The pharmaceutical industry continues to search for new drugs that effectively and safely cope with obesity, type 2 diabetes, and nonalcoholic steatohepatitis (NASH), three inextricably linked metabolic diseases that affect many hundreds of millions of people.

It should be understood that we are only talking about prescription drugs that have proven their therapeutic validity in strictly controlled clinical trials. We are not talking about fat burners, diet pills, herbal or “natural” remedies, and dietary supplements (food supplements, nutritional supplements, nutraceuticals, health supplements), which are offered in abundance on the Internet.

  • Remember: Absolutely all of the fat burners, diet pills, herbal or “natural” remedies, and dietary supplements (food supplements, nutritional supplements, nutraceuticals, health supplements) advertised on the Internet DO NOT WORK. None of them promote weight loss with scientifically proven and clinically significant effectiveness and at the same time unqualified safety. Without exception, all of the above products, which are actively promoted on the Internet and can be ordered by mail order, either provide very little effect for those wishing to lose weight (as confirmed in clinical trials), or their effect on humans has not been proven in any way (only in animal models), or they are harmful to health (in some cases fatal).

The first generation of weight loss drugs provided very modest weight loss. These prescription weight loss medications, indicated for long-term body weight management, allowed for 5.5%–10.4% weight loss over the one-year course of treatment. For the sake of clarity, similar results can be achieved by intensive lifestyle changes through diet and exercise.

Such a negligible effect of the weight loss pills offered by pharmaceutical companies led to the fact that the world market of prescription weight loss drugs for a long time was, well, very limited, although obesity is a global problem. Consumers simply did not want to spend money on ineffective drugs, and often more believed the tales of miraculous slimming pills, which are ubiquitously sold on the Internet and which promise amazing results.

  • The first generation of prescription weight loss drugs includes the following medications: Meridia (sibutramine), Xenical/Alli (orlistat), Belviq (lorcaserin), Qsymia (phentermine + topiramate), Contrave/Mysimba (bupropion + naltrexone), and Saxenda (liraglutide).

That all changed in early June 2021 when Novo Nordisk offered Wegovy (semaglutide), which seriously raised the bar for effectiveness in the pharmacological fight against obesity.

Wegovy: Most Effective Drug for Weight Loss

Semaglutide can help you lose 15% of your weight in a year. And even more.

If the effectiveness of Wegovy is averaged — that is, without regard to the presence or absence of diabetes, whether or not one follows a program of lifestyle changes (diet with caloric restriction and increased physical activity), the degree of adherence to treatment (compliance with therapeutic regime, which involves weekly subcutaneous injections of the drug) — it turns out that one year of stable therapy with Wegovy (plus 4-month period of gradually increasing the dose) can achieve 15.2% weight loss.

Wegovy, which has managed to cross the 15% weight loss threshold, is a second-generation prescription weight loss drug.

Novo Nordisk went to Wegovy relatively leisurely, first taking up the treatment of type 2 diabetes: Ozempic (semaglutide) appeared in December 2017 and Rybelsus (semaglutide) as an oral version of Ozempic in tablets was introduced in September 2019.

Wegovy: Impressive Success of Semaglutide for Weight Loss

Novo Nordisk’s newest drug did well in treating obesity and overweight.

Weight loss is especially important for patients with type 2 diabetes, because it helps reduce blood glucose levels. For example, a 5%–10% decrease in body weight is reflected by a 0.3%–1.0% decrease in glycated hemoglobin (HbA1c). It is reasonable to stick to the approximate calculation that the loss of each kilogram is accompanied by a decrease in HbA1c level by 0.1%. Note that such a linear correlation may fluctuate: with the same degree of weight loss the decrease in HbA1c level will be greater with poor glycemic control than with good glycemic control.

The pharmaceutical companies are not stopping there, and now other weight loss “pills,” promising even more impressive effectiveness, are being actively tested clinically.

The key idea for treating obesity with prescription weight loss medications is to make them as effective as bariatric surgery for weight loss.

Bariatric surgery, which, being very diverse in the way it is performed, leads to proper weight loss in a short period of time. Moreover, the effect lasts for a long time, up to 10 years. Despite a number of advantages of such surgical procedures, which also relieve type 2 diabetes, hypertension, sleep apnea, joint pains, depression, etc., bariatrics is in most cases an irreversible surgical intervention, and complications may accompany it, including vitamin and mineral deficiencies (due to insufficient absorption of nutrients). In contrast, pharmacotherapy for obesity can always be reversed: If the body begins to respond inappropriately to the medications used, they are easily discontinued.

  • According to a retrospective review of case histories of 45,500 bariatric patients from 2005–2015, Roux-en-Y gastric bypass (RYGB) resulted in an average annual weight loss of 31.2%, sleeve gastrectomy (SG) of 25.2%, and laparoscopic adjustable gastric band (LAGB) of 13.7%.
  • When it comes to getting rid of directly excess weight, which is defined as the number of excess pounds above ideal body weight, according to a systematic review and meta-analysis of data from 1993–2017, the results of bariatric surgery, in descending order of effectiveness, are as follows:
  • one anastomosis gastric bypass (OAGB) provided an average of 80.9% elimination of excess weight
  • duodenal switch (DS) — 75.2%
  • biliopancreatic diversion (BPD) — 71,5%
  • sleeve gastrectomy (SG) — 57,0%
  • Roux-en-Y gastric bypass (RYGB) — 55,4%
  • gastroplasty, including vertical banded gastroplasty (VBG) and horizontal gastroplasty (HGP) — 50,9%
  • laparoscopic adjustable gastric band (LAGB) — 45,9%.



