NEWS & VIEWS OBESITY
A new paradigm for treating obesity and diabetes mellitus André J. Scheen and Nicolas Paquot Refers to Finan, B. et al. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat. Med. 21, 27–36 (2015)
An innovative strategy that uses a well-balanced monomeric peptide triagonist to target three metabolically related hormone receptors has been developed. This strategy seems to be the most effective pharmacological approach to reverse obesity and its metabolic comorbidities in rodents and could open new ways to tackle the dual burden of obesity and diabetes mellitus in humans. The management of patients with obesity and type 2 diabetes mellitus (T2DM) is challenging in clinical practice. The recurrent failure of lifestyle changes and available pharmacological approaches in the management of these patients has led to many patients undergoing bariatric surgery and has stimulated the search for new pharmacological strategies.1
‘‘
…this … strategy has the potential to reverse obesity and related metabolic disorders
’’
Finan and colleagues have reported the discovery of a new agonist that simultaneously targets three key metabolically related peptide hormone receptors—the receptors for glucagon-like peptide 1 (GLP‑1), glucose-d ependent insulinotropic polypeptide (GIP) and glucagon (Figure 1). 2 This monomeric peptide exerts a balanced agonist effect and was proved to be remarkably effective at reducing body weight, improving glucose control and reversing hepatic steatosis in various rodent models of either diet-induced or genetically determined obesity and/or diabetes mellitus. Through elegant studies in which knockout mice for the individual receptors were used, Finan and colleagues were able to demonstrate that the unimolecular tri agonist targeted each of the three receptors.2 The researchers were also able to ascertain how much blocking each receptor contributed to the overall metabolic benefits of the
monomeric peptide. They found that the overall metabolic efficacy of the new drug predominantly resulted from synergistic glucagon action that increased energy expenditure, GLP‑1 action that reduced caloric intake and improved glucose control and GIP action that potentiated the socalled incretin effect. Interestingly, the last two actions buffer against the diabetogenic effect of the inherent glucagon-mimicking activity of the peptide. Thus, these preclinical studies in rodents suggest that this unimolecular, polypharmaceutical strategy has the potential to reverse obesity and related metabolic disorders.2 Further studies should confirm whether this innovative pharmaco logical approach, which proved superior to therapy with any existing dual coagonists and best-in-class monoagonists in rodents, might be effective and safe for the treatment of obesity and T2DM in humans and thus ultimately offer a valuable pharmacological alternative to bariatric surgery.3 The dramatic rise of the twin epidemics of T2DM and obesity is associated with increased mortality and morbidity and is one of the most important public-health challenges worldwide. 1 Striking parallel increases in the prevalence of the two entities reflect the importance of body fatness as a contributing factor to the incidence of T2DM and its complications. Despite the importance of strategies to control weight in the prevention and management of T2DM, long-term results with lifestyle or available drug interventions are generally dis appointing.1 Notably, therapeutic attempts
NATURE REVIEWS | ENDOCRINOLOGY
GLP-1 ■ Enhanced insulin secretion (incretin effect) ■ Reduced glucagon secretion ■ Anorectic effects GIP Triagonist ■ Enhanced insulin secretion ■ (incretin effect) ■ Buffered ■ diabetogenic effects of glucagon
Glucagon Increased hepatic glucose production Increased energy expenditure
Figure 1 | Complementary (but also Nature Reviews | Endocrinology opposing) effects of the individual components of a peptide triagonist targeting GLP‑1, GIP and glucagon receptors that could be used to treat obesity and type 2 diabetes mellitus. Abbreviations: GIP, glucosedependent insulinotropic polypeptide; GLP‑1, glucagon-like peptide 1.
