2 This disorder precluded lung-protective ventilation for many patients in the conventional group. We refute the assertion that the conventionally treated patients in the ECMO group constitute a third group. Because of the strict minimisation and equality between the intervention and control groups, the control group must have contained a similar number of patients with equally “mild” respiratory failure. We agree with the conclusion that survival without severe disability at 6 months was better in the “transfer for consideration of ECMO” group than in the control group. We believe that high-frequency ventilation is useful in the treatment of severe respiratory failure and is complementary to ECMO in achieving lung-protective ventilation. GJP is a clinician who provides ECMO services. He also received a travel grant to present results of the CESAR trial at the Children’s National Medical Centre conference (February, 2008) from Chalice Medical. DE and MM declare that they have no conflicts of interest.
Liraglutide for weight loss in obese people Arne Astrup and colleagues (Nov 7, p 1606)1 report the results of a phase 2 trial in which liraglutide—an analogue of glucagon-like peptide 1 (GLP-1)— was shown to reduce bodyweight in obese patients in a dose-dependent manner. The proposed mode of action is through suppression of appetite and energy intake, and delayed gastric emptying. However, it is important to clarify the possible effect of adverse drug reactions on weight loss. The incidence of nausea and vomiting increased with dose from 24·2% and 4·2% in those who received 1·2 mg liraglutide daily, up to 47·3% and 11·8% in those who received 3·0 mg. These figures greatly exceeded those for orlistat and placebo, where nausea occurred in 4–5% and vomiting in 2%. To exclude the possibility that the greater weight loss associated with liraglutide treatment is not mainly a consequence of nausea and vomiting, a comparison of the change in bodyweight between patients who did and patients who did not experience these adverse drug reactions should be presented.
*Pär Hallberg, Sofie Schwan, Håkan Melhus [email protected]
*Giles J Peek, Diana Elbourne, Miranda Mugford [email protected]
1
1
2
Bein Th, Weber F, Philipp A, et al. A new pumpless extracorporeal interventional lung assist in critical hypoxemia/hypercapnia. Crit Care Med 2006; 34: 1372–77. Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000; 342: 1301–08.
For the Extracorporeal Life Support Organization website see http://www.elso.med.umich. edu/
PH received a scholarship in clinical pharmacology from MSD Sweden in 2005. SS and HM declare that they have no conflicts of interest.
Clinical Pharmacology, Uppsala University Hospital, 75185 Uppsala, Sweden (PH, HM); and Uppsala Drug Information Center, Uppsala County Council, Uppsala, Sweden (SS)
Glenfield Hospital, Leicester LE3 9QP, UK (GJP); London School of Hygiene and Tropical Medicine, London, UK (DE); and University of East Anglia, Norwich, UK (MM)
Photolibrary
4
Astrup A, Rössner S, Van Gaal L, et al, on behalf of the NN8022-1807 Study Group. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet 2009; 374: 1606–16.
Arne Astrup and colleagues1 report that treatment of obese individuals with liraglutide, an acylated analogue of glucagon-like peptide 1 (GLP-1), results in more weight loss than placebo or the lipase-inhibitor orlistat. Liraglutide is mainly indicated for the treatment of type 2 diabetes 551
Correspondence
mellitus, and in Astrup and colleagues’ study was used mostly in patients without established diabetes. The mechanism by which obesity lowers GLP-1 secretion is not known, but it is likely to be related to the development of insulin resistance that accompanies weight gain.2 In Astrup and colleagues’ trial, about a third of all obese individuals had a prediabetic status and metabolic syndrome characterised by increased insulin resistance, but the effects of liraglutide on weight loss in the subgroups of patients with and without metabolic syndrome are not reported. This is of importance because the potency of GLP-1 with respect to enhancing glucose-induced insulin secretion seems lower in patients with metabolic syndrome.3 Thus, the effects of GLP-1 analogues on weight loss may be much more effective in patients with metabolic syndrome than in “normal” obese individuals. However, the latter represent the majority. Additionally, whether this form of weight loss is harmful in selected patients, such as older people or those who are at increased cardiovascular risk, is not clear. Indeed, in a study of more than 15 000 patients, those classified as obese had better intermediate-term survival after acute coronary syndromes than patients with a normal body-mass index.4 In patients with chronic heart failure or other chronic illnesses, the relation between obesity and better survival, and between weight loss and impaired survival, is even stronger.5 We declare that we have no conflicts of interest.
