Anti-obesity counseling -
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Drugs Today 43 , 13—25 Huthmacher, J. Efficacy and safety of short- and long-acting glucagon-like peptide 1 receptor agonists on a background of basal insulin in type 2 diabetes: a meta-analysis.
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This article shows that the insulinotropic effect of GIP is impaired in patients with T2D. Chan, J. Roth, J. Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies. Natl Acad. USA , — Trevaskis, J.
Amylin-mediated restoration of leptin responsiveness in diet-induced obesity: magnitude and mechanisms. Endocrinology , — Cavaco, M. Peptibodies: an elegant solution for a long-standing problem.
Mroz, P. Optimized GIP analogs promote body weight lowering in mice through GIPR agonism not antagonism. Zhang, Q. The glucose-dependent insulinotropic polypeptide GIP regulates body weight and food intake via CNS-GIPR signaling.
e5 This article shows that long-acting GIP decreases body weight and food intake via CNS GIPR signalling. Glucose-dependent insulinotropic polypeptide receptor-expressing cells in the hypothalamus regulate food intake.
e6 Dowsett, G. A survey of the mouse hindbrain in the fed and fasted states using single-nucleus RNA sequencing. Day, J. A new glucagon and GLP-1 co-agonist eliminates obesity in rodents.
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The role of GIP in the regulation of GLP-1 satiety and nausea. Diabetes 70 , — This article shows that GIP attenuates GLP1-mediated effects on emesis in rodents and shrews. Hojberg, P. Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes.
Diabetologia 52 , — This article shows that an insulin-mediated decrease of hyperglycaemia restores the insulinotropic effects of GIP. Samms, R. How may GIP enhance the therapeutic efficacy of GLP-1?
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A novel dual glucagon-like peptide and glucagon receptor agonist SAR results of randomized, placebo-controlled first-in-human and first-in-patient trials.
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Obesity 18 , 21—26 Turek, V. Restoration of leptin responsiveness in diet-induced obese mice using an optimized leptin analog in combination with exendin-4 or FGF Bello, N. Dose combinations of exendin-4 and salmon calcitonin produce additive and synergistic reductions in food intake in nonhuman primates.
Neary, N. Peptide YY3—36 and glucagon-like peptide—36 inhibit food intake additively. Synergistic metabolic benefits of an exenatide analogue and cholecystokinin in diet-induced obese and leptin-deficient rodents. Clemmensen, C. Dual melanocortin-4 receptor and GLP-1 receptor agonism amplifies metabolic benefits in diet-induced obese mice.
EMBO Mol. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Unimolecular polypharmacy for treatment of diabetes and obesity. The novel GIP, GLP-1, and glucagon triple receptor agonist LY exhibits robust efficacy in preclinical models of obesity and diabetes.
In American Diabetes Association 81st Scientific Sessions American Diabetes Association, The role of leptin in anorexia nervosa: clinical implications. Psychiatry 12 , 23—35 Chou, S. Leptin is an effective treatment for hypothalamic amenorrhea.
Welt, C. Recombinant human leptin in women with hypothalamic amenorrhea. Chehab, F. Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Licinio, J. Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults.
Milos, G. Short-term metreleptin treatment of patients with anorexia nervosa: rapid on-set of beneficial cognitive, emotional, and behavioral effects. Psychiatry 10 , Immunogenicity associated with metreleptin treatment in patients with obesity or lipodystrophy.
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Lutz, T. Control of food intake and energy expenditure by amylin — therapeutic implications. Young, A. Roles of amylin in diabetes and in regulation of nutrient load. Nutrition 14 , — Boyle, C. Amylin — its role in the homeostatic and hedonic control of eating and recent developments of amylin analogs to treat obesity.
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KBP, a novel DACRA with prolonged receptor activation, is superior to davalintide in terms of efficacy on body weight. Hjuler, S. KBP improves bodyweight and glucose homeostasis with indices of increased insulin sensitivity irrespective of route of administration. Mack, C. Davalintide AC , a novel amylin-mimetic peptide: enhanced pharmacological properties over native amylin to reduce food intake and body weight.
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Ghrelin and appetite control in humans — potential application in the treatment of obesity. Peptides 32 , — Lu, S. An acyl-ghrelin-specific neutralizing antibody inhibits the acute ghrelin-mediated orexigenic effects in mice.
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Cells 8 , Geisler, J. Perry, R. Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats. Axelrod, C. BAMmediated mitochondrial uncoupling protects against obesity and improves glycemic control.
Alexopoulos, S. Mitochondrial uncoupler BAM15 reverses diet-induced obesity and insulin resistance in mice. Hale, C. Growth differentiation factor 15 as a potential therapeutic for treating obesity.
Assadi, A. GDF15, an update of the physiological and pathological roles it plays: a review. Kempf, T. GDF is an inhibitor of leukocyte integrin activation required for survival after myocardial infarction in mice. Mullican, S. GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates.
Borner, T. GDF15 induces anorexia through nausea and emesis. Other medications such as metformin, zonisamide, and other GLP-1 RAs normally used for treating diabetes are often prescribed " off label " and at the discretion of the prescriber for the treatment of obesity.
Medication treatment of obesity has been a tumultuous arena plagued by many instances of therapeutics being unable to demonstrate sufficient safety data to warrant FDA approval, such as rimonabant Acomplia ; or of adverse effects necessitating market withdrawal, such as lorcaserin Belviq , sibutramine Meridia , dexfenfluramine Redux , fenfluramine Pondimin , and the infamous combination medication fen-phen — a drug which, despite its extreme popularity in the s, was never actually granted FDA approval.
Unfortunately, the rocky anti-obesity medication landscape often leads to discomfort among clinicians in using the many safe and effective tools we currently have for treating obesity, or worse, hesitance to address obesity as a health concern at all.
For those who do prescribe anti-obesity pharmacotherapy, challenges arise with the exorbitant cost of some of the newer therapeutics, as well as refusal of many private and public insurers to cover anti-obesity medications.
Sometimes patients or their advocates may have success in lobbying their employers to opt in to insurance coverage for obesity management. However, for those on Medicare or Medicaid, there is currently absolutely no coverage for anti-obesity medications.
Patients without coverage are left with the choice of paying out of pocket for a lower-cost generic anti-obesity medication; taking a medication primarily intended for treating other medical conditions such as diabetes or seizures that may also help with weight loss; or, if their BMI and health status is severe enough to satisfy insurance requirements, they may opt for bariatric surgery, a much more widely covered insurance benefit.
The Treat and Reduce Obesity Act is a bill that was first introduced to Congress in and most recently reintroduced in , with the goal of amending the Medicare Social Security Act to authorize insurance coverage of obesity counseling services and FDA-approved anti-obesity medications.
This remains the largest hurdle in the obesity treatment landscape: gaining sufficient buy-in from government agencies, employers, and insurers by convincing them that medications targeting the most prevalent chronic disease in the US are actually worth paying for. Second, decreased appetite was common.
There are two randomized, placebo-controlled, double-blind clinical trials for subcutaneous injection of SAR [ 72 ]. As a result, SAR lowered fasting blood glucose and glycated hemoglobin in T2DM patients, and reduced weight by up to 5. No clinical studies have yet been performed to verify the long-term weight loss effect of SAR In a randomized, placebo-controlled, double-blind, combined multiple-ascending dose and phase 2a study, T2DM patients glycated hemoglobin A1c 6.
The body weight in the MEDItreated group was 3. Gastrointestinal disease and loss of appetite were more frequent in the MEDI group than in the placebo group. In , cetilistat, a pancreatic lipase inhibitor, was approved as a treatment for obesity in Japan, which was marketed as Oblean® by Takeda.
It has a role in the same way as orlistat by inhibiting pancreatic lipase, an enzyme that hydrolyzes triglycerides into absorbable free fatty acids in the intestine. The recommended dose was mg three times a day immediately after each meal. A week, multicenter, randomized, double-blind, phase 2 clinical trial was conducted in obese patients with diabetes.
The cetilistat group lost 3. Glycosylated hemoglobin was also reduced. Its side effects were similar to those of the orlistat group and were well tolerated. However, there are no studies on the long-term effects of cetilistat on weight loss and safety.
Tesofensine also known as NS is a novel triple monoamine reuptake inhibitor with intrinsic inhibitory activity on norepinephrine, serotonin, and dopamine transporter function. Its appetite suppression and energy consumption-increasing effects have been confirmed; therefore, it is expected to be an obesity treatment [ 75 ].
The mean weight loss after 24 weeks was 2. The most common side effects were dry mouth, nausea, constipation, hard stools, diarrhea, and insomnia. In the tesofensine 0. The results of a phase 3 study of tesofensine have not been reported.
Ghrelin, known as the hunger hormone, is produced by the peripheral organs and acts to centrally stimulate the appetite [ 78 ]. Two major forms of ghrelin exist in circulation: acylated ghrelin AG which is active form of circulating ghrelin and unacylated ghrelin UAG. Ghrelin O-acyl transferase GOAT has been considered the main enzyme responsible for acylation of ghrelin, and emerging as an important molecule in treating obesity [ 79 ].
In preclinical studies, treatment with GOAT inhibitor resulted in decreased food intake [ 77 , 80 ]. Recently, GLWL Research Inc.
Montreal, QC, Canada has completed a phase 2 trial to evaluate the efficacy, safety, and pharmacokinetics of GLWL 01 orally available GOAT inhibitor for treating hyperphagia in patients with Prader-Willi syndrome PWS aged 16—65 years NCT [ 81 ].
Leptin, produced by adipocytes, was initially considered a potential target for development in anti-obesity medication as early animal studies showed the linkage between leptin deficiency and severe obesity [ 11 ].
However, on the contrary, human study showed that patients with obesity were leptin-resistant and had higher levels of leptin [ 82 ]. Currently, mechanisms to improve leptin resistance through combination therapy have been explored.
Metreleptin Myalept is an injectable human recombinant leptin analogue and approved in Japan and the USA for the treatment of complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy [ 83 ].
Human studies including children have demonstrated the effect of Metreleptin on improving hyperglycemia, hypertriglyceridemia, and hepatic fatty steatosis in patients with lipodystropy characterized by congenital or acquired loss of adipose tissue [ 84 , 85 ].
Anti-metreleptin antibodies with neutralizing activity have been identified in patients treated with metreleptin [ 86 ]. The consequences are not well characterized due to the small number of reports however, could include inhibition of endogenous leptin action resulting in loss of the drug efficacy.
Regardless of treatment with metreleptin, T cell lymphoma has been reported in patients with acquired generalized lipodystrophy. Because of these, metreleptin is not indicated for use in patients with general obesity without concurrent evidence of generalized lipodystrophy or those with HIV-related lipodystrophy [ 87 ].
Amylin secreted by pancreatic β-cells acts to reduce post-prandial glucagon secretion, slow gastric emptying, and centrally increase satiety [ 88 ]. Pramlintide, amylin analogue, was licensed by the FDA in for diabetic patients.
Early studies showed that pramlintide use in patients with insulin-treated diabetes improved glycemic control and supported weight reduction by decreasing food intake [ 89 ].
A subsequent study of pramlintide demonstrated an additional mean weight loss of 3. placebo in obese patients without T2DM or with non-insulin-treated T2DM [ 89 ]. While pramlintide monotherapy resulted in 1.
Davalintide, a second-generation amylin analogue, was developed and completed phase II trials. However, weight reduction with the drug were disappointing causing discontinuation in its development [ 91 ].
As the human amylin receptor consists of calcitonin receptor with activity-modifying proteins amylin analogues in combination with calcitonin receptor agonists, known as dual action amylin and calcitonin receptor agonists, are novel anti-obesity agent targets of study [ 92 ]. While animal studies KBP, KBP showed anti-obesity effect [ 93 , 94 ], human clinical trials are still awaited.
Setmelanotide also known as RM is a potent and selective melanocortin-4 receptor MC4R agonist [ 95 ]. The activation of MC4R, a seven-transmembrane domain G protein-coupled receptor, inhibits food intake and stimulates energy expenditure, leading a negative energy balance and potentially weight reduction.
With high affinity to the human MC4R, setmelanotide activates MC4R efficiently and has potential in resolving obesity [ 96 , 97 ]. In a phase 2, randomized, double-blind, placebo-controlled pilot study to evaluate the effects of a once daily subcutaneous injectable formulation of setmelanotide NCT , 40 patients with Prader-Willi syndrome PWS aged 16—65 years treated with the highest dose achieved clinically meaningful weight reduction despite modest improvement in hyperphagia [ 98 ].
SGLT-2 inhibitors, such as dapagliflozin, empagliflozin, and canagliflozin, block glucose reabsorption from the renal tubules and result in glycosuria energy deficit. Previous RCTs reported that selective SGLT2 inhibitors, a new class of anti-diabetes drugs, have been shown to reduce body weight 1—3 kg reduction in diabetic patients with and without obesity [ 99 , , , ].