to normalize body weight and glycaemia with single agents have generally had poor results.1 Furthermore, most of the classic glucose-lowering agents are accompanied by weight gain, which increases the challenge of managing most individuals with T2DM who are overweight or have obesity.1 Incretin-based therapies are increasingly being used in clinical practice for the management of T2DM. 4 The dipep tidyl peptidase 4 (DPP‑4) enzyme rapidly degrades GLP‑1 and GIP, two gastrointestinal hormones that potentiate insulin secretion in response to a meal.4 Therapeutic approaches for enhancing incretin action include degradation-resistant GLP‑1 receptor agonists (incretin mimetics) and inhibitors of DPP‑4 activity (incretin enhancers).4 In addition to its incretin effect, GLP‑1 suppresses glucagon secretion, inhibits gastric emptying and reduces appetite and food intake.5 Both oral DPP‑4 inhibitors (known as gliptins) and injectable GLP‑1 receptor agonists exert a glucose-lowering effect with no or only a minimal risk of hypoglycaemia, with the injectable agents being more potent than the oral compounds.4 Furthermore, DPP‑4 inhibitors are weight-neutral, whereas GLP‑1 receptor agonists reduce body weight. 4 However, the amount of weight lost is generally moderate and cannot compete with the drastic weight reduction ADVANCE ONLINE PUBLICATION | 1
© 2015 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS Practice point Whereas inhibition of glucagon is classically considered as a potential target for treating diabetes mellitus, activating glucagon receptors simultaneously with GLP‑1 and GIP receptors has the potential of treating both hyperglycaemia and excess weight, a strategy that opens a new paradigm in the management of obesity and type 2 diabetes mellitus.
induced by bariatric surgery. The benefits of bariatric surgery, however, extend well beyond weight loss and include dramatic improvement of T2DM. By mimicking the profound changes in the enteroendocrine responses that are secondary to changes in gastrointestinal anatomy, drugs based on gut hormones represent an exciting possibility for the treatment of T2DM and obesity.1,3 Emerging data from preclinical studies supports the feasibility of using two or more agonists, or single co-agonists, for the treatment of obesity and T2DM.3 The therapeutic value of the triagonist developed by Finan and colleagues cannot be accurately determined from these preclinical studies. One crucial feature that needs to be established before using such a triagonist in humans is a well-balanced stimulation of the glucagon receptor. Indeed, glucagon is a counter-regulatory hormone that has a potent hyperglycaemic effect, as it increases hepatic glucose output through the stimulation of both glycogeno lysis and gluconeogenesis.6 Some experimental data suggest that suppression or inactivation of glucagon might provide therapeutic advantages over insulin monotherapy.6 Many attempts have been made to inhibit glucagon secretion and/or action, with the aim of improving glucose control in T2DM, but without obvious success so far (except for incretin-based therapies7). The activation of the glucagon receptor proposed by Finan and colleagues drastically contrasts with previous attempts to inhibit the action of glucagon. The theory is that glucagon could have some beneficial activities, whereas its diabetogenic effects might be counteracted by the co-activation of
GLP‑1 and GIP receptors. Glucagon, at least partly by inhibiting secretion of orexin A, might increase energy expenditure and thus promote weight loss, as shown in animals and humans, irrespective of changes in levels of glucose or insulin.8 Furthermore, data from the past 2 years have shown that coadminis tration of GLP‑1 during glucagon infusion in humans results in increased energy expendi ture, reduction in food intake and ameli oration of hyperglycaemia.9,10 Thus, GLP‑1 protects against glucagon‑induced hyper glycaemia and the glucagon-induced increase in energy expenditure is maintained. These observations support the concept of GLP‑1 and glucagon dual agonism as a possible treatment for obesity and T2DM. Of note, GIP action to potentiate the incretin effect, as present in the new triagonist, could also contribute to the buffer against the diabeto genic effect of inherent stimulation of the glucagon receptor.5 Finan and colleagues are confident that the glucagon activity of the triagonist can be selectively fine-tuned with minimal structural or chemical changes.2 If this fine-tuning is possible, the ability to choose among several options that differ in their inherent molecular pharmacology would certainly increase the likelihood of success in humans.
‘‘
…such studies … open a new paradigm for the management of T2DM…
’’
The pharmacological outcomes of target ing a particular pathway in humans are often difficult to predict from results in animal models and safety issues are always critical in humans. Cardiovascular safety is becoming a major concern for the development of any new antidiabetic agents and glucagon is known to have some cardiovascular effects in humans that still need to be investigated. Furthermore, humans have a different meta bolic profile to that of rodents5 and many promising strategies to treat obesity and/or diabetes mellitus in rodents are not successful in humans.1 Whether novel mechanisms identified in preclinical studies, such as that
2 | ADVANCE ONLINE PUBLICATION
by Finan and colleagues,2 have potential translational relevance for the treatment of human disease requires extensive research.3 Nevertheless, such studies targeting glucagon simultaneously with GLP‑1 and GIP receptors open a new paradigm for the management of T2DM, especially when associated with obesity. Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liège, University of Liège, Liège, Belgium (A.J.S., N.P.). Correspondence to: A.J.S. [email protected] Competing interests A.J.S. has received lecturer/advisor/investigator fees from AstraZeneca/BMS, Boehringer Ingelheim, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, NovoNordisk, Sanofi and Takeda. N.P. has received lecturer fees from Merck Sharp & Dohme and NovoNordisk. 1.