*Thomas Thum, Stefan D Anker [email protected] Department of Molecular and Translational Therapeutic Strategies, Medical School Hannover, 30625 Hannover, Germany (TT); Applied Cachexia Research, Department of Cardiology, Charité Campus Virchow Klinikum, Berlin, Germany (SDA); and Centre for Clinical and Basic Research, IRCCS San Raffaele, Rome, Italy (SDA) 1
552
Astrup A, Rössner S, Van Gaal L, et al, on behalf of the NN8022-1807 Study Group. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet 2009; 374: 1606–16.
2
3
4
5
Rask E, Olsson T, Soderberg S, et al. Impaired incretin response after a mixed meal is associated with insulin resistance in nondiabetic men. Diabetes Care 2001; 24: 1640–45. Kjems LL, Holst JJ, Volund A, Madsbad S. The influence of GLP-1 on glucose-stimulated insulin secretion: effects on beta-cell sensitivity in type 2 and nondiabetic subjects. Diabetes 2003; 52: 380–86. Eisenstein EL, McGuire DK, Bhapkar MV, et al. Elevated body mass index and intermediateterm clinical outcomes after acute coronary syndromes. Am J Med 2005; 118: 981–90. von Haehling S, Horwich TB, Fonarow GC, Anker SD. Tipping the scale: heart failure, body mass index, and prognosis. Circulation 2007; 116: 588–90.
Authors’ reply Pär Hallberg and colleagues raise the very relevant question as to what extent the reduction in energy intake and resulting weight loss produced by analogues of glucagonlike peptide 1 (GLP-1) is brought about only by enhanced satiety and whether nausea or vomiting may also contribute. Stimulation of the GLP-1 receptor is known to produce dose-dependent enhanced satiety, and inhibition of energy intake at ad-libitum meals without nausea.1 At higher doses, GLP-1 receptor agonists produce nausea and vomiting, presumably through a transient effect on delayed gastric emptying. In patients with type 2 diabetes, higher doses of GLP-1 receptor agonists are consistently found to produce greater weight loss and more frequent nausea and vomiting2 than in patients without diabetes, and this result was also found in our trial of nondiabetic obese patients. We have now done a post-hoc analysis of weight loss for patients who had at least one adverse event of nausea or vomiting, compared with those who did not report either (table). Placebo
The difference in weight loss between individuals with nausea or vomiting and those without was only significant for the group taking liraglutide 3·0 mg (1·8 kg, p=0·04). The dosedependent weight loss produced by increasing doses of liraglutide was maintained for participants with (p=0·0002) and without nausea or vomiting (p<0·0001). Hence nausea and vomiting cannot be major contributors to the weight loss produced by GLP-1. Thomas Thum and Stefan Anker raise the interesting issue of whether there are subpopulations of obese individuals who may respond differently to treatment with GLP-1 receptor agonists. Liraglutide doses of up to 1·8 mg have been extensively investigated for glycaemic control in patients with type 2 diabetes, and the benefit–risk profile has proven favourable in a broad population of these patients.2 Our phase 2 dose-ranging trial was not powered to assess efficacy in subpopulations, but we have now done a post-hoc analysis. This analysis shows that the weight loss of individuals with metabolic syndrome was 2·9, 4·6, 4·7, and 8·1 kg for participants treated with placebo, orlistat, liraglutide 1·2 mg, and liraglutide 3·0 mg, respectively. For those without metabolic syndrome, weight loss was 3·1, 4·3, 5·3, and 7·3 kg (metabolic syndrome vs no metabolic syndrome: p=0·80, p=0·76, p=0·49, and p=0·38, respectively). There is therefore no evidence to support the suggestion that efficacy of liraglutide is different between obese individuals with metabolic syndrome and those without.