Glucagon-like peptide-1 receptor (GLP1R) agonists have long proven their usefulness in the treatment of type 2 diabetes and obesity. This is evidenced by an extensive armamentarium of related drugs, whose global sales in 2019, 2020, and 2021 combined brought in $10.6 billion, $12.8 billion, and $16.8 billion:

  • Victoza (liraglutide), Saxenda (liraglutide), Ozempic (semaglutide), Rybelsus (semaglutide), and Wegovy (semaglutide) by Novo Nordisk
  • Trulicity (dulaglutide) by Eli Lilly
  • Byetta (exenatide) by AstraZeneca
  • Bydureon/Byetta Long (exenatide) by AstraZeneca
  • Adlyxin/Lyxumia (lixenatide) by Sanofi
  • Tanzeum/Eperzan (albiglutide) by GlaxoSmithKline.
What Is Glucagon-Like Peptide-1 (GLP-1)?

Glucagon-like peptide-1 (GLP-1), which is a peptide hormone, is secreted by enteroendocrine L-cells in the mucosa in the distal ileum and colon and by certain neurons of the solitary tract in the medulla oblongata.

GLP-1 stimulates insulin secretion in a glucose-dependent manner, provides insulin replenishment in pancreatic beta cells to prevent depletion during its secretion, and increases the mass of beta cells by stimulating their proliferation and neogenesis and suppressing apoptosis. GLP-1 suppresses glucagon secretion at glucose levels above fasting levels.

Agonist activation of GLP-1 receptors (GLP1Rs) signaling has an insulinotropic effect that promotes insulin secretion in response to food intake. GLP1Rs are expressed in pancreatic beta cells, various types of gastrointestinal cells, and neurons of the central and peripheral nervous systems.

Additional effects of GLP1Rs agonism are manifested by delayed gastric content evacuation, decreased gastric juice secretion, and decreased gastric motility. All this leads to suppression of appetite and reduction of postprandial blood glucose level increase, but is reflected by undesirable phenomena in the form of nausea. Among others: decrease in plasma glucagon level (glucagon increases blood glucose concentration and promotes gluconeogenesis and glycogenolysis) and activation of anorexigenic pathways in the brain (mediates weight loss).

The metabolic effects of GLP1R agonism are not accompanied by a risk of hypoglycemic events in diabetics.

Despite the fact that GLP1R agonists are quite adequate for the task of reducing body weight and blood sugar levels, their effectiveness is still insufficient, and therefore it makes sense to enhance it.

This can be done by additional activation of incretins, a group of metabolic hormones that stimulate blood glucose lowering. Incretins are released after a meal, by a glucose-dependent mechanism, increasing insulin production secreted by beta cells of pancreatic islets of Langerhans. In addition to glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) is one of the incretins. Together GLP-1 and GIP are responsible for the secretion of approximately 70% of insulin in response to food intake.

What is Glucose-Dependent Insulinotropic Polypeptide (GIP)?

Glucose-dependent insulinotropic polypeptide (GIP), formerly known as gastric inhibitory polypeptide (mistakenly thought to inhibit gastric juice secretion), is a peptide hormone of the secretin family that is secreted by enteroendocrine K-cells of the duodenum and jejunum mucosa.

The function of GIP is to induce insulin secretion, which is stimulated primarily by glucose hyperosmolarity in the duodenum. GIP suppresses apoptosis of pancreatic beta cells by promoting their proliferation. GIP receptors (GIPRs) are expressed in many organs and tissues, including the central nervous system, allowing GIP to affect appetite and satiety regulation.

GIP, unlike GLP-1, simultaneously exhibits dose-dependent glucagonotropic and insulinotropic effects, depending on glycemia: in euglycemia (normoglycemia) and hypoglycemia it stimulates glucagon secretion, in hyperglycemia it stimulates insulin secretion and has glucagonostatic action. In the first case, it prevents fat formation, in the second case, on the contrary, it leads to its accumulation.

Although both GIPRs and GLP1Rs are present in pancreatic beta cells, the expression of GIPRs in tissues outside the pancreas differs from that of GLP1Rs. Thus, GIPRs are abundantly present in adipose tissue and many non-overlapping regions of the central nervous system.

Eli Lilly did just that, adding the GIPR agonist to the GLP1R agonist. The resulting combination formed the basis of tirzepatide. It is appropriate to note that combining GLP1R and GIPR agonists is justified by the fact that the therapeutic benefit from GIPR alone is strongly insufficient, since the incretin response to GIP is severely impaired in type 2 diabetes due to the suppression of GIPR regulation by high circulating blood glucose levels. But resistance to GIP is easily overcome by antidiabetic drugs such as GLP1R agonists.

In May 2022, the corresponding drug Mounjaro (tirzepatide) appeared for the treatment of type 2 diabetes to improve glycemic control. The combination of incretin agonists proved its worth: The effectiveness of Mounjaro surpassed that of all other GLP1R agonists, including Ozempic.

sugar 1024x645 - Most Effective Weight Loss Drugs: Present and Future
Mounjaro: New Dual-Action Drug for Type 2 Diabetes Mellitus

Tirzepatide by Eli Lilly is a powerful new antidiabetic drug.

Eli Lilly is now conducting an extensive clinical program to make sure that tirzepatide is suitable for weight loss in obesity or overweight and for as wide a patient population as possible. The finished drug would not be called Mounjaro, but something else to distinguish it from the antidiabetic drug. Novo Nordisk is turning to the same branding approach, which has differentiated between Ozempic and Wegovy even though they are based on the same semaglutide.

Pharmacology Features of Tirzepatide

The pharmacology of tirzepatide differs from that of other multi-incretin agonists in clinical trials. The pertinent characterization of tirzepatide is as follows: “imbalanced” dual agonist equally in terms of both enhanced affinity and potency in favor of GIPR over GLP1R and shifted agonism at GLP1R compared to pleiotropic activity at GIPR.