Scheen, A. J. & Van Gaal, L. F. Combating the dual burden: therapeutic targeting of common pathways in obesity and type 2 diabetes. Lancet Diabetes Endocrinol. 2, 911–922 (2014). 2. Finan, B. et al. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat. Med. 21, 27–36 (2015). 3. Sadry, S. A. & Drucker, D. J. Emerging combinatorial hormone therapies for the treatment of obesity and T2DM. Nat. Rev. Endocrinol. 9, 425–433 (2013). 4. Neumiller, J. J. Incretin-based therapies. Med. Clin. North Am. 99, 107–129 (2015). 5. Campbell, J. E. & Drucker, D. J. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab. 17, 819–837 (2013). 6. Unger, R. H. & Cherrington, A. D. Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. J. Clin. Invest. 122, 4–12 (2012). 7. Lund, A., Bagger, J. I., Christensen, M., Knop, F. K. & Vilsbøll, T. Glucagon and type 2 diabetes: the return of the α cell. Curr. Diab. Rep. 14, 555 (2014). 8. Arafat, A. M. et al. Glucagon regulates orexin A secretion in humans and rodents. Diabetologia 57, 2108–2116 (2014). 9. Tan, T. M. et al. Coadministration of glucagonlike peptide‑1 during glucagon infusion in humans results in increased energy expenditure and amelioration of hyperglycemia. Diabetes 62, 1131–1138 (2013). 10. Cegla, J. et al. Coinfusion of low-dose GLP‑1 and glucagon in man results in a reduction in food intake. Diabetes 63, 3711–3720 (2014). Published online 27 January 2015; doi:10.1038/nrendo.2015.3
www.nature.com/nrendo © 2015 Macmillan Publishers Limited. All rights reserved
A new paradigm for treating obesity and diabetes mellitus André J. Scheen and Nicolas Paquot Refers to Finan, B. et al. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat. Med. 21, 27–36 (2015)
An innovative strategy that uses a well-balanced monomeric peptide triagonist to target three metabolically related hormone receptors has been developed. This strategy seems to be the most effective pharmacological approach to reverse obesity and its metabolic comorbidities in rodents and could open new ways to tackle the dual burden of obesity and diabetes mellitus in humans. The management of patients with obesity and type 2 diabetes mellitus (T2DM) is challenging in clinical practice. The recurrent failure of lifestyle changes and available pharmacological approaches in the management of these patients has led to many patients undergoing bariatric surgery and has stimulated the search for new pharmacological strategies.1
‘‘
…this … strategy has the potential to reverse obesity and related metabolic disorders
’’
Finan and colleagues have reported the discovery of a new agonist that simultaneously targets three key metabolically related peptide hormone receptors—the receptors for glucagon-like peptide 1 (GLP‑1), glucose-d ependent insulinotropic polypeptide (GIP) and glucagon (Figure 1). 2 This monomeric peptide exerts a balanced agonist effect and was proved to be remarkably effective at reducing body weight, improving glucose control and reversing hepatic steatosis in various rodent models of either diet-induced or genetically determined obesity and/or diabetes mellitus. Through elegant studies in which knockout mice for the individual receptors were used, Finan and colleagues were able to demonstrate that the unimolecular tri agonist targeted each of the three receptors.2 The researchers were also able to ascertain how much blocking each receptor contributed to the overall metabolic benefits of the
