Tag: semaglutide

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Metformin’s Weight Loss Tied to “Anti-hunger” Molecule

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A new study finds that the modest weight loss from taking metformin is attributable to an appetite-suppressing molecule that is abundant after exercise

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An “anti-hunger” molecule produced after vigorous exercise is responsible for the moderate weight loss caused by the diabetes medication metformin, according to a new study in mice and humans. The anti-hunger molecule, lac-phe, was discovered by Stanford Medicine researchers in 2022.

The finding, made jointly by researchers at Stanford Medicine and at Harvard Medical School and published in Nature Metabolism, further cements the critical role the molecule, called lac-phe, plays in metabolism, exercise and appetite. It may pave the way to a new class of weight loss drugs.

“Until now, the way metformin, which is prescribed to control blood sugar levels, also brings about weight loss has been unclear,” said Jonathan Long, PhD, an assistant professor of pathology. “Now we know that it is acting through the same pathway as vigorous exercise to reduce hunger. Understanding how these pathways are controlled may lead to viable strategies to lower body mass and improve health in millions of people.”

Many people with diabetes who are prescribed metformin lose around 2% to 3% of their body weight within the first year of starting the drug. Although this amount of weight loss is modest when compared with the 15% or more often seen by people taking semaglutide, the discoveries that led to those drugs also grew from observations of relatively minor, but reproducible, weight loss in people taking first-generation versions of the medications.

Post-workout appetite loss

When Long and colleagues at Baylor University discovered lac-phe in 2022, they were on the hunt for small molecules responsible for curtailing hunger after vigorous exercise. What they found was a mishmash of lactate and an amino acid called phenylalanine. They dubbed the hybrid molecule lac-phe and went on to show that it’s not only more abundant after exercise but it also causes people (as well as mice and even racehorses) to feel less hungry immediately after a hard workout.

“There is an intimate connection between lac-phe production and lactate generation,” Long said. “Once we understood this relationship, we started to think about other aspects of lactate metabolism.”

Metformin was an obvious candidate because as it stimulates the breakdown of glucose (thus reducing blood sugar levels) it can trigger the generation of lactate.

The researchers found that obese laboratory mice given metformin had increased levels of lac-phe in their blood. They ate less than their peers and lost about 2 grams of body weight during the nine-day experiment.

Long and his colleagues also analysed stored blood plasma samples from people with Type 2 diabetes before and 12 weeks after they had begun taking metformin to control their blood sugar. They saw significant increases in the levels of lac-phe in people after metformin compared with their levels before treatment. Finally, 79 participants in a large, multi-ethnic study of atherosclerosis who were also taking metformin had significantly higher levels of lac-phe circulating in their blood than those who were not taking the drug.

“It was nice to confirm our hunch experimentally,” Long said. “The magnitude of effect of metformin on lac-phe production in mice was as great as or greater than what we previously observed with exercise. If you give a mouse metformin at levels comparable to what we prescribe for humans, their lac-phe levels go through the roof and stay high for many hours.”

Further research revealed that lac-phe is produced by intestinal epithelial cells in the animals; blocking the ability of mice to make lac-phe erased the appetite suppression and weight loss previously observed.

Finally, a statistical analysis of the people in the atherosclerosis study who lost weight during the several-year study and follow-up period found a meaningful association between metformin use, lac-phe production and weight loss.

“The fact that metformin and sprint exercise affect your body weight through the same pathway is both weird and interesting,” Long said. “And the involvement of the intestinal epithelial cells suggests a layer of gut-to-brain communication that deserves further exploration. Are there other signals involved?”

Long noted that, while semaglutide drugs are injected into the bloodstream, metformin is an oral drug that is already prescribed to millions of people. “These findings suggest there may be a way to optimize oral medications to affect these hunger and energy balance pathways to control body weight, cholesterol and blood pressure. I think what we’re seeing now is just the beginning of new types of weight loss drugs.”

Source: Stanford Medicine

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Semaglutide Cuts CVD Events by 20% in People with Obesity or Overweight but not Diabetes

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By HualinXMN – Own work, CC BY-SA 4.0

In a large, international clinical trial, people with obesity or overweight but not diabetes taking semaglutide for more than three years had a 20% lower risk of cardiovascular disease outcomes and lost an average of 9.4% of their body weight.

Semaglutide, a GLP-1 medication primarily prescribed for people with Type 2 diabetes, is also FDA-approved for weight loss in people with obesity.

These results were shared in a late-breaking science presentation at the American Heart Association’s Scientific Sessions 2023 and the full manuscript was also published in The New England Journal of Medicine.

“This news is very encouraging for people with overweight or obesity because no treatment specifically directed at the management of obesity and overweight in people without Type 1 or Type 2 diabetes has been tested in a randomised trial and been shown to influence cardiovascular outcomes,” said lead study author A. Michael Lincoff, MD.

While prior research has confirmed the benefits of semaglutide in managing blood sugar, decreasing cardiovascular disease events and reducing weight in people with Type 2 diabetes, this study specifically investigated the potential impact of semaglutide on cardiovascular disease in people with overweight or obesity and cardiovascular disease who did not have either Type 1 or Type 2 diabetes.

In this randomised, controlled, double-blind trial, participants were assigned to take either 2.4mg of semaglutide (the FDA-approved semaglutide dose for weight management) or a placebo once a week, which is higher than the FDA-approved semaglutide dose limit for Type 2 diabetes of 2.0mg/week. Each person in the study used a ‘pen’ to inject the medicine or placebo into a skin fold in their stomach, thigh or upper arm each week on the same day, and the dose started at 0.24mg and gradually increased every four weeks up to 2.4mg, and mean follow-up for all participants was 40 months.

In addition to taking either semaglutide or placebo for the trial, all participants also received standard of care treatment for cardiovascular disease, such as cholesterol modifying medications, antiplatelet therapies, beta blockers or other treatments. The authors note that heart disease diagnoses varied among the participants, therefore, treatment was adjusted to meet each individual’s diagnosis and needs, as well as the treatment guidelines in their country of residence.

The study, which ran from October 2018 through June 2023, indicated the following:

  • There was a 20% reduction in the risk of heart attacks, strokes or death due to cardiovascular disease in the participants who took semaglutide, compared to the participants in the placebo group.
  • In the semaglutide group, the participants’ body weight was reduced, on average, by 9.4% compared to a reduction of 0.9% among the adults in the placebo group.
  • There were no new safety concerns found in the study, which researchers note is encouraging since the SELECT trial is the largest and longest (4.5 years) trial of semaglutide in adults without Type 1 or Type 2 diabetes.
  • The number of serious adverse events was lower in the semaglutide group. Previous studies of medications of the GLP-1 receptor agonist class have shown an association with gallbladder disorders, and in SELECT, there was a slightly higher rate of gallbladder disorders in the semaglutide vs placebo group (2.8% vs 2.3%, respectively).
  • Semaglutide was stopped more frequently than placebo for gastrointestinal intolerance, a known side effect of this class of medications; however, there was no higher rate of serious gastrointestinal events.
  • The researchers noted that this medication did not lead to an increased rate of pancreatitis, which has been a concern with prior medications of this type.
  • Of note, other weight-loss medications that are not GLP-1 receptor agonists have been associated with increased risks of psychiatric disorders or cancer; these risks were not elevated with semaglutide in the SELECT trial.

“It’s been estimated that within about ten years, over half of the world’s population will have overweight or obesity,” said Dr Lincoff. “And while GLP-1 medications are frequently prescribed for patients with vascular disease and Type 2 diabetes, there is a significant number of people who do not have Type 1 or Type 2 diabetes but do have vascular disease and overweight or obesity for whom these medications are often not available due to access to care issues, insurance coverage or other factors. This population may now potentially benefit from semaglutide, and importantly, our results indicate the magnitude of cardiovascular risk reduction with semaglutide among people without Type 1 or Type 2 diabetes is the same as what we have seen in people with Type 2 diabetes. Our findings expand the opportunity to treat patients who have overweight or obesity and existing heart disease without Type 1 or Type 2 diabetes, and we have a chance to significantly reduce their risk of a secondary cardiovascular event including death.”

Among the study limitations were including adults with prior cardiovascular disease, thereby not investigating primary prevention of cardiovascular disease (people with no history of a heart attack, stroke and/or peripheral artery disease). In addition, 28% of the study participants were female, which is not proportionate to the number of women with cardiovascular disease and overweight or obesity in the general population.

Additional analyses will include identifying the mediators of the cardiovascular benefit to determine to what extent the results were driven by reduction of metabolically unhealthy body fat, positive impacts on inflammation or blood sugar, direct effects of the medication itself on plaque build-up in the arteries, or a combination of one or more variables.

Source: American Heart Association

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Hold the GLP-1 Agonists Before Surgery, New Advice Says

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Patients taking Glucagon-like peptide-1 (GLP-1) receptor agonists should stop taking them before they have surgery, due to the risk of aspirating while under general anaesthesia. This is the latest advice from the American Society of Anesthesiologists (ASA).

Initially approved by the Food and Drug Administration (FDA) for type 2 diabetes mellitus and cardiovascular risk reduction, GLP-1 agonists have shot up in popularity due to their effectiveness in weight loss. Despite having recent FDA approval, they have been used off-label for this purpose for quite some time.

When it comes to surgery, a number of organisations have recommended to hold these drugs either the day before or day of the procedure. For patients on weekly dosing, it is recommended to hold the dose for a week, the ASA notes.

GLP-1 agonists are associated with adverse gastrointestinal effects such as nausea, vomiting and delayed gastric emptying. The effects on gastric emptying are reported to be reduced with long-term use, most likely through rapid tachyphylaxis at the level of vagal nerve activation. Based on recent anecdotal reports, there are concerns that delayed gastric emptying from GLP-1 agonists can increase the risk of regurgitation and pulmonary aspiration of gastric contents during general anaesthesia and deep sedation. Patient taking GLP-1 agonists are more likely to have increased residual gastric contents as predicted by adverse gastrointestinal symptoms (nausea, vomiting, dyspepsia, abdominal distension).

The use of GLP-1 agonists in paediatrics has primarily been reported for the management of type 2 diabetes mellitus and obesity. The published literature on GLP-1 agonists in paediatrics is predominantly from paediatric patients 10 to 18 years old and concerns are similar to those reported in adults. During the conduct of general anaesthesia/deep sedation, children on GLP-1 agonists have similar gastrointestinal adverse events at a rate similar to adults.

In a review of the literature, the ASA Task Force on Preoperative Fasting found that, beyond a few case reports, there was little evidence for guidance on preoperative management of GLP-1 agonists. Nevertheless, they made recommendations for elective procedures. In the case of urgent or emergent procedures, they suggested treating the patient as ‘full stomach’.

If the patient’s GLP-1 agonists prescribed for diabetes management are held for longer than the dosing schedule, the guidelines urge surgeons to consider consulting an endocrinologist for bridging the antidiabetic therapy in order to avoid hyperglycaemia.

They further recommend that if gastrointestinal symptoms, such as severe nausea/vomiting/retching, abdominal bloating, or abdominal pain, are present, surgeons should consider delaying elective procedures. If the patient has no gastrointestinal symptoms and the GLP-1 agonists have been held as advised, the surgical team can carry on as normal.

Source: American Society of Anesthesiologists

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For Weight Loss, the Side Effects of GLP-1 Agonists can be Hard to Stomach

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GLP-1 agonists are being lauded as game-changers in the fight against obesity, but GLP-1 agonist drugs like semaglutide may come with a heightened risk of severe gastrointestinal problems, according to new research published in JAMA.

Designing their study for the side effects rather than the efficacy of the drugs, the researchers found that GLP-1 agonists are associated with an increased risk of serious medical conditions including gastroparesis (stomach paralysis), pancreatitis and bowel obstruction.

While previous studies highlighted some of these risks in patients with diabetes, this study from the University of British Columbia is the first large, population-level study to examine adverse gastrointestinal events in non-diabetic patients using the drugs specifically for weight loss.

“Given the wide use of these drugs, these adverse events, although rare, must be considered by patients thinking about using them for weight loss,” said first author Mohit Sodhi, a graduate of UBC’s experimental medicine program and fourth year UBC medical student studying the adverse events of commonly prescribed medications. “The risk calculus will differ depending on whether a patient is using these drugs for diabetes, obesity or just general weight loss. People who are otherwise healthy may be less willing to accept these potentially serious adverse events.”

GLP-1 agonists have exploded in popularity over the past decade as an off-label weight-loss tool, reaching approximately 40 million prescriptions in the US in 2022.

It was only in 2021 that some forms of the medications were approved as a treatment for obesity. However, randomised clinical trials examining the efficacy of the medications for weight loss were not designed to capture rare gastrointestinal events due to their small sample sizes and short follow-up periods.

“There have been anecdotal reports of some patients using these drugs for weight loss and then presenting with repeated episodes of nausea and vomiting secondary to a condition referred to as gastroparesis,” said senior author Dr Mahyar Etminan, an epidemiologist and associate professor in the department of ophthalmology and visual sciences at the UBC faculty of medicine. “But until now, there hasn’t been any data from large epidemiologic studies.”

To help fill this knowledge gap, UBC researchers examined health insurance claim records for approximately 16 million US patients and looked at people prescribed either semaglutide or liraglutide, two main GLP-1 agonists, between 2006 and 2020. They included patients with a recent history of obesity, and excluded those with diabetes or who had been prescribed another antidiabetic drug.

The researchers analysed the records to see how many patients developed one of four gastrointestinal conditions, and compared that rate to patients using another weight-loss drug, bupropion-naltrexone. Compared to bupropion-naltrexone, GLP-1 agonists were associated with a:

  • 9.09 times higher risk of pancreatitis, which can cause severe abdominal pain and, in some cases, require hospitalisation and surgery.
  • 4.22 times higher risk of bowel obstruction, resulting in symptoms like cramping, bloating, nausea and vomiting. Depending on the severity, surgery may be required.
  • 3.67 times higher risk of gastroparesis, limiting the passage of food from the stomach to the small intestine and results in symptoms like vomiting, nausea and abdominal pain.

Additionally, the study found a non-significant higher incidence of biliary disease.

The researchers say that although the events are rare, with millions around the world using the drugs, it could still lead to hundreds of thousands of people experiencing these conditions.

“These drugs are becoming increasingly accessible, and it is concerning that, in some cases, people can simply go online and order these kinds of medications when they may not have a full understanding of what could potentially happen. This goes directly against the mantra of informed consent,” said Sodhi.

In the meantime, the researchers hope that regulatory agencies and drug makers will consider updating the warning labels for their products, which currently don’t include the risk of gastroparesis.

“This is critical information for patients to know so they can seek timely medical attention and avoid serious consequences,” said Sodhi.

Source: University of British Columbia

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Semaglutide Eliminates Insulin Injections in Some Newly-diagnosed Type 1 Diabetes Patients

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Novolog insulin pen. Photo by Dennis Klicker on Unsplash

Treating newly diagnosed Type 1 diabetes patients with semaglutide may drastically reduce or even eliminate their need for injected insulin, according to the remarkable findings of a small University at Buffalo study reported in the New England Journal of Medicine.

“Our findings from this admittedly small study are, nevertheless, so promising for newly diagnosed Type 1 diabetes patients that we are now absolutely focused on pursuing a larger study for a longer period of time,” says Paresh Dandona, MD, PhD, professor and senior author on the paper.

A total of 10 patients at UB’s Clinical Research Center in the Division of Endocrinology were studied from 2020 to 2022, all of whom had been diagnosed in the past three to six months with Type 1 diabetes. The mean HbA1c level over 90 days at diagnosis was 11.7, far above the American Diabetes Association’s HbA1c recommendation of 7 or below.

The patients were treated first with a low dose of semaglutide while also taking meal-time (bolus) insulin and basal (background) insulin. As the study continued, semaglutide dosing was increased while mealtime insulin was reduced in order to avoid hypoglycaemia.

“Within three months, we were able to eliminate all of the mealtime insulin doses for all of the patients,” says Dandona, “and within six months we were able to eliminate basal insulin in 7 of the 10 patients. This was maintained until the end of the 12-month follow-up period.”

During that time, the patients’ mean HbA1c fell to 5.9 at six months and 5.7 at 12 months.

Applying Type 2 diabetes drugs to treat Type 1 diabetes

For more than a decade, Dandona has been interested in how drugs developed for Type 2 diabetes might be utilized in treating Type 1 diabetes as well.

He and his colleagues were the first to study how liraglutide, another drug for Type 2 diabetes, might work in patients with Type 1 diabetes in a study he published in 2011.

“As we extended this work, we found that a significant proportion of such diabetics still have some insulin reserve in the beta cells of their pancreas,” Dandona explains. “This reserve is most impressive at the time of diagnosis, when 50% of the capacity is still present. This allowed us to hypothesise that semaglutide, which works through stimulation of insulin secretion from the beta cell, could potentially replace mealtime insulin administration.”

From the outset, the goal of the current study was to see if semaglutide treatment could be used to replace mealtime insulin, thereby reducing the insulin dosage, improving glycaemic control, reducing the HbA1c and eliminating potentially dangerous swings in blood sugar and hypoglycaemia.

The most common side effects for patients were nausea and vomiting as well as appetite suppression, which led a number of patients to experience weight loss, an outcome that Dandona says is generally an advantage since 50% of patients with Type 1 diabetes in the US are overweight or obese.

“As we proceeded with the study, we found that even the dose of basal insulin could be reduced or eliminated altogether in a majority of these patients,” he says. “We were definitely surprised by our findings and also quite excited. If these findings are borne out in larger studies over extended follow-up periods, it could possibly be the most dramatic change in treating Type 1 diabetes since the discovery of insulin in 1921.”

Source: University at Buffalo

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Semaglutide Also Cuts Cardiovascular Risk, Could Change Cardiology Practice

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By HualinXMN – Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=133759262

According to results from the SELECT trial run by Novo Nordisk, