GLP-1 receptor agonist: Difference between revisions

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GLP-1 agonists are under development for [[substance use disorder]], a condition with few pharmacological treatment options. They reduce the self-administered intake of drugs and alcohol in non-human animals, although this effect has not been proven in humans. The mechanism of this addiction-reducing effect is unknown.<ref>{{cite journal |last1=Klausen |first1=Mette Kruse |last2=Thomsen |first2=Morgane |last3=Wortwein |first3=Gitta |last4=Fink‐Jensen |first4=Anders |title=The role of glucagon‐like peptide 1 (GLP‐1) in addictive disorders |journal=British Journal of Pharmacology |date=2022 |volume=179 |issue=4 |pages=625–641 |doi=10.1111/bph.15677 |url=https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bph.15677 |language=en |issn=0007-1188}}</ref> GLP-1 agonists are also under investigation for the treatment of [[binge eating disorder]], which is the most common eating disorder.<ref>{{cite journal |last1=Da Porto |first1=Andrea |last2=Casarsa |first2=Viviana |last3=Colussi |first3=Gianluca |last4=Catena |first4=Cristiana |last5=Cavarape |first5=Alessandro |last6=Sechi |first6=Leonardo |title=Dulaglutide reduces binge episodes in type 2 diabetic patients with binge eating disorder: A pilot study |journal=Diabetes & Metabolic Syndrome: Clinical Research & Reviews |date=July 2020 |volume=14 |issue=4 |pages=289–292 |doi=10.1016/j.dsx.2020.03.009}}</ref><ref>{{cite journal |last1=Richards |first1=Jesse |last2=Bang |first2=Neha |last3=Ratliff |first3=Erin L. |last4=Paszkowiak |first4=Maria A. |last5=Khorgami |first5=Zhamak |last6=Khalsa |first6=Sahib S. |last7=Simmons |first7=W. Kyle |title=Successful treatment of binge eating disorder with the GLP-1 agonist semaglutide: A retrospective cohort study |journal=Obesity Pillars |date=September 2023 |volume=7 |pages=100080 |doi=10.1016/j.obpill.2023.100080}}</ref>
GLP-1 agonists are under development for [[substance use disorder]], a condition with few pharmacological treatment options. They reduce the self-administered intake of drugs and alcohol in non-human animals, although this effect has not been proven in humans. The mechanism of this addiction-reducing effect is unknown.<ref>{{cite journal |last1=Klausen |first1=Mette Kruse |last2=Thomsen |first2=Morgane |last3=Wortwein |first3=Gitta |last4=Fink‐Jensen |first4=Anders |title=The role of glucagon‐like peptide 1 (GLP‐1) in addictive disorders |journal=British Journal of Pharmacology |date=2022 |volume=179 |issue=4 |pages=625–641 |doi=10.1111/bph.15677 |url=https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bph.15677 |language=en |issn=0007-1188}}</ref> GLP-1 agonists are also under investigation for the treatment of [[binge eating disorder]], which is the most common eating disorder.<ref>{{cite journal |last1=Da Porto |first1=Andrea |last2=Casarsa |first2=Viviana |last3=Colussi |first3=Gianluca |last4=Catena |first4=Cristiana |last5=Cavarape |first5=Alessandro |last6=Sechi |first6=Leonardo |title=Dulaglutide reduces binge episodes in type 2 diabetic patients with binge eating disorder: A pilot study |journal=Diabetes & Metabolic Syndrome: Clinical Research & Reviews |date=July 2020 |volume=14 |issue=4 |pages=289–292 |doi=10.1016/j.dsx.2020.03.009}}</ref><ref>{{cite journal |last1=Richards |first1=Jesse |last2=Bang |first2=Neha |last3=Ratliff |first3=Erin L. |last4=Paszkowiak |first4=Maria A. |last5=Khorgami |first5=Zhamak |last6=Khalsa |first6=Sahib S. |last7=Simmons |first7=W. Kyle |title=Successful treatment of binge eating disorder with the GLP-1 agonist semaglutide: A retrospective cohort study |journal=Obesity Pillars |date=September 2023 |volume=7 |pages=100080 |doi=10.1016/j.obpill.2023.100080}}</ref>
==Adverse effects==
==Adverse effects==
The most common adverse effects of GLP-1 agonists are gastrointestinal.<ref name="Wharton"/> These adverse effects limit the maximum tolerated dose and require gradual [[dose escalation]].<ref name=Knerr/> Nausea, vomiting, diarrhea, and constipation are all commonly reported.<ref name="Wharton">{{cite journal |last1=Wharton |first1=Sean |last2=Davies |first2=Melanie |last3=Dicker |first3=Dror |last4=Lingvay |first4=Ildiko |last5=Mosenzon |first5=Ofri |last6=Rubino |first6=Domenica M. |last7=Pedersen |first7=Sue D. |title=Managing the gastrointestinal side effects of GLP-1 receptor agonists in obesity: recommendations for clinical practice |journal=Postgraduate Medicine |date=2022 |volume=134 |issue=1 |pages=14–19 |doi=10.1080/00325481.2021.2002616 |url=https://www.tandfonline.com/doi/full/10.1080/00325481.2021.2002616 |language=en |issn=0032-5481}}</ref>
The most common adverse effects of GLP-1 agonists are gastrointestinal.<ref name="Wharton"/> These adverse effects limit the maximum tolerated dose and require gradual [[dose escalation]].<ref name=Knerr/> Nausea, vomiting, diarrhea, and constipation are all commonly reported.<ref name="Wharton">{{cite journal |last1=Wharton |first1=Sean |last2=Davies |first2=Melanie |last3=Dicker |first3=Dror |last4=Lingvay |first4=Ildiko |last5=Mosenzon |first5=Ofri |last6=Rubino |first6=Domenica M. |last7=Pedersen |first7=Sue D. |title=Managing the gastrointestinal side effects of GLP-1 receptor agonists in obesity: recommendations for clinical practice |journal=Postgraduate Medicine |date=2022 |volume=134 |issue=1 |pages=14–19 |doi=10.1080/00325481.2021.2002616 |url=https://www.tandfonline.com/doi/full/10.1080/00325481.2021.2002616 |language=en |issn=0032-5481}}</ref> Reactions at the injection site are also common, especially with shorter acting drugs.<ref name="Yu" />


Human trials and meta-analyses have found no association between the drugs and [[pancreatitis]] or [[pancreatic cancer]]. However, some case reports of pancreatitis have emerged in postmarketing reports, and the [[American Association of Clinical Endocrinologists]] recommends caution in people with a history of pancreatitis. Discontinuation is recommended if acute pancreatitis occurs. A FDA black box warning is required for the risk of [[thyroid C-cell tumors]], and the drugs are contraindicated if there is a family or personal history of [[medullary thyroid cancer]] or [[multiple endocrine neoplasia type 2a]] or [[multiple endocrine neoplasia type 2b|2b]].<ref name=Nachawi>{{cite journal |last1=Nachawi |first1=Noura |last2=Rao |first2=Pratibha PR |last3=Makin |first3=Vinni |title=The role of GLP-1 receptor agonists in managing type 2 diabetes |journal=Cleveland Clinic Journal of Medicine |date=2022 |volume=89 |issue=8 |pages=457–464 |url=https://www.ccjm.org/node/11495?utm_source=TrendMD&utm_medium=cpc&utm_campaign=Cleveland_Clinic_Journal_of_Medicine_TrendMD_1}}</ref>
Human trials and meta-analyses have found no association between the drugs and [[pancreatitis]] or [[pancreatic cancer]]. However, some case reports of pancreatitis have emerged in postmarketing reports, and the [[American Association of Clinical Endocrinologists]] recommends caution in people with a history of pancreatitis. Discontinuation is recommended if acute pancreatitis occurs. A FDA black box warning is required for the risk of [[thyroid C-cell tumors]], and the drugs are contraindicated if there is a family or personal history of [[medullary thyroid cancer]] or [[multiple endocrine neoplasia type 2a]] or [[multiple endocrine neoplasia type 2b|2b]].<ref name=Nachawi>{{cite journal |last1=Nachawi |first1=Noura |last2=Rao |first2=Pratibha PR |last3=Makin |first3=Vinni |title=The role of GLP-1 receptor agonists in managing type 2 diabetes |journal=Cleveland Clinic Journal of Medicine |date=2022 |volume=89 |issue=8 |pages=457–464 |url=https://www.ccjm.org/node/11495?utm_source=TrendMD&utm_medium=cpc&utm_campaign=Cleveland_Clinic_Journal_of_Medicine_TrendMD_1}}</ref> In mice, long-term use of GLP-1 agonists stimulates [[calcitonin]] secretion, leading to [[Parafollicular cell|C-cell]] hypertrophy and an increased risk of thyroid cancer. However, no increased secretion of calcitonin has been observed in humans.<ref name="Yu">{{cite journal |last1=Yu |first1=Minzhi |last2=Benjamin |first2=Mason M. |last3=Srinivasan |first3=Santhanakrishnan |last4=Morin |first4=Emily E. |last5=Shishatskaya |first5=Ekaterina I. |last6=Schwendeman |first6=Steven P. |last7=Schwendeman |first7=Anna |title=Battle of GLP-1 delivery technologies |journal=Advanced Drug Delivery Reviews |date=2018 |volume=130 |pages=113–130 |doi=10.1016/j.addr.2018.07.009}}</ref>


Like insulin, GLP-1 agonists can cause or exacerbate [[retinopathy]], but this is believed to be caused indirectly by a rapid drop in glucose rather than a direct effect.<ref name=Nachawi/>
Like insulin, GLP-1 agonists can cause or exacerbate [[retinopathy]], but this is believed to be caused indirectly by a rapid drop in glucose rather than a direct effect.<ref name=Nachawi/>