Liraglutide
Orlistat
1·2 mg
1·8 mg
2·4 mg
3·0 mg
n=6 –1·9 (1·4)
n=25 –5·2 (2·6)
n=30 –6·3 (4·8)
n=38 –7·3 (4·8)
n=48 –8·5 (4·4)
n=6 –3·4 (3·3)
Without nausea or n=92 vomiting –3·1 (3·4)
n=69 –5·1 (3·8)
n=60 –5·7 (5·0)
n=54 –6·1 (4·5)
n=44 –6·7 (4·6)
n=89 –4·5 (4·2)
With nausea or vomiting
Table: Mean (SD) weight loss (kg) in patients who reported at least one adverse event of nausea or vomiting, compared with those who did not report either
www.thelancet.com Vol 375 February 13, 2010
5
Kumar A, Zarychanski R, Pinto R, for the Canadian Critical Care Trials Group H1N1 Collaborative. Critically ill patients with 2009 influenza A(H1N1) infection in Canada. JAMA 2009; 302: 1872–79. Kahn JM, Asch RJ, Iwashyna TJ, et al. Physician attitudes toward regionalization of adult critical care: a national survey. Crit Care Med 2009; 37: 2149–54.
Authors’ reply In answer to Thilo Busch and colleagues, inhaled nitric oxide (iNO) was used to transport patients who were critically hypoxic or who developed recurrent hypoxia after weaning from extracorporeal membrane oxygenation (ECMO). We are not aware of any studies to show that iNO improves survival in adults. It remains to be seen whether an iNO-based algorithm would reduce the need for ECMO without compromising survival. We agree with Jayant Jainandunsing and Farouq Ismael that the molecular albumin recirculating system (MARS) was important in the ECMO group. MARS was not prohibited in the conventional group, but no centre elected to use it. It is possible that, by preventing death from respiratory failure, ECMO allowed patients to develop progressive multisystem and liver failure, which required MARS. We would like to clarify that sample-size adjustments were supported by the independent data monitoring committee on the basis of the primary endpoint of death or severe disability at 6 months. With the exception of data coordinating staff, who reported to the data monitoring committee, the trial team was unaware of the results of the study until after completion. In answer to Thomas Bein and colleagues, the incidence of serious adverse events in CESAR was about what we expect in our own normal institutional experience. Although CESAR patients received ECMO using roller pumps, they did not receive high anticoagulation. The evolution of newer extracorporeal systems such as interventional www.thelancet.com Vol 375 February 13, 2010
lung assist1 is interesting, but it is important to recognise their benefits and limitations—ie, interventional lung assist is a carbon dioxide removal device with a reported 10% incidence of leg ischaemia. We encourage workers to report their results to the Extracorporeal Life Support Organization. Finally, CESAR patients were significantly more hypoxic than those in the ARDS-Network study.2 This disorder precluded lung-protective ventilation for many patients in the conventional group. We refute the assertion that the conventionally treated patients in the ECMO group constitute a third group. Because of the strict minimisation and equality between the intervention and control groups, the control group must have contained a similar number of patients with equally “mild” respiratory failure. We agree with the conclusion that survival without severe disability at 6 months was better in the “transfer for consideration of ECMO” group than in the control group. We believe that high-frequency ventilation is useful in the treatment of severe respiratory failure and is complementary to ECMO in achieving lung-protective ventilation. GJP is a clinician who provides ECMO services. He also received a travel grant to present results of the CESAR trial at the Children’s National Medical Centre conference (February, 2008) from Chalice Medical. DE and MM declare that they have no conflicts of interest.
Liraglutide for weight loss in obese people Arne Astrup and colleagues (Nov 7, p 1606)1 report the results of a phase 2 trial in which liraglutide—an analogue of glucagon-like peptide 1 (GLP-1)— was shown to reduce bodyweight in obese patients in a dose-dependent manner. The proposed mode of action is through suppression of appetite and energy intake, and delayed gastric emptying. However, it is important to clarify the possible effect of adverse drug reactions on weight loss. The incidence of nausea and vomiting increased with dose from 24·2% and 4·2% in those who received 1·2 mg liraglutide daily, up to 47·3% and 11·8% in those who received 3·0 mg. These figures greatly exceeded those for orlistat and placebo, where nausea occurred in 4–5% and vomiting in 2%. To exclude the possibility that the greater weight loss associated with liraglutide treatment is not mainly a consequence of nausea and vomiting, a comparison of the change in bodyweight between patients who did and patients who did not experience these adverse drug reactions should be presented.
*Pär Hallberg, Sofie Schwan, Håkan Melhus [email protected]
*Giles J Peek, Diana Elbourne, Miranda Mugford [email protected]
1
1
2
Bein Th, Weber F, Philipp A, et al. A new pumpless extracorporeal interventional lung assist in critical hypoxemia/hypercapnia. Crit Care Med 2006; 34: 1372–77. Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000; 342: 1301–08.
For the Extracorporeal Life Support Organization website see http://www.elso.med.umich. edu/
PH received a scholarship in clinical pharmacology from MSD Sweden in 2005. SS and HM declare that they have no conflicts of interest.
Clinical Pharmacology, Uppsala University Hospital, 75185 Uppsala, Sweden (PH, HM); and Uppsala Drug Information Center, Uppsala County Council, Uppsala, Sweden (SS)
Glenfield Hospital, Leicester LE3 9QP, UK (GJP); London School of Hygiene and Tropical Medicine, London, UK (DE); and University of East Anglia, Norwich, UK (MM)
Photolibrary
4
Astrup A, Rössner S, Van Gaal L, et al, on behalf of the NN8022-1807 Study Group. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet 2009; 374: 1606–16.
Arne Astrup and colleagues1 report that treatment of obese individuals with liraglutide, an acylated analogue of glucagon-like peptide 1 (GLP-1), results in more weight loss than placebo or the lipase-inhibitor orlistat. Liraglutide is mainly indicated for the treatment of type 2 diabetes 551
Correspondence
mellitus, and in Astrup and colleagues’ study was used mostly in patients without established diabetes. The mechanism by which obesity lowers GLP-1 secretion is not known, but it is likely to be related to the development of insulin resistance that accompanies weight gain.2 In Astrup and colleagues’ trial, about a third of all obese individuals had a prediabetic status and metabolic syndrome characterised by increased insulin resistance, but the effects of liraglutide on weight loss in the subgroups of patients with and without metabolic syndrome are not reported. This is of importance because the potency of GLP-1 with respect to enhancing glucose-induced insulin secretion seems lower in patients with metabolic syndrome.3 Thus, the effects of GLP-1 analogues on weight loss may be much more effective in patients with metabolic syndrome than in “normal” obese individuals. However, the latter represent the majority. Additionally, whether this form of weight loss is harmful in selected patients, such as older people or those who are at increased cardiovascular risk, is not clear. Indeed, in a study of more than 15 000 patients, those classified as obese had better intermediate-term survival after acute coronary syndromes than patients with a normal body-mass index.4 In patients with chronic heart failure or other chronic illnesses, the relation between obesity and better survival, and between weight loss and impaired survival, is even stronger.5 We declare that we have no conflicts of interest.
*Thomas Thum, Stefan D Anker [email protected] Department of Molecular and Translational Therapeutic Strategies, Medical School Hannover, 30625 Hannover, Germany (TT); Applied Cachexia Research, Department of Cardiology, Charité Campus Virchow Klinikum, Berlin, Germany (SDA); and Centre for Clinical and Basic Research, IRCCS San Raffaele, Rome, Italy (SDA) 1
552
Astrup A, Rössner S, Van Gaal L, et al, on behalf of the NN8022-1807 Study Group. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet 2009; 374: 1606–16.
2
3
4
5
Rask E, Olsson T, Soderberg S, et al. Impaired incretin response after a mixed meal is associated with insulin resistance in nondiabetic men. Diabetes Care 2001; 24: 1640–45. Kjems LL, Holst JJ, Volund A, Madsbad S. The influence of GLP-1 on glucose-stimulated insulin secretion: effects on beta-cell sensitivity in type 2 and nondiabetic subjects. Diabetes 2003; 52: 380–86. Eisenstein EL, McGuire DK, Bhapkar MV, et al. Elevated body mass index and intermediateterm clinical outcomes after acute coronary syndromes. Am J Med 2005; 118: 981–90. von Haehling S, Horwich TB, Fonarow GC, Anker SD. Tipping the scale: heart failure, body mass index, and prognosis. Circulation 2007; 116: 588–90.
Authors’ reply Pär Hallberg and colleagues raise the very relevant question as to what extent the reduction in energy intake and resulting weight loss produced by analogues of glucagonlike peptide 1 (GLP-1) is brought about only by enhanced satiety and whether nausea or vomiting may also contribute. Stimulation of the GLP-1 receptor is known to produce dose-dependent enhanced satiety, and inhibition of energy intake at ad-libitum meals without nausea.1 At higher doses, GLP-1 receptor agonists produce nausea and vomiting, presumably through a transient effect on delayed gastric emptying. In patients with type 2 diabetes, higher doses of GLP-1 receptor agonists are consistently found to produce greater weight loss and more frequent nausea and vomiting2 than in patients without diabetes, and this result was also found in our trial of nondiabetic obese patients. We have now done a post-hoc analysis of weight loss for patients who had at least one adverse event of nausea or vomiting, compared with those who did not report either (table). Placebo
The difference in weight loss between individuals with nausea or vomiting and those without was only significant for the group taking liraglutide 3·0 mg (1·8 kg, p=0·04). The dosedependent weight loss produced by increasing doses of liraglutide was maintained for participants with (p=0·0002) and without nausea or vomiting (p<0·0001). Hence nausea and vomiting cannot be major contributors to the weight loss produced by GLP-1. Thomas Thum and Stefan Anker raise the interesting issue of whether there are subpopulations of obese individuals who may respond differently to treatment with GLP-1 receptor agonists. Liraglutide doses of up to 1·8 mg have been extensively investigated for glycaemic control in patients with type 2 diabetes, and the benefit–risk profile has proven favourable in a broad population of these patients.2 Our phase 2 dose-ranging trial was not powered to assess efficacy in subpopulations, but we have now done a post-hoc analysis. This analysis shows that the weight loss of individuals with metabolic syndrome was 2·9, 4·6, 4·7, and 8·1 kg for participants treated with placebo, orlistat, liraglutide 1·2 mg, and liraglutide 3·0 mg, respectively. For those without metabolic syndrome, weight loss was 3·1, 4·3, 5·3, and 7·3 kg (metabolic syndrome vs no metabolic syndrome: p=0·80, p=0·76, p=0·49, and p=0·38, respectively). There is therefore no evidence to support the suggestion that efficacy of liraglutide is different between obese individuals with metabolic syndrome and those without.
Liraglutide
Orlistat
1·2 mg
1·8 mg
2·4 mg
3·0 mg
n=6 –1·9 (1·4)
n=25 –5·2 (2·6)
n=30 –6·3 (4·8)
n=38 –7·3 (4·8)
n=48 –8·5 (4·4)
n=6 –3·4 (3·3)
Without nausea or n=92 vomiting –3·1 (3·4)
n=69 –5·1 (3·8)
n=60 –5·7 (5·0)
n=54 –6·1 (4·5)
n=44 –6·7 (4·6)
n=89 –4·5 (4·2)
With nausea or vomiting
Table: Mean (SD) weight loss (kg) in patients who reported at least one adverse event of nausea or vomiting, compared with those who did not report either
www.thelancet.com Vol 375 February 13, 2010