monomeric peptide. They found that the overall metabolic efficacy of the new drug predominantly resulted from synergistic glucagon action that increased energy expenditure, GLP‑1 action that reduced caloric intake and improved glucose control and GIP action that potentiated the socalled incretin effect. Interestingly, the last two actions buffer against the diabetogenic effect of the inherent glucagon-mimicking activity of the peptide. Thus, these preclinical studies in rodents suggest that this unimolecular, polypharmaceutical strategy has the potential to reverse obesity and related metabolic disorders.2 Further studies should confirm whether this innovative pharmaco logical approach, which proved superior to therapy with any existing dual coagonists and best-in-class monoagonists in rodents, might be effective and safe for the treatment of obesity and T2DM in humans and thus ultimately offer a valuable pharmacological alternative to bariatric surgery.3 The dramatic rise of the twin epidemics of T2DM and obesity is associated with increased mortality and morbidity and is one of the most important public-health challenges worldwide. 1 Striking parallel increases in the prevalence of the two entities reflect the importance of body fatness as a contributing factor to the incidence of T2DM and its complications. Despite the importance of strategies to control weight in the prevention and management of T2DM, long-term results with lifestyle or available drug interventions are generally dis appointing.1 Notably, therapeutic attempts
NATURE REVIEWS | ENDOCRINOLOGY
GLP-1 ■ Enhanced insulin secretion (incretin effect) ■ Reduced glucagon secretion ■ Anorectic effects GIP Triagonist ■ Enhanced insulin secretion ■ (incretin effect) ■ Buffered ■ diabetogenic effects of glucagon
Glucagon Increased hepatic glucose production Increased energy expenditure
Figure 1 | Complementary (but also Nature Reviews | Endocrinology opposing) effects of the individual components of a peptide triagonist targeting GLP‑1, GIP and glucagon receptors that could be used to treat obesity and type 2 diabetes mellitus. Abbreviations: GIP, glucosedependent insulinotropic polypeptide; GLP‑1, glucagon-like peptide 1.
to normalize body weight and glycaemia with single agents have generally had poor results.1 Furthermore, most of the classic glucose-lowering agents are accompanied by weight gain, which increases the challenge of managing most individuals with T2DM who are overweight or have obesity.1 Incretin-based therapies are increasingly being used in clinical practice for the management of T2DM. 4 The dipep tidyl peptidase 4 (DPP‑4) enzyme rapidly degrades GLP‑1 and GIP, two gastrointestinal hormones that potentiate insulin secretion in response to a meal.4 Therapeutic approaches for enhancing incretin action include degradation-resistant GLP‑1 receptor agonists (incretin mimetics) and inhibitors of DPP‑4 activity (incretin enhancers).4 In addition to its incretin effect, GLP‑1 suppresses glucagon secretion, inhibits gastric emptying and reduces appetite and food intake.5 Both oral DPP‑4 inhibitors (known as gliptins) and injectable GLP‑1 receptor agonists exert a glucose-lowering effect with no or only a minimal risk of hypoglycaemia, with the injectable agents being more potent than the oral compounds.4 Furthermore, DPP‑4 inhibitors are weight-neutral, whereas GLP‑1 receptor agonists reduce body weight. 4 However, the amount of weight lost is generally moderate and cannot compete with the drastic weight reduction ADVANCE ONLINE PUBLICATION | 1
© 2015 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS Practice point Whereas inhibition of glucagon is classically considered as a potential target for treating diabetes mellitus, activating glucagon receptors simultaneously with GLP‑1 and GIP receptors has the potential of treating both hyperglycaemia and excess weight, a strategy that opens a new paradigm in the management of obesity and type 2 diabetes mellitus.
induced by bariatric surgery. The benefits of bariatric surgery, however, extend well beyond weight loss and include dramatic improvement of T2DM. By mimicking the profound changes in the enteroendocrine responses that are secondary to changes in gastrointestinal anatomy, drugs based on gut hormones represent an exciting possibility for the treatment of T2DM and obesity.1,3 Emerging data from preclinical studies supports the feasibility of using two or more agonists, or single co-agonists, for the treatment of obesity and T2DM.3 The therapeutic value of the triagonist developed by Finan and colleagues cannot be accurately determined from these preclinical studies. One crucial feature that needs to be established before using such a triagonist in humans is a well-balanced stimulation of the glucagon receptor. Indeed, glucagon is a counter-regulatory hormone that has a potent hyperglycaemic effect, as it increases hepatic glucose output through the stimulation of both glycogeno lysis and gluconeogenesis.6 Some experimental data suggest that suppression or inactivation of glucagon might provide therapeutic advantages over insulin monotherapy.6 Many attempts have been made to inhibit glucagon secretion and/or action, with the aim of improving glucose control in T2DM, but without obvious success so far (except for incretin-based therapies7). The activation of the glucagon receptor proposed by Finan and colleagues drastically contrasts with previous attempts to inhibit the action of glucagon. The theory is that glucagon could have some beneficial activities, whereas its diabetogenic effects might be counteracted by the co-activation of
GLP‑1 and GIP receptors. Glucagon, at least partly by inhibiting secretion of orexin A, might increase energy expenditure and thus promote weight loss, as shown in animals and humans, irrespective of changes in levels of glucose or insulin.8 Furthermore, data from the past 2 years have shown that coadminis tration of GLP‑1 during glucagon infusion in humans results in increased energy expendi ture, reduction in food intake and ameli oration of hyperglycaemia.9,10 Thus, GLP‑1 protects against glucagon‑induced hyper glycaemia and the glucagon-induced increase in energy expenditure is maintained. These observations support the concept of GLP‑1 and glucagon dual agonism as a possible treatment for obesity and T2DM. Of note, GIP action to potentiate the incretin effect, as present in the new triagonist, could also contribute to the buffer against the diabeto genic effect of inherent stimulation of the glucagon receptor.5 Finan and colleagues are confident that the glucagon activity of the triagonist can be selectively fine-tuned with minimal structural or chemical changes.2 If this fine-tuning is possible, the ability to choose among several options that differ in their inherent molecular pharmacology would certainly increase the likelihood of success in humans.
‘‘
…such studies … open a new paradigm for the management of T2DM…
’’
The pharmacological outcomes of target ing a particular pathway in humans are often difficult to predict from results in animal models and safety issues are always critical in humans. Cardiovascular safety is becoming a major concern for the development of any new antidiabetic agents and glucagon is known to have some cardiovascular effects in humans that still need to be investigated. Furthermore, humans have a different meta bolic profile to that of rodents5 and many promising strategies to treat obesity and/or diabetes mellitus in rodents are not successful in humans.1 Whether novel mechanisms identified in preclinical studies, such as that
2 | ADVANCE ONLINE PUBLICATION
by Finan and colleagues,2 have potential translational relevance for the treatment of human disease requires extensive research.3 Nevertheless, such studies targeting glucagon simultaneously with GLP‑1 and GIP receptors open a new paradigm for the management of T2DM, especially when associated with obesity. Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liège, University of Liège, Liège, Belgium (A.J.S., N.P.). Correspondence to: A.J.S. [email protected] Competing interests A.J.S. has received lecturer/advisor/investigator fees from AstraZeneca/BMS, Boehringer Ingelheim, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, NovoNordisk, Sanofi and Takeda. N.P. has received lecturer fees from Merck Sharp & Dohme and NovoNordisk. 1.
Scheen, A. J. & Van Gaal, L. F. Combating the dual burden: therapeutic targeting of common pathways in obesity and type 2 diabetes. Lancet Diabetes Endocrinol. 2, 911–922 (2014). 2. Finan, B. et al. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat. Med. 21, 27–36 (2015). 3. Sadry, S. A. & Drucker, D. J. Emerging combinatorial hormone therapies for the treatment of obesity and T2DM. Nat. Rev. Endocrinol. 9, 425–433 (2013). 4. Neumiller, J. J. Incretin-based therapies. Med. Clin. North Am. 99, 107–129 (2015). 5. Campbell, J. E. & Drucker, D. J. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab. 17, 819–837 (2013). 6. Unger, R. H. & Cherrington, A. D. Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. J. Clin. Invest. 122, 4–12 (2012). 7. Lund, A., Bagger, J. I., Christensen, M., Knop, F. K. & Vilsbøll, T. Glucagon and type 2 diabetes: the return of the α cell. Curr. Diab. Rep. 14, 555 (2014). 8. Arafat, A. M. et al. Glucagon regulates orexin A secretion in humans and rodents. Diabetologia 57, 2108–2116 (2014). 9. Tan, T. M. et al. Coadministration of glucagonlike peptide‑1 during glucagon infusion in humans results in increased energy expenditure and amelioration of hyperglycemia. Diabetes 62, 1131–1138 (2013). 10. Cegla, J. et al. Coinfusion of low-dose GLP‑1 and glucagon in man results in a reduction in food intake. Diabetes 63, 3711–3720 (2014). Published online 27 January 2015; doi:10.1038/nrendo.2015.3
www.nature.com/nrendo © 2015 Macmillan Publishers Limited. All rights reserved