GLP-1 agonists increase the risk of [[gallstones]] when used to induce rapid weight loss.<ref name="Wharton"/>
GLP-1 agonists increase the risk of [[gallstones]] when used to induce rapid weight loss.<ref name="Wharton"/>
==Drug delivery==
Native GLP-1 is a peptide hormone with a [[half-life]] of 2 minutes because it is rapidly cleared by the enzyme [[dipeptidyl peptidase-4]].<ref name="Yu" /> As a result, different GLP-1 agonist drugs are modified in various ways to extend the half-life, resulting in drugs that can be dosed multiple times per day, daily, weekly, or even less often.<ref name="Yu" /> Most synthetic GLP-1 agonists are delivered via [[subcutaneous injection]], which is a barrier to their use and reason for discontinuation.<ref name=Antza>{{cite journal |last1=Antza |first1=Christina |last2=Nirantharakumar |first2=Krishnarajah |last3=Doundoulakis |first3=Ioannis |last4=Tahrani |first4=Abd A. |last5=Toulis |first5=Konstantinos A. |title=The development of an oral GLP-1 receptor agonist for the management of type 2 diabetes: evidence to date |journal=Drug Design, Development and Therapy |date=2019 |volume=13 |pages=2985–2996 |doi=10.2147/DDDT.S166765 |url=https://www.tandfonline.com/doi/full/10.2147/DDDT.S166765 |language=English}}</ref> Self-injected drugs are especially difficult for people with vision or motor difficulties, which are common in people with type 2 diabetes.<ref name="Yu" /> Attempts to develop an orally bioavailable GLP-1 agonist, either a modified peptide, as in the case of oral semaglutide,<ref name=Antza/> or a [[small molecule]] drug have produced additional drug candidates.<ref name=Knerr/> Other companies have tested inhaled or [[transdermal]] administration.<ref name="Yu" />
==Cost==
==Cost==
GLP-1 agonists are more expensive than other treatments for type 2 diabetes. A study compared the cost effectiveness of GLP-1 agonists to [[long-acting insulin]] in Taiwanese type 2 diabetes patients. In patients with CVD, GLP-1 agonists were estimated to save money due to fewer cardiovascular incidents. In patients without CVD, the cost per QALY was $9,093.<ref>{{cite journal |last1=Yang |first1=Chun-Ting |last2=Yao |first2=Wen-Yu |last3=Ou |first3=Huang-Tz |last4=Kuo |first4=Shihchen |title=Value of GLP-1 receptor agonists versus long-acting insulins for type 2 diabetes patients with and without established cardiovascular or chronic kidney diseases: A model-based cost-effectiveness analysis using real-world data |journal=Diabetes Research and Clinical Practice |date=April 2023 |volume=198 |pages=110625 |doi=10.1016/j.diabres.2023.110625 |url=https://pubmed.ncbi.nlm.nih.gov/36924833/ |issn=1872-8227}}</ref> In the United States, cost is the highest barrier to GLP-1 agonist usage and was reported as the reason for discontinuation in 48.6 percent of US patients who stopped using the drugs.<ref>{{cite journal |last1=Moore |first1=Peyton W. |last2=Malone |first2=Kevin |last3=VanValkenburg |first3=Delena |last4=Rando |first4=Lauren L. |last5=Williams |first5=Brooke C. |last6=Matejowsky |first6=Hannah G. |last7=Ahmadzadeh |first7=Shahab |last8=Shekoohi |first8=Sahar |last9=Cornett |first9=Elyse M. |last10=Kaye |first10=Alan D. |title=GLP-1 Agonists for Weight Loss: Pharmacology and Clinical Implications |journal=Advances in Therapy |date=2023 |volume=40 |issue=3 |pages=723–742 |doi=10.1007/s12325-022-02394-w}}</ref> According to another study, GLP-1 agonists are not cost effective for pediatric obesity in the United States.<ref>{{cite journal |last1=Lim |first1=Francesca |last2=Bellows |first2=Brandon K. |last3=Tan |first3=Sarah Xinhui |last4=Aziz |first4=Zainab |last5=Woo Baidal |first5=Jennifer A. |last6=Kelly |first6=Aaron S. |last7=Hur |first7=Chin |title=Cost-Effectiveness of Pharmacotherapy for the Treatment of Obesity in Adolescents |journal=JAMA Network Open |date=2023 |volume=6 |issue=8 |pages=e2329178 |doi=10.1001/jamanetworkopen.2023.29178 |language=en |issn=2574-3805}}</ref>
GLP-1 agonists are more expensive than other treatments for type 2 diabetes. A study compared the cost effectiveness of GLP-1 agonists to [[long-acting insulin]] in Taiwanese type 2 diabetes patients. In patients with CVD, GLP-1 agonists were estimated to save money due to fewer cardiovascular incidents. In patients without CVD, the cost per QALY was $9,093.<ref>{{cite journal |last1=Yang |first1=Chun-Ting |last2=Yao |first2=Wen-Yu |last3=Ou |first3=Huang-Tz |last4=Kuo |first4=Shihchen |title=Value of GLP-1 receptor agonists versus long-acting insulins for type 2 diabetes patients with and without established cardiovascular or chronic kidney diseases: A model-based cost-effectiveness analysis using real-world data |journal=Diabetes Research and Clinical Practice |date=April 2023 |volume=198 |pages=110625 |doi=10.1016/j.diabres.2023.110625 |url=https://pubmed.ncbi.nlm.nih.gov/36924833/ |issn=1872-8227}}</ref> In the United States, cost is the highest barrier to GLP-1 agonist usage and was reported as the reason for discontinuation in 48.6 percent of US patients who stopped using the drugs.<ref>{{cite journal |last1=Moore |first1=Peyton W. |last2=Malone |first2=Kevin |last3=VanValkenburg |first3=Delena |last4=Rando |first4=Lauren L. |last5=Williams |first5=Brooke C. |last6=Matejowsky |first6=Hannah G. |last7=Ahmadzadeh |first7=Shahab |last8=Shekoohi |first8=Sahar |last9=Cornett |first9=Elyse M. |last10=Kaye |first10=Alan D. |title=GLP-1 Agonists for Weight Loss: Pharmacology and Clinical Implications |journal=Advances in Therapy |date=2023 |volume=40 |issue=3 |pages=723–742 |doi=10.1007/s12325-022-02394-w}}</ref> According to another study, GLP-1 agonists are not cost effective for pediatric obesity in the United States.<ref>{{cite journal |last1=Lim |first1=Francesca |last2=Bellows |first2=Brandon K. |last3=Tan |first3=Sarah Xinhui |last4=Aziz |first4=Zainab |last5=Woo Baidal |first5=Jennifer A. |last6=Kelly |first6=Aaron S. |last7=Hur |first7=Chin |title=Cost-Effectiveness of Pharmacotherapy for the Treatment of Obesity in Adolescents |journal=JAMA Network Open |date=2023 |volume=6 |issue=8 |pages=e2329178 |doi=10.1001/jamanetworkopen.2023.29178 |language=en |issn=2574-3805}}</ref>
Line 50: Line 52:


==Combination and multiple target drugs==
==Combination and multiple target drugs==
Some GLP-1 agonists, such as [[tirzepatide]], are also agonists of the [[GIP receptor]] and/or [[glucagon receptor]]. These additional targets are hoped to improve the amount of weight loss caused by the drugs.<ref name=Knerr>{{cite journal |last1=Knerr |first1=Patrick J. |last2=Mowery |first2=Stephanie A. |last3=Finan |first3=Brian |last4=Perez-Tilve |first4=Diego |last5=Tschöp |first5=Matthias H. |last6=DiMarchi |first6=Richard D. |title=Selection and progression of unimolecular agonists at the GIP, GLP-1, and glucagon receptors as drug candidates |journal=Peptides |date=2020 |volume=125 |pages=170225 |doi=10.1016/j.peptides.2019.170225 |language=en}}</ref>
Some GLP-1 agonists, such as [[tirzepatide]], are also agonists of the [[GIP receptor]] and/or [[glucagon receptor]]. These additional targets are hoped to improve the amount of weight loss caused by the drugs.<ref name=Knerr>{{cite journal |last1=Knerr |first1=Patrick J. |last2=Mowery |first2=Stephanie A. |last3=Finan |first3=Brian |last4=Perez-Tilve |first4=Diego |last5=Tschöp |first5=Matthias H. |last6=DiMarchi |first6=Richard D. |title=Selection and progression of unimolecular agonists at the GIP, GLP-1, and glucagon receptors as drug candidates |journal=Peptides |date=2020 |volume=125 |pages=170225 |doi=10.1016/j.peptides.2019.170225 |language=en}}</ref> Combination with glucagon agonism is likely to make the drugs more efficacious for weight loss, at the expense of additional risk and a lower [[therapeutic index]].<ref name=Knerr>{{cite journal |last1=Knerr |first1=Patrick J. |last2=Mowery |first2=Stephanie A. |last3=Finan |first3=Brian |last4=Perez-Tilve |first4=Diego |last5=Tschöp |first5=Matthias H. |last6=DiMarchi |first6=Richard D. |title=Selection and progression of unimolecular agonists at the GIP, GLP-1, and glucagon receptors as drug candidates |journal=Peptides |date=2020 |volume=125 |pages=170225 |doi=10.1016/j.peptides.2019.170225}}</ref>


GLP-1 agonists are available as combination medications with insulin to treat type 2 diabetes.<ref>{{cite journal |last1=Castellana |first1=Marco |last2=Cignarelli |first2=Angelo |last3=Brescia |first3=Francesco |last4=Laviola |first4=Luigi |last5=Giorgino |first5=Francesco |title=GLP ‐1 receptor agonist added to insulin versus basal‐plus or basal‐bolus insulin therapy in type 2 diabetes: A systematic review and meta‐analysis |journal=Diabetes/Metabolism Research and Reviews |date=2019 |volume=35 |issue=1 |doi=10.1002/dmrr.3082 |url=https://onlinelibrary.wiley.com/doi/abs/10.1002/dmrr.3082 |language=en |issn=1520-7552}}</ref> The experimental formula [[cagrilintide/semaglutide]] combines semaglutide with a [[dual amylin and calcitonin receptor agonist]] for additional weight loss.<ref>{{cite journal |last1=Holst |first1=Jens Juul |last2=Jepsen |first2=Sara Lind |last3=Modvig |first3=Ida |title=GLP-1 – Incretin and pleiotropic hormone with pharmacotherapy potential. Increasing secretion of endogenous GLP-1 for diabetes and obesity therapy |journal=Current Opinion in Pharmacology |date=2022 |volume=63 |pages=102189 |doi=10.1016/j.coph.2022.102189 |url=https://www.sciencedirect.com/science/article/pii/S1471489222000133 |issn=1471-4892}}</ref>
GLP-1 agonists are available as combination medications with insulin to treat type 2 diabetes, although it is unclear whether these combination formulas offer an advantage over dosing insulin and GLP-1 agonists separately.<ref name="Yu"/><ref>{{cite journal |last1=Castellana |first1=Marco |last2=Cignarelli |first2=Angelo |last3=Brescia |first3=Francesco |last4=Laviola |first4=Luigi |last5=Giorgino |first5=Francesco |title=GLP ‐1 receptor agonist added to insulin versus basal‐plus or basal‐bolus insulin therapy in type 2 diabetes: A systematic review and meta‐analysis |journal=Diabetes/Metabolism Research and Reviews |date=2019 |volume=35 |issue=1 |doi=10.1002/dmrr.3082 |url=https://onlinelibrary.wiley.com/doi/abs/10.1002/dmrr.3082 |language=en |issn=1520-7552}}</ref> The experimental formula [[cagrilintide/semaglutide]] combines semaglutide with a [[dual amylin and calcitonin receptor agonist]] for additional weight loss.<ref>{{cite journal |last1=Holst |first1=Jens Juul |last2=Jepsen |first2=Sara Lind |last3=Modvig |first3=Ida |title=GLP-1 – Incretin and pleiotropic hormone with pharmacotherapy potential. Increasing secretion of endogenous GLP-1 for diabetes and obesity therapy |journal=Current Opinion in Pharmacology |date=2022 |volume=63 |pages=102189 |doi=10.1016/j.coph.2022.102189 |url=https://www.sciencedirect.com/science/article/pii/S1471489222000133 |issn=1471-4892}}</ref>


==Off-label and recreational use==
==Off-label and recreational use==

Revision as of 05:09, 6 November 2023

Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of drugs that reduce blood sugar and energy intake by activating the GLP-1 receptor. They mimic the actions of the endogenous incretin hormone GLP-1 that is released by the gut after eating.

GLP-1 agonists were initially developed for type 2 diabetes. The 2022 American Diabetes Association standards of medical care recommend GLP-1 agonists as a first line therapy for type 2 diabetes, specifically in patients with atherosclerotic cardiovascular disease or obesity. The drugs were also noted to reduce food intake and body weight significantly, and some have also been approved to treat obesity in the absence of diabetes. They are also in development for other indications, such as non-alcoholic fatty liver disease, polycystic ovary syndrome, and diseases of the reward system such as addictions.

Mechanism of action

GLP-1 agonists work by activating the GLP-1 receptor. They slow gastric emptying, inhibit the release of glucagon, and stimulate insulin production, therefore reducing hyperglycemia in people with type 2 diabetes. They also reduce food intake and therefore body weight, making them an effective treatment for obesity.[1] Another class of anti-diabetes drugs, the DPP-4 inhibitors, work by reducing the breakdown of endogenous GLP-1, and are generally considered less potent than GLP-1 agonists.[2]

Indications

Type 2 diabetes

GLP-1 agonists were developed initially for type 2 diabetes.[3] The 2022 American Diabetes Association (ADA) standards of medical care in diabetes include GLP-1 agonist or SGLT2 inhibitor as a first line pharmacological therapy for type 2 diabetes in patients who have or are at high risk for atherosclerotic cardiovascular disease or heart failure. They are also a first line treatment for people with both type 2 diabetes and kidney disease. Both types of medication can be combined with metformin.[4][5] One of the advantages of GLP-1 agonists over older insulin secretagogues, such as sulfonylureas or meglitinides, is that they have a lower risk of causing hypoglycemia.[6] The ADA also recommends use of GLP-1 agonists instead of starting insulin in people with type 2 diabetes who need additional glucose control, except where there is catabolism, hyperglycemia above a certain threshold, or autoimmune diabetes is suspected.[4]

A 2021 meta-analysis found a 12 percent reduction in all-cause mortality when GLP-1 analogs are used in the treatment of type 2 diabetes, as well as significant improvements in cardiovascular and renal outcomes.[7] A meta-analysis including 13 cardiovascular outcome trials found that SGLT-2 inhibitors reduce the risk for three-point MACE, especially in subjects with an estimated glomerular filtration rate (eGFR) below 60 mL/min, whereas GLP-1 receptor agonists were more beneficial in persons with higher eGFR.[8] Likewise, the risk reduction due to SGLT-2 inhibitors was larger in populations with a higher proportion of albuminuria, but this relationship was not observed for GLP-1 receptor agonists. This suggests differential use of the two substance classes in patients with preserved and reduced renal function or with and without diabetic nephropathy, respectively.[8] GLP-1 agonists and SGLT2 inhibitors work to reduce HbA1c by different mechanisms, and can be combined for enhanced effect. It is also possible that they provide additive cardioprotective effects.[9]

GLP-1 agonists are not FDA approved for type 1 diabetes, but can be used off-label in addition to insulin to help type 1 diabetes patients improve their body weight and glucose control.[4]

Cardiovascular disease

GLP-1 agonists have demonstrated a cardioprotective effect when used to treat obesity.[10]

Obesity

GLP-1 agonists are recommended as an add-on therapy to lifestyle intervention (calorie restriction and exercise) in people with a BMI over 30 or a BMI over 27 with at least one weight-related comorbidity.[11] Although some GLP-1 agonists such as semaglutide are more effective than other weight loss drugs, they are still less effective than bariatric surgery in causing weight loss.[12] GLP-1 agonists' weight reduction effects come from a combination of peripheral effects as well as activity in the brain via the central nervous system.[13]

Non-alcoholic fatty liver disease

GLP-1 agonists are being studied for the treatment of non-alcoholic fatty liver disease (NAFLD). They are at least as effective as the medications in current use, pioglitazone and Vitamin E, and significantly reduce steatosis, ballooning necrosis, lobular inflammation, and fibrosis according to a 2023 systematic review.[14] Semaglutide is in a Phase III study for non-alcoholic steatohepatitis, the more severe form of NAFLD, as of 2023.[15]

Polycystic ovary syndrome

GLP-1 agonists are recommended as a treatment for polycystic ovary syndrome, alone or in combination with metformin. The combination therapy has shown greater efficacy in improving body weight, insulin sensitivity, hyperandrogenism, and menstrual cycle irregularities.[16]

Depression

GLP-1 agonists have shown antidepressant and neuroprotective effects. They can also be used as treatment for the negative metabolic consequences of second-generation antipsychotics.[17][18]

Reward system disorders

GLP-1 agonists are under development for substance use disorder, a condition with few pharmacological treatment options. They reduce the self-administered intake of drugs and alcohol in non-human animals, although this effect has not been proven in humans. The mechanism of this addiction-reducing effect is unknown.[19] GLP-1 agonists are also under investigation for the treatment of binge eating disorder, which is the most common eating disorder.[20][21]

Adverse effects

The most common adverse effects of GLP-1 agonists are gastrointestinal.[11] These adverse effects limit the maximum tolerated dose and require gradual dose escalation.[22] Nausea, vomiting, diarrhea, and constipation are all commonly reported.[11] Reactions at the injection site are also common, especially with shorter acting drugs.[23]

Human trials and meta-analyses have found no association between the drugs and pancreatitis or pancreatic cancer. However, some case reports of pancreatitis have emerged in postmarketing reports, and the American Association of Clinical Endocrinologists recommends caution in people with a history of pancreatitis. Discontinuation is recommended if acute pancreatitis occurs. A FDA black box warning is required for the risk of thyroid C-cell tumors, and the drugs are contraindicated if there is a family or personal history of medullary thyroid cancer or multiple endocrine neoplasia type 2a or 2b.[4] In mice, long-term use of GLP-1 agonists stimulates calcitonin secretion, leading to C-cell hypertrophy and an increased risk of thyroid cancer. However, no increased secretion of calcitonin has been observed in humans.[23]

Like insulin, GLP-1 agonists can cause or exacerbate retinopathy, but this is believed to be caused indirectly by a rapid drop in glucose rather than a direct effect.[4]

GLP-1 agonists increase the risk of gallstones when used to induce rapid weight loss.[11]

Drug delivery

Native GLP-1 is a peptide hormone with a half-life of 2 minutes because it is rapidly cleared by the enzyme dipeptidyl peptidase-4.[23] As a result, different GLP-1 agonist drugs are modified in various ways to extend the half-life, resulting in drugs that can be dosed multiple times per day, daily, weekly, or even less often.[23] Most synthetic GLP-1 agonists are delivered via subcutaneous injection, which is a barrier to their use and reason for discontinuation.[24] Self-injected drugs are especially difficult for people with vision or motor difficulties, which are common in people with type 2 diabetes.[23] Attempts to develop an orally bioavailable GLP-1 agonist, either a modified peptide, as in the case of oral semaglutide,[24] or a small molecule drug have produced additional drug candidates.[22] Other companies have tested inhaled or transdermal administration.[23]

Cost

GLP-1 agonists are more expensive than other treatments for type 2 diabetes. A study compared the cost effectiveness of GLP-1 agonists to long-acting insulin in Taiwanese type 2 diabetes patients. In patients with CVD, GLP-1 agonists were estimated to save money due to fewer cardiovascular incidents. In patients without CVD, the cost per QALY was $9,093.[25] In the United States, cost is the highest barrier to GLP-1 agonist usage and was reported as the reason for discontinuation in 48.6 percent of US patients who stopped using the drugs.[26] According to another study, GLP-1 agonists are not cost effective for pediatric obesity in the United States.[27]

Approved

Combination and multiple target drugs

Some GLP-1 agonists, such as tirzepatide, are also agonists of the GIP receptor and/or glucagon receptor. These additional targets are hoped to improve the amount of weight loss caused by the drugs.[22] Combination with glucagon agonism is likely to make the drugs more efficacious for weight loss, at the expense of additional risk and a lower therapeutic index.[22]

GLP-1 agonists are available as combination medications with insulin to treat type 2 diabetes, although it is unclear whether these combination formulas offer an advantage over dosing insulin and GLP-1 agonists separately.[23][34] The experimental formula cagrilintide/semaglutide combines semaglutide with a dual amylin and calcitonin receptor agonist for additional weight loss.[35]

Off-label and recreational use

Besides their medical uses, GLP-1 agonists are also sought by many people for cosmetic weight loss, popularized by influencers and celebrities.[36] Gray market sellers offer unauthorized products claimed to be GLP-1 agonists online. This practice is illegal in the United States, but some buyers turn to unauthorized retailers due to being denied insurance coverage and not being able to afford the name brand drug.[37][38][39][40][41]

References

  1. ^ Drucker, Daniel J. (2022). "GLP-1 physiology informs the pharmacotherapy of obesity". Molecular Metabolism. 57: 101351. doi:10.1016/j.molmet.2021.101351. ISSN 2212-8778.
  2. ^ "GLP-1 Receptor Agonists vs. DPP-4 Inhibitors for Type 2 Diabetes".
  3. ^ Brown, Emily; Heerspink, Hiddo J L; Cuthbertson, Daniel J; Wilding, John P H (2021). "SGLT2 inhibitors and GLP-1 receptor agonists: established and emerging indications". The Lancet. 398 (10296): 262–276. doi:10.1016/S0140-6736(21)00536-5.
  4. ^ a b c d e Nachawi, Noura; Rao, Pratibha PR; Makin, Vinni (2022). "The role of GLP-1 receptor agonists in managing type 2 diabetes". Cleveland Clinic Journal of Medicine. 89 (8): 457–464.
  5. ^ American Diabetes Association Professional Practice Committee (January 2022). "9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2022". Diabetes Care. 45 (Suppl 1): S125–S143. doi:10.2337/dc22-S009. PMID 34964831. S2CID 245538347.
  6. ^ American Diabetes Association (January 2012). "Standards of medical care in diabetes--2012". Diabetes Care. 35 (Suppl 1): S11–S63. doi:10.2337/dc12-s011. PMC 3632172. PMID 22187469.
  7. ^ Sattar, Naveed; Lee, Matthew M Y; Kristensen, Søren L; Branch, Kelley R H; Del Prato, Stefano; Khurmi, Nardev S; Lam, Carolyn S P; Lopes, Renato D; McMurray, John J V; Pratley, Richard E; Rosenstock, Julio; Gerstein, Hertzel C (2021). "Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials". The Lancet Diabetes & Endocrinology. 9 (10): 653–662. doi:10.1016/s2213-8587(21)00203-5.
  8. ^ a b Sohn, Minji; Dietrich, Johannes W.; Nauck, Michael A.; Lim, Soo (2023). "Characteristics predicting the efficacy of SGLT-2 inhibitors versus GLP-1 receptor agonists on major adverse cardiovascular events in type 2 diabetes mellitus: a meta-analysis study". Cardiovascular Diabetology. 22 (1). doi:10.1186/s12933-023-01877-6.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  9. ^ DeFronzo, Ralph A. (2017). "Combination therapy with GLP-1 receptor agonist and SGLT2 inhibitor". Diabetes, Obesity & Metabolism. 19 (10): 1353–1362. doi:10.1111/dom.12982. ISSN 1463-1326.
  10. ^ Pedrosa, Maurício Reis; Franco, Denise Reis; Gieremek, Hannah Waisberg; Vidal, Camila Maia; Bronzeri, Fernanda; de Cassia Rocha, Alexia; de Carvalho Cara, Luis Gabriel; Fogo, Sofia Lenzi; Eliaschewitz, Freddy Goldberg (2022). "GLP-1 Agonist to Treat Obesity and Prevent Cardiovascular Disease: What Have We Achieved so Far?". Current Atherosclerosis Reports. 24 (11): 867–884. doi:10.1007/s11883-022-01062-2. ISSN 1534-6242.
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  12. ^ Müller, Timo D.; Blüher, Matthias; Tschöp, Matthias H.; DiMarchi, Richard D. (March 2022). "Anti-obesity drug discovery: advances and challenges". Nature Reviews Drug Discovery. 21 (3): 201–223. doi:10.1038/s41573-021-00337-8. ISSN 1474-1784.
  13. ^ Grill, Harvey J (2020). "A Role for GLP-1 in Treating Hyperphagia and Obesity". Endocrinology. 161 (8). doi:10.1210/endocr/bqaa093.
  14. ^ Gu, Yunpeng; Sun, Lei; He, Yining; Yang, Luping; Deng, Chaohua; Zhou, Run; Kong, Tingting; Zhang, Wei; Chen, Yutong; Li, Jie; Shi, Junping (4 March 2023). [10.1080/17474124.2023.2172397 "Comparative efficacy of glucagon-like peptide 1 (GLP-1) receptor agonists, pioglitazone and vitamin E for liver histology among patients with nonalcoholic fatty liver disease: systematic review and pilot network meta-analysis of randomized controlled trials"]. Expert Review of Gastroenterology & Hepatology. 17 (3): 273–282. doi:10.1080/17474124.2023.2172397. {{cite journal}}: Check |url= value (help)
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  18. ^ Pozzi, Marco; Mazhar, Faizan; Peeters, Gabriëlla G. A. M.; Vantaggiato, Chiara; Nobile, Maria; Clementi, Emilio; Radice, Sonia; Carnovale, Carla (2019). "A systematic review of the antidepressant effects of glucagon-like peptide 1 (GLP-1) functional agonists". Journal of Affective Disorders. 257: 774–778. doi:10.1016/j.jad.2019.05.044. ISSN 0165-0327.
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  20. ^ Da Porto, Andrea; Casarsa, Viviana; Colussi, Gianluca; Catena, Cristiana; Cavarape, Alessandro; Sechi, Leonardo (July 2020). "Dulaglutide reduces binge episodes in type 2 diabetic patients with binge eating disorder: A pilot study". Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 14 (4): 289–292. doi:10.1016/j.dsx.2020.03.009.
  21. ^ Richards, Jesse; Bang, Neha; Ratliff, Erin L.; Paszkowiak, Maria A.; Khorgami, Zhamak; Khalsa, Sahib S.; Simmons, W. Kyle (September 2023). "Successful treatment of binge eating disorder with the GLP-1 agonist semaglutide: A retrospective cohort study". Obesity Pillars. 7: 100080. doi:10.1016/j.obpill.2023.100080.
  22. ^ a b c d Knerr, Patrick J.; Mowery, Stephanie A.; Finan, Brian; Perez-Tilve, Diego; Tschöp, Matthias H.; DiMarchi, Richard D. (2020). "Selection and progression of unimolecular agonists at the GIP, GLP-1, and glucagon receptors as drug candidates". Peptides. 125: 170225. doi:10.1016/j.peptides.2019.170225. Cite error: The named reference "Knerr" was defined multiple times with different content (see the help page).
  23. ^ a b c d e f g Yu, Minzhi; Benjamin, Mason M.; Srinivasan, Santhanakrishnan; Morin, Emily E.; Shishatskaya, Ekaterina I.; Schwendeman, Steven P.; Schwendeman, Anna (2018). "Battle of GLP-1 delivery technologies". Advanced Drug Delivery Reviews. 130: 113–130. doi:10.1016/j.addr.2018.07.009.
  24. ^ a b Antza, Christina; Nirantharakumar, Krishnarajah; Doundoulakis, Ioannis; Tahrani, Abd A.; Toulis, Konstantinos A. (2019). "The development of an oral GLP-1 receptor agonist for the management of type 2 diabetes: evidence to date". Drug Design, Development and Therapy. 13: 2985–2996. doi:10.2147/DDDT.S166765.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  25. ^ Yang, Chun-Ting; Yao, Wen-Yu; Ou, Huang-Tz; Kuo, Shihchen (April 2023). "Value of GLP-1 receptor agonists versus long-acting insulins for type 2 diabetes patients with and without established cardiovascular or chronic kidney diseases: A model-based cost-effectiveness analysis using real-world data". Diabetes Research and Clinical Practice. 198: 110625. doi:10.1016/j.diabres.2023.110625. ISSN 1872-8227.
  26. ^ Moore, Peyton W.; Malone, Kevin; VanValkenburg, Delena; Rando, Lauren L.; Williams, Brooke C.; Matejowsky, Hannah G.; Ahmadzadeh, Shahab; Shekoohi, Sahar; Cornett, Elyse M.; Kaye, Alan D. (2023). "GLP-1 Agonists for Weight Loss: Pharmacology and Clinical Implications". Advances in Therapy. 40 (3): 723–742. doi:10.1007/s12325-022-02394-w.
  27. ^ Lim, Francesca; Bellows, Brandon K.; Tan, Sarah Xinhui; Aziz, Zainab; Woo Baidal, Jennifer A.; Kelly, Aaron S.; Hur, Chin (2023). "Cost-Effectiveness of Pharmacotherapy for the Treatment of Obesity in Adolescents". JAMA Network Open. 6 (8): e2329178. doi:10.1001/jamanetworkopen.2023.29178. ISSN 2574-3805.
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  29. ^ Busko, Marlene (15 April 2014). "FDA Approves Weekly Injectable Diabetes Drug: Albiglutide". Medscape (News, FDA Approvals).
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  32. ^ Tibble CA, Cavaiola TS, Henry RR (10 January 2014). "Longer acting GLP-1 receptor agonists and the potential for improved cardiovascular outcomes: a review of current literature". Expert Review of Endocrinology & Metabolism. 8 (3). Taylor & Francis: 247–259. doi:10.1586/eem.13.20. eISSN 1744-8417. ISSN 1744-6651. PMID 30780817. S2CID 73313508.
  33. ^ Frías JP, Davies MJ, Rosenstock J, Pérez Manghi FC, Fernández Landó L, Bergman BK, et al. (August 2021). "Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes". The New England Journal of Medicine. 385 (6): 503–515. doi:10.1056/NEJMoa2107519. PMID 34170647. S2CID 235635529.
  34. ^ Castellana, Marco; Cignarelli, Angelo; Brescia, Francesco; Laviola, Luigi; Giorgino, Francesco (2019). "GLP ‐1 receptor agonist added to insulin versus basal‐plus or basal‐bolus insulin therapy in type 2 diabetes: A systematic review and meta‐analysis". Diabetes/Metabolism Research and Reviews. 35 (1). doi:10.1002/dmrr.3082. ISSN 1520-7552.
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