In previous clinical trials that examined SGLT2 inhibitors in combination with phentermine, additional weight loss was achieved 6. Similarly, SGLT-2 inhibitors combined with a GLP-1 agonist caused a greater weight reduction than individual administration of each agent [ , ].
In addition, it has been reported that by inhibiting SGLT-1, expressed in the small intestine, absorption of intestinal glucose and galactose decreases, while GLP-1 and PYY increase.
AMP-activated protein kinase AMPK and mammalian sirtuin 1 Sirt1 are regulators of lipid and energy metabolism that inhibit fat accumulation and stimulate fatty acid oxidation via reciprocal activation [ ]. L-leucine is known as an allosteric activator of Sirt1 and metformin is a synergistic coactivator of sirtuin pathway signaling.
Sirt1 also is stimulated by nitric oxide NO , which is enhanced through sildenafil, a phosphodiesterase type 5 inhibitor. Given the high prevalence and severity of obesity endemic, there are many fewer therapeutic options for weight control medication than those for other chronic diseases such as hypertension, T2DM, and dyslipidemia.
Despite a lot of evidence demonstrating significant weight loss effects and safety of pharmacotherapy, and many guidelines emphasize the importance of anti-obesity medications for patients who fail to lose weight with lifestyle modification; these medications are still underused [ 8 , ].
One of the main reasons for the under-prescription of anti-obesity drugs is the side effects. Since obesity develops via multifactorial pathways, a single drug might exhibit limited efficacy. Thus, a high dose is often required, which often causes unacceptable side effects.
The majority of side effects of anti-obesity drugs are dose-dependent. Therefore, combination therapy consisting of multiple anti-obesity drugs with complementary modes of action is warranted to broaden the target energy regulatory systems and maximize the effect on weight management while maintaining safety and tolerability [ ].
Meanwhile, current anti-obesity drugs approved for chronic weight loss generally have favorable effects on cardio-metabolic parameters. Thus, many patients with obesity are reluctant to discuss their body weight with doctors because they feel ashamed or helpless to seek care for it [ ].
Physicians may also be too busy to address the weight problems of their patients and consider it more efficient to treat obesity-related comorbidities [ , ]. Weight loss is extremely challenging to achieve and sustain, and long-term management of obesity often requires adjunctive pharmacological interventions.
The high cost of long-term use of these medications also prevents adequate prescription. Furthermore, once drug therapy is discontinued, weight reduction is not generally sustained; thus, adherence and persistence with the medication are essential determinants of real-clinical strategies for weight control [ ].
In a recent study investigating persistence with anti-obesity medications, liraglutide 3. Male sex, older age, concominent hyperlipidemia, and never phentermine users were associated with higher persistence [ ].
As a result, the decision to initiate drug therapy in an obese individual should be made after the risks and benefits are considered. Importantly, health providers should determine the risk-benefit profile of a given anti-obesity drug on a patient-by-patient basis.
Furthermore, the treatment goals should be clear. Patient preferences based on tolerability markedly affect adherence and can cause poor adherence or discontinuation, thereby negating the treatment effects [ , ]. The goal of treatment with anti-obesity drugs in obese individuals should be long-term maintenance of weight reduction and improvement in overall health.
Obesity, similar to hypertension and diabetes, is a chronic progressive disease, resulting from multiple environmental and genetic factors that require lifelong management.
In case of hypertension and diabetes, drugs are used if BP and blood sugar levels are not controlled by adequate therapeutic lifestyle changes. If BP and blood sugar are properly controlled with drugs without any serious side effects, the drugs are administered continuously.
Anti-obesity drugs should be treated in similar manner. However, obese patients as well as some doctors are still reluctant to continue using anti-obesity drugs. Through this review along with safety data, we looked at drugs with long-term usage that reduce weight and improve comorbid diseases or conditions in patients with obesity.
Most of the previous trials conducted on these drugs also controlled diet and exercise in both the placebo and treatment groups. Thus, these medications were proposed for use as pharmacotherapy in conjunction with healthy eating, physical activity, and behavioral modification.
It is necessary to select these anti-obesity drugs that have proven long-term effectiveness and are safe. In addition, physicians should continue to follow-up on the problems and prognosis of patients with obesity. GBD Causes of Death Collaborators. Global, regional, and national age-sex-specific mortality for causes of death in countries and territories, a systematic analysis for the Global Burden of Disease Study Google Scholar.
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