Tirzepatide shows an affinity for GIPR equal to that of native GIP, but binds GLP1R with an affinity weakened by approximately 5-fold relative to that of native GLP-1.

The imbalanced nature of tirzepatide is critical to maximizing its efficacy as a dual agonist because dose escalation for GLP1R activation is usually limited by gastrointestinal adverse events such as nausea and vomiting, whereas GIPR activation is not associated with such events. As a consequence, the pharmacological profile of tirzepatide, which favors GIPR potentiation, provides an opportunity for full engagement in this pathway while minimizing GLP1R agonist–related tolerability issues.

SURMOUNT-1 (NCT04184622), the first completed phase 3 (randomized, double-blind, placebo-controlled, multicenter, international) clinical trial of tirzepatide, showed that its weekly administration by subcutaneous injection at doses of 5, 10, or 15 mg for 72 weeks resulted in weight loss of 16.0% (16.1 kg), 21.4% (22.2 kg), and 22.5%(23.6 kg) — versus 2.4% (2.4 kg) in the placebo group.

Tirzepatide: Strong Weight-Loss Drug

Losing 24 kilograms in a year and a half.

The baseline weight of adult patients (n=2,539) who were obese or overweight (and without type 2 diabetes) was an average of 104.8 kg, and the reported weight loss rates were fair for those participants who strictly followed the treatment protocol. Subjects were instructed to follow a lifestyle change program, which involved reducing caloric intake (by 500 kcal/day) and increased physical activity (at least 150 min/week).

Tirzepatide was characterized by acceptable tolerability, and adverse events, mostly mild-to-moderate, mainly came, as with other GLP1R agonists, from the gastrointestinal tract (nausea, diarrhea, constipation, dyspepsia, and vomiting).

Tirzepatide, first, crossed the 20% threshold in the task of pharmacological weight loss in obesity or overweight and, second, a third of patients (36%) achieved weight loss of 25% or more, which is comparable to the results of bariatric surgery. Thus, tirzepatide, which has taken the place of today’s strongest weight loss drug, is appropriately classified as a third-generation prescription weight loss drug.



Eli Lilly, emboldened by the success of tirzepatide and determined that it was possible to go further to enhance the effectiveness of obesity and type 2 diabetes treatment, has engaged in the development of retatrutide.

Retatrutide (LY3437943), being a multi-receptor incretin agonist, is a glucagon-like peptide-1 receptor (GLP1R) agonist, a glucose-dependent insulinotropic polypeptide receptor (GIPR) agonist, and a glucagon receptor (GCGR) agonist — the so-called GGG triple agonist.

What Is Glucagon?

Glucagon is a peptide hormone in the secretin family produced by alpha cells of the pancreas. Glucagon increases the concentration of glucose and fatty acids in the blood and is considered the body’s main catabolic hormone. The action of glucagon is opposite to that of insulin, which decreases extracellular glucose levels.

The pancreas releases glucagon when blood glucose levels become too low. Glucagon forces the liver to begin glycogenolysis, the conversion of stored glycogen into glucose, which enters the bloodstream. High blood glucose levels, on the other hand, stimulate the release of insulin, which allows glucose to be absorbed and used by insulin-dependent tissues. Thus, glucagon and insulin are part of a feedback system that maintains stable blood glucose levels. Glucagon increases energy expenditure and is elevated under conditions of stress.

Glucagon increases blood glucose concentrations by stimulating gluconeogenesis and glycogenolysis. Glucagon decreases fatty acid synthesis in adipose tissue and the liver and stimulates lipolysis in these tissues, causing them to release fatty acids into the circulatory stream where they can be catabolized for energy in tissues like skeletal muscles.

Pharmacology Features of Retatrutide

The balance of retatrutide activity is modified towards GIPR agonism: The drug compound is characterized by 1.7-fold and 2.5-fold reduced potency at GLP1R and GCGR, respectively, and 7-fold increased potency at GIPR; all in relation to native ligands.

This was done to mitigate possible adverse events, which in the case of GLP1R agonism are generally tolerable gastrointestinal side effects, whereas in the case of GCGR agonism are more pronounced and severe systemic ones.

The NCT04143802 phase 1 (randomized, double-blind, placebo-controlled, active-controlled, multicenter) clinical trial enrolled adult patients (n=72) with type 2 diabetes who follow diet and exercise or take a stable dose of metformin.

For 12 weeks, participants received weekly subcutaneous injections of retatrutide, Trulicity, a GLP1R agonist, or placebo.

The retatrutide subgroups (3, 6, or 12 mg) recorded dose-dependent weight reductions of 4.4 kg, 7.5 kg, and 8.7 kg (10.1%), whereas the Trulicity and placebo groups registered weight gains of 0.4 and 0.3 kg.

Eli Lilly pointed to the fact that the observed weight loss with retatrutide was nearly double that observed with tirzepatide in a similar patient population. Allegedly, the reduction in food intake probably contributes to the weight loss process, but the large contribution comes from the increase in energy expenditure provided by retatrutide, as appetite scores were not actually different in this study comparing retatrutide and dulaglutide and the study comparing tirzepatide and dulaglutide.

Retatrutide was characterized by acceptable tolerability with mostly mild gastrointestinal adverse events (nausea and diarrhea) and some increase in heart rate.

Clinical trials of retatrutide are ongoing: 72-week NCT04881760 phase 2 in adult patients (n=494) with obesity or overweight and 36-week NCT04867785 phase 2 in adult patients (n=300) with type 2 diabetes.



In parallel, Eli Lilly is testing mazdutide (LY3305677, OXM-3, IBI362), which combines a glucagon-like peptide-1 receptor (GLP1R) agonist and a glucagon receptor (GCGR) agonist.

Mazdutide is a synthetic analog of oxyntomodulin modified for prolonged action.

What Is Oxyntomodulin?

Oxyntomodulin (OXM) is a peptide gut hormone produced in response to food intake by the L cells of the mucosa of the colon and distal part of the jejunum, as well as in the brainstem. Oxyntomodulin activates glucagon-like peptide-1 receptor (GLP1R) and glucagon receptors receptor (GCGR), promoting increased energy expenditure while decreasing energy intake, weight loss, and improved glycemia. [1] [2]

Oxyntomodulin-mediated weight loss occurs through GCGR activation, leading to anorexigenic effects and increased energy expenditure. GLP1R agonism is reflected by improved glucose homeostasis by increasing insulin secretion and overcoming the hyperglycemic action of GCGR activation. [3] [4] [5]

Oxyntomodulin behaves as a differential agonist depending on the receptor: it acts as a GLP1R partial agonist and a GCGR full agonist. [6] Oxyntomodulin activates GLP1R and GCGR with less potency than native GLP-1 and glucagon. [7] [8] Oxyntomodulin is characterized by agonism biased toward GLP1R relative to GCGR. [6]

The NCT03928379 phase 1 (randomized, double-blind, placebo-controlled) clinical trial invited adult patients (n=24) with type 2 diabetes and obesity or overweight.

For 16 weeks, subjects received weekly subcutaneous injections of mazdutide or placebo.

In the maximum dose (10 mg) mazdutide subgroup, the weight loss was 12.7% (11.2 kg) — versus 2.0 kg in the placebo group.

Mazdutide was characterized by acceptable tolerability: adverse events mainly gastrointestinal, similar to other GLP1R agonists.

Meanwhile, China’s Innovent Biologics, which licensed mazdutide from Eli Lilly in late August 2019, conducted its own NCT04904913 phase 2 (randomized, double-blind, placebo-controlled) clinical trial among adult patients (n=248) with obese or overweight and without type 2 diabetes.

For 24 weeks, participants received weekly subcutaneous injections of mazdutide or placebo.

The mazdutide subgroups (3.0 mg, 4.5 mg, or 6.0 mg) showed weight reductions of 7.2% (6.4 kg), 10.6% (9.1 kg), and 11.6% (9.9 kg) — versus a 1.1% (1.1 kg) reduction in the placebo group (p<0.0001).

The proportion of subjects who lost at least 5% of their body weight was 58%, 83%, and 80% — vs. 5.0%. The proportion of subjects who lost at least 10% of their body weight was 19%, 49%, and 51% — vs. 0.0%.

Mazdutide was characterized by acceptable tolerability: the most common adverse events, mostly mild-to-moderate, were diarrhea, nausea, and upper respiratory tract infections, similar to other GLP1R agonists.

In a prior 12-week NCT04440345 phase 1/2 (randomized, double-blind, placebo-controlled) clinical trial among adult patients (n=60) with obesity or overweight and without type 2 diabetes, weekly administration of mazdutide (3.0 mg, 4.5 mg, 6.0 mg, or 9,0 mg) provided a 4.8% (3.8 kg), 6.4% (5.8 kg), 6.1% (5.1 kg), and 11,7% (9,2 kg)  decrease in body weight from baseline 86.3 kg — versus a 0.6% (0.4 kg) increase from baseline 80.3 kg in the placebo group.

Administration of mazdutide at a dose of 10 mg for 16 weeks resulted in a weight loss of 9.5% (7.6 kg).

The 12-week NCT04466904 phase 1b (randomized, double-blind, placebo-controlled, active-controlled) clinical trial tested mazdutide therapy in adult patients (n=42) with type 2 diabetes (both normal weight and overweight or obese participants were eligible). The treatment was accompanied by a reduced-calorie diet and increased physical activity.

Participants received weekly subcutaneous injections of mazdutide (3.0 mg, 4.5 mg, or 6.0 mg), the GLP1R agonist Trulicity (dulaglutide), or placebo.

The mazdutide subgroups showed respective weight reductions of 0.9% (0.6 kg), 5.0% (3.5 kg), and 5.4% (3.8 kg) — versus a weight reduction of 0.9% (0.7 kg) in the dulaglutide group and 1.1% (0.8 kg) in the placebo group.

Innovent continues its clinical validation of mazdutide: the 48-week NCT04904913 phase 2 clinical trial in adult patients (n=240) with overweight or obesity and the 20-week NCT04965506 phase 2 clinical trial in adult patients (n=252) with type 2 diabetes.


Retatrutide and Mazdutide: Some Questions

In 2023, Eli Lilly will decide which weight loss drug, retatrutide or mazdutide, to move forward for evaluation in phase 3 clinical trials. All depending on their ultimate efficacy, the bar for which is set by tirzepatide.

For now, the safety of retatrutide and mazdutide remains an open and very pressing question. At one time, for example, Novo Nordisk bet heavily on NN9277 (NNC9204-1177), a GLP1R and GCGR dual agonist, and NN9423 (NNC9204-1706), a GLP1R, GIPR and GCGR triple agonist. But then abandoned them because of significant safety concerns identified.

The 12-week NCT03308721 phase 1 clinical trial found that weekly subcutaneous injections of NN9277 promoted weight loss in obese or overweight patients. The differences in weight loss relative to placebo were 0.4%, 3.3%, 7.4%, 9.5%, 9.7%, 12.6%, and 9.1% for NN9277 doses of 200 mcg, 600 mcg, 1300 mcg, 1900 mcg, 2800 mcg, 4200 mcg, and 6000 mcg, respectively.

However, the safety profile of NN9277 cannot be called successful. The following adverse events have been reported: increased heart rate (including blunted night-time dip), decreased reticulocyte levels (indicates bone marrow suppression), increased inflammatory markers (fibrinogen and C-reactive protein), increased liver enzymes (AST and ALT), impaired glucose tolerance (despite clinically significant weight loss), reduced plasma levels of most amino acids (reflects increased hepatic gluconeogenesis).

Eli Lilly is aware of the problems of Novo Nordisk’s experimental drugs and therefore the pharmacological characteristics of retatrutide and mazdutide have been modified accordingly by balancing the agonist activity at GLP-1, GIP, and GCG receptors in order to avoid the above mentioned adverse events, which mainly stem from effects on glucagon. But in any case, large-scale clinical trials will be needed to definitively confirm the safety.



Altimmune is developing pemvidutide (ALT-801, SP-1373, VPD-107), which, like mazdutide, is a synthetic prolonged-acting oxintomodulin analog, a dual agonist of glucagon-like peptide-1 (GLP1R) and glucagon (GCGR) receptors.

Altimmune took possession of pemvidutide in July 2019 following the acquisition of Spitfire Pharma.

Pharmacology Features of Pemvidutide

Pemvidutide is characterized by balanced (1:1) glucagon-like peptide-1 receptor (GLP1R) and glucagon receptor (GCGR) binding activity. [1] [2]

Since the potency of pemvidutide at GLP1R is comparable to that of semaglutide, the enhancement of the therapeutically beneficial effect of pemvidutide is due to additional activation of GCGR. [3]

The 48-week MOMENTUM (NCT05295875) phase 2 (randomized, double-blind, placebo-controlled, multicenter) clinical trial testing weekly subcutaneous injections of pemvidutide (three different doses) in the treatment of obese or overweight adults (n=320) who have previously tried to lose weight is ongoing. This therapy is conducted on a background of an intensive lifestyle change program (reduced caloric intake and increased physical activity).

The 12-week NCT04561245 phase 1 (randomized, double-blind, placebo-controlled) clinical trial enrolled adult patients (n=34) who were overweight or obese (without diabetes) and received weekly subcutaneous injections of placebo or pemvidutide (1.2 mg, 1.8 mg, or 2.4 mg). Caloric restriction and increased physical activity were not required.

Administration of pemvidutide resulted in body weight reductions of 4.9% (4.7 kg), 10.3% (8.8 kg), and 9.0% (8.4 kg) — versus a reduction of 1.6% (1.5 kg) in the placebo group.

At least 5% weight loss was 33%, 100%, and 89% of patients in the pemvidutide groups and 20% in the placebo group. At least 10% weight loss occurred in 17%, 56%, and 33% of patients in the pemvidutide groups and 0% in the placebo group. 

The adverse events accompanying the administration of pemvidutide were mild-to-moderate in severity and were noted from the gastrointestinal tract: nausea, vomiting, diarrhea, and constipation.

Given that the subjects noted very significant reductions in liver fat as measured by magnetic resonance imaging (MRI)–estimated proton density fat fraction (PDFF), Altimune is testing pemvidutide in the treatment of non-alcoholic fatty liver disease (NAFLD) in the 12-week clinical trial NCT05006885 phase 1b and in the 12-week follow-up NCT05292911 phase 1b.

  • NCT05006885 demonstrated that weekly subcutaneous injections of pemvidutide at a dose of 1.2 mg, 1.8 mg, or 2.4 mg provided a reduction in liver fat fraction of absolute 9%, 15%, and 11% and relative 47%, 69%, and 57% — versus a reduction of absolute 0.2% and relative 4% in the placebo group (p<0.001). Weight loss was 3.4% (3.5 kg), 4.3% (4.3 kg), and 3.7% (3.6 kg) — vs. 0.2% (0.2 kg). The small weight loss is related to the fact that the NAFLD patient population is significantly different from the obese patient population.


Balance and Potency Issue of GLP-1 and Glucagon Receptors Co-agonism

One of the key issues in creating synthetic versions of oxyntomodulin is the selection of the optimal balance and potency of glucagon-like peptide-1 receptor (GLP1R) and glucagon receptor (GCGR) co-agonism. These metrics are important because even with a theoretically well-designed molecule, its effects, therapeutic and adverse, may be correspondingly insufficient or beyond acceptable tolerance.

The dual agonism of GLP1R/GCGR must be balanced in some way, where the activation strength of the first and second receptors relative to each other can be either equal or shifted to one side. The potency of synthetic oxytomodulin as an action force (molar activity) at GLP1R/GCGR compared to the potency of their native ligands, GLP-1 and glucagon, is also relevant.

For example, pegapamodutide (LM008, OPK880033, TT401, LY2944876), which passed through the hands of Eli Lilly, Transition Therapeutics and OPKO Health and showed relatively modest weight loss results [1] [2] aimed to treat Chinese patients with type 2 diabetes, as diabetics in Asia have a low body mass index (BMI) compared to Western patients. To this end, OPKO formed a joint venture with China’s LeaderMed Health Group. Pegapamodutide is characterized by unbalanced agonist activity biased toward GLP1R versus GCGR.

SAR425899 by Sanofi was positioned as a GLP1R/GCGR dual agonist, but then it turned out that the molecule has a high occupation of the first receptors but no significant occupation of the second. [3] That is, in fact, SAR425899 is only a GLP-1 receptors agonist, and binds to them with the same potency as native GLP-1. This was reflected by an increased incidence of gastrointestinal adverse events. [4] [5]

Cotadutide (MEDI0382) by AstraZeneca showed relatively modest weight loss when considering the results of other GLP1R/GCGR dual agonists. [6] [7] [8] The binding affinity of cotadutide is biased toward GLP1R: it is five times higher than with GCGR. [9] This is done to prevent adverse effects of glucagon, including an increase in blood glucose levels. The potency of cotadutide to GLP1R and GCG are 3-4 times and 8 times lower, respectively, compared to the potency of native GLP-1 and GCG.

Efinopegdutide (HM12525A, JNJ-64565111, MK-6024), which is backed by Hanmi Pharmaceutical of Korea, provided decent weight loss (in severely obese patients) but had no effect on improving glycemic control in patients with type 2 diabetes. [10] [11] And this is unusual because efinopegdutide is a balanced (1:1) GLP1R/GCGR agonist, i.e. their activation is performed at the same level. [12] The potency of efinopegdutide at GLP1R and GCG is 3 times lower than that of native GLP-1 and GCG.

As a result, development of SAR425899 has been halted and cotadutide and efinopegdutide have been repurposed for the treatment of other metabolic diseases. Cotadutide and efinopegdutide are very good at reducing fat fraction levels in the liver, which is due to hepatic glucagon signaling followed by increased fatty acid oxidation. Therefore, cotadutide is in the PROXYMO-ADV (NCT05364931) phase 2/3 clinical trial for treating non-alcoholic steatohepatitis (NASH) with stage 2/3 fibrosis, and efinopegdutide is being tested with Merck & Co. in the NCT04944992 phase 2a clinical trial for treating non-alcoholic fatty liver disease (NAFLD).



Novo Nordisk has scheduled for launch the REDEFINE 2 (NCT05394519) phase 3 (randomized, double-blind, placebo-controlled, multicenter, international) clinical trial that will test a combination of cagrilintide and semaglutide [CagriSema] in the weight loss task among adult patients (n=1200) with type 2 diabetes.

Inclusion criteria for the trial included body mass index (BMI) ≥ 27.0 kg/m2, glycated hemoglobin (HbA1c) levels ≤ 10.0%, adherence to a lifestyle change strategy or undergoing therapy with oral antidiabetic drugs (metformin, alpha-glucosidase inhibitors, glinides, gliflozins, glitazones, sulfonylurea derivatives).

For 68 weeks, participants will receive weekly subcutaneous injections of either 2.4-mg semaglutide and 2.4-mg cagrilintide or placebo.

The reasonableness of the combination of cagrilintide and semaglutide was evidenced in the NCT03600480 phase 1b (randomized, double-blind, placebo-controlled) clinical trial, which included adult patients (n=95) who were overweight or obese and without type 2 diabetes.

After 20 weeks, the subgroup of participants who weekly received 2.4 mg each of injectable cagrilintide and semaglutide showed a weight reduction of 17.1% (15.9 kg) from baseline of 92.1 kg — versus 9.8% (8.9 kg) from baseline of 99.6 kg in the semaglutide alone group. This weight loss was achieved without any of the lifestyle changes commonly recommended for those wanting to lose weight.

  • By comparison, in the STEP 1 (NCT03548935) phase 3 clinical trial, monotherapy with 2.4-mg semaglutide over 68 weeks resulted in a 14.9% (15.3 kg) or 16.9% (17.4 kg) weight loss from baseline of 105.4 kg — depending on the degree of patient adherence to treatment. At the same time, subjects were instructed to reduce caloric intake (a deficit of approximately 500 kcal/day) and increase physical activity (at least 150 min/week).

Cagrilintide administered at other doses (0.16 mg, 0.30 mg, 0.60 mg, or 1.2 mg) with 2.4-mg semaglutide showed dose-dependent reductions in body weight of 8.3% (8.0 kg), 10.0% (9.3 kg), 10.6% (10.1 kg), and 15.7% (14.6 kg).

Such impressive results of the cagrilintide and semaglutide cocktail, fast and powerful, requiring neither dieting nor exercise, suggest a future ad catchphrase “Two drugs — lose two pounds a week.”

BioPharma Media

The combined therapy was well tolerated: the most common adverse reactions in the form of gastrointestinal disorders, such as nausea and vomiting, were mild-to-moderate in severity. At the same time, their frequency was comparable to that observed with a GLP1R agonist like semaglutide alone and did not increase in a dose-dependent manner. In other words, there were no serious safety problems with cagrilintide.

Cagrilintide’s Mechanism of Action

Cagrilintide (AM833, NN9838, NNC0174-0833) is an acylated long-acting amylin analog with agonist effects on native amylin receptors (AMYR) and calcitonin.

Amylin is a glucoregulatory pancreatic hormone that is secreted together with insulin and is involved in delaying gastric emptying and suppressing postprandial glucagon release. Amylin reduces energy intake and participates in the regulation of appetite and satiety through receptor activation in the area postrema and nucleus tractus solitarii in the brainstem. Amylin plays a role in the regulation of food choices and preferences through the hypothalamus, ventral tegmental area, and lateral dorsal tegmental nucleus.

Cagrilintide regulates energy homeostasis and activates the satiety signal, which leads to a decrease in food intake and an increase in energy expenditure on the background of fat tissue loss. Cagrilintide affects the homeostatic and hedonic areas of the brain, inducing a feeling of satiety and, moreover, influencing specific food choices, which contributes to changes in eating behavior.

Because cagrilintide and semaglutide act on different receptors in different brain regions to induce satiety, their combined administration leads to an additive effect on appetite regulation. Moreover, the ability of cagrilintide to affect food choices contributes to changes in eating behavior, further enhancing treatment efficacy. Given the heterogeneity of obesity and the different phenotypes of body size, influencing different and complementary pathophysiological mechanisms results in increased weight loss.

In the 26-week NCT03856047 phase 2 (randomized, double-blind, placebo-controlled, active-controlled, multicenter, international) clinical trial among adult patients (n=706) with obesity or overweight and without type 2 diabetes, there was a statistically significant benefit of weekly monotherapy with cagrilintide over placebo or Victoza (liraglutide), a GLP1R agonist.

The weight loss provided by cagrilintide was 6.0%–10.8% (6.4–11.5 kg). The effect of cagrilintide was dose-dependent (it appeared stronger with increasing doses of 0.3 mg, 0.6 mg, 1.2 mg, 2.4 mg, or 4.5 mg) and was not characterized by reaching a plateau by the end of the study. In the placebo and liraglutide groups, the loss of extra pounds was 3.0% (3.3 kg) and 9.0% (9.6 kg). In the maximum 4.5-mg dose cagrilintide subgroup, weight reductions of at least 5%, 10%, or 15% were seen for 88.7%, 53.5%, and 18.7% of patients.

Cagrilintide was characterized by acceptable tolerability: Mild-to-moderate adverse events were reported mainly from the gastrointestinal tract (nausea, constipation, diarrhea) and were reported in 41%–63% of patients — versus 32% in the placebo group.

The 76-week NCT05016882 phase 2 (randomized, double-blind, placebo-controlled, multicenter, international) clinical trial investigating increased doses of cagrilintide (7.5 mg, 15 mg, and 30 mg) in combination with 2.4-mg semaglutide to treat nonalcoholic stepatohepatitis (NASH) with stage 2, 3, or 4 fibrosis among adult patients (n=672) is ongoing.



This year, Versanis Bio plans to organize a phase 2b clinical trial of bimagrumab targeting the treatment of obesity and overweight in patients without diabetes. Both bimagrumab monotherapy and its combination with an incretin agonist will be tested.

Unlike all other existing and experimental drugs for weight loss, the mechanism of action of bimagrumab is unique because it is aimed directly at reducing fat mass while increasing lean mass.

Bimagrumab, discovered by Germany’s MorphoSys, was developed by Novartis. The Swiss pharma giant studied bimagrumab in the treatment of sporadic inclusion body myositis (sIBM), a rare progressive muscle disease characterized by muscle weakness and atrophy. But after the corresponding RESILIENT (NCT01925209) phase 2b/3 clinical trial failed, Novartis gave bimagrumab to Versanis.

Bimagrumab was once hoped for: The drug, whose sales were expected to exceed $4 billion a year, was intended to increase physical function, muscle strength, and mobility in patients not only with sIBM, but also cachexia, chronic obstructive pulmonary disease (COPD), and sarcopenia.

Bimagrumab’s Mechanism of Action

Bimagrumab (BYM338) is a fully human monoclonal antibody that competitively binds to activin A receptor types 2A and 2B (ACVR2A and ACVR2B; ActRIIA and ActRIIB) with greater affinity than natural ligands such as myostatin, growth and differentiation factor 11 (GDF11, BMP11), and activin that negatively regulate skeletal muscle growth. Blockade of activin receptors leads to suppression of the action of these ligands, which is reflected by stimulation of muscle growth. [1] [2]

Pharmacological suppression of activin receptors enhances the differentiation of brown adipocytes and causes growth and activation of brown adipose tissue. Given, first, the important role of brown adipose tissue in increasing energy expenditure (due to non-shivering thermogenesis), second, improvement of glucose homeostasis and insulin sensitivity during its activation, third, regression of this tissue with age, increasing the amount of brown adipose tissue and stimulating its functions has great potential in the treatment of metabolic disorders. [3] [4]

The possibility of simultaneous recovery of muscle mass and strength with increased energy expenditure, which bimagrumab provides, seems very attractive in the task of treating obesity and overweight.

The NCT03005288 phase 2 (randomized, double-blind, placebo-controlled, multicenter) clinical trial invited adult patients (n=58) with obesity or overweight on the back of type 2 diabetes mellitus.

Subjects received intravenous infusions of placebo or bimagrumab (10 mg/kg, maximum 1200 mg) every 4 weeks for 48 weeks.

The experimental treatment was carried out together with the implementation of a lifestyle change program (reduced caloric intake and increased physical activity). Participants could continue on anti-diabetic therapy (metformin or glyptins, mono- or co-administered).

Baseline averages of patients: age 60.4 years, body weight 93.6 kg, fat mass 35.4 kg.

Subjects’ weight decreased 6.5% (5.9 kg) in the bimagrumab group — versus a decrease of 0.8% (0.8 kg) in the placebo group (p<0.001). It might seem that the therapeutic effect of bimagrumab in the weight loss task is insignificant, but this is not the case.

The fact is that the administration of bimagrumab led to a significant loss of fat mass, the weight of which decreased by 20.5% (7.5 kg) — vs. a decrease of 0.5% (0.2 kg) in the control group. In contrast, lean mass added 3.6% (1.7 kg), whereas it decreased 0.8% (0.4 kg) in the placebo group. Waist circumference, waist-to-hip ratio, and glycated hemoglobin (Hb1Ac) levels also decreased statistically significantly in the bimagrumab group.

When the results are separated by sex of the subjects, fat mass decreased (placebo-adjusted) by 22.1% (7.5 kg) and 18.4% (6.2 kg) in men and women, respectively, whereas lean mass increased (placebo-adjusted) by 5.1% (2.8 kg) and 2.5% (1.0 kg).

  • By comparison, an analysis of data from adult patients (n=140) who were obese or overweight (without diabetes) in the 68-week STEP 1 (NCT03548935) phase 3 clinical trial and followed a lifestyle change program showed that 2.4-mg semaglutide reduced fat mass by 24.7% (10.4 kg), but simultaneously reduced lean mass by 13.2% (6.9 kg).
  • An analysis of data from adult patients (n=160) who were obese or overweight (without diabetes) in the 68-week SURMOUNT-1 (NCT04184622) phase 3 clinical trial and adhered to a lifestyle change program demonstrated that tirzepatide (pooled three dose subgroups of 5 mg, 10 mg, and 15 mg) reduced fat mass by 33.9% with an associated 10.9% reduction in lean mass.

Bimagrumab was characterized by acceptable tolerability. The most common adverse events included diarrhea (in 41% of patients), muscle spasms (41%), upper respiratory tract infections (16%), increased lipase levels (11%), and nausea (11%). All were generally mild in severity. Diarrhea occurred mostly after the first dose of bimagrumab, then its frequency dropped sharply.

In a 10-week clinical trial involving adult patients (n=10) who were obese or overweight and in prediabetes (insulin resistance and impaired glucose tolerance), a single dose of bimagrumab (30 mg/kg) was followed by an 8.7% (2.3 kg) decrease in fat mass and a 3.8% (2.0 kg) increase in lean mass. There was no recommendation to follow a lifestyle modification program (reduced caloric intake and increased physical activity).

A pooled analysis of five phase 2 clinical trials of bimagrumab among adult patients (n=569) without diabetes, 41% of whom were overweight or obese, showed that after 24 weeks of treatment, the bimagrumab maximum-dose group lost 14.6% of fat mass — versus adding 2.4% in the placebo group. In comparison, the fat loss in the NCT03005288 was similar at 16.5% after 24 weeks of therapy.


What Are Most Effective Weight Loss Drugs?

Comparison of prescription weight loss drugs’ effectiveness

DrugDosage†TargetMaximum weight loss from baseline, % (kg)Weight loss per month, % (kg)PatientsTreatment durationClinical trial
Semaglutide2.4 mgGLP1R18.2 (18.7)1.1 (1.1)Without T2D68 weeks*STEP 4 (NCT03548987) phase 3
Tirzepatide15.0 mgGLP1R/GIPR22.5 (23.6)1.3 (1.3)Without T2D72 weeks*SURMOUNT-1 (NCT04184622) phase 3
Retatrutide12.0 mgGLP1R/GIPR/GCGR10.1 (8.7)3.4 (2.9)With T2D12 weeks*NCT04143802 phase 1
Mazdutide10.0 mgGLP1R/GCGR12.7 (11.2)3.2 (2.8)With T2D16 weeksNCT03928379 phase 1
Mazdutide9.0 mgGLP1R/GCGR11.7 (9.2)3.9 (3.1)Without T2D12 weeksNCT04440345 phase 1/2
Mazdutide6.0 mgGLP1R/GCGR11.6 (9.9) 1.9 (1.7)Without T2D24 weeksNCT04904913 phase 2
Mazdutide6.0 mgGLP1R/GCGR5.4 (3.8)1.8 (1.3)With T2D12 weeks*NCT04466904 phase 1b
Pemvidutide1.8 mgGLP1R/GCGR10.3 (8.8)3.4 (2.9)Without T2D12 weeksNCT04561245 phase 1
Cagrilintide4.5 mgAMYR10.8 (11.5)1.7 (1.8)Without T2D26 weeksNCT03856047 phase 2 
Cagrilintide + semaglutide2.4 mg + 2.4 mgAMYR + GLP1R15.6 (16.5)2.0 (2.1)With T2D32 weeksNCT04982575 phase 2
Cagrilintide + semaglutide2.4 mg + 2.4 mgAMYR + GLP1R17.1 (15.9)3.4 (3.2)Without T2D20 weeksNCT03600480 phase 1b
Bimagrumab10.0 mg/kg**ACVR2A/ACVR2B20.5 (7.5)**1.7 (0.6)**With T2D48 weeks*NCT03005288 phase 2
Unless otherwise indicated, the drug is administered subcutaneously once a week.

* Treatment was accompanied by an intensive lifestyle change program (reduced caloric intake and increased physical activity).

** Intravenous infusion once a month.

*** This weight loss refers to a loss of fat mass directly, not a decrease in total body weight.

Abbreviations: GLP-1R, glucagon-like peptide-1 receptor, GIPR, glucose-dependent insulinotropic polypeptide receptor, GCGR, glucagon receptor, AMYR, amylin receptor, ACVR2A/ACVR2B, activin A receptor types 2A and 2B.

This comparison of the effectiveness of prescription weight loss medications for long-term weight management for obesity or overweight is for illustrative purposes only, as there have been no clinical trials directly comparing these drugs.
Avatar photo

Julia Mardi

BioPharma Media’s Scientific Editor.

Julia strives to recognize in advance in which direction the pharmaceutical industry is moving. Her professional interests include gene therapy, immune checkpoint inhibitors, molecular biology, and drug repurposing.

For more information about Julia and her contact data, see Our Team.

Avatar photo

Timur Burkhanayev

BioPharma Media’s Data Analyst.

Timur mines and analyzes scientific and business data, providing meaningful insights. His professional interests include budgeting, forecasting, financial analyses, and data processing tools.

For more information about Timur and his contact data, see Our Team.

Join the Conversation

1 Comment

  1. This site is the worst I have ever seen for reading (attempting to read) complex information. Get rid of the ridiculous flashing and rotating ads!!

Leave a comment
Tell us what you think of what we posted. It is possible that you have comments, additions, or even remarks. BioPharma Media welcomes readers' feedback and criticism.

Please pay special attention that BioPharma Media enters into correspondence on any issues except those indicated in section 5 of the Terms of Use, which will never, under any circumstances, be responded to or answered.

Your email address will not be published. Required fields are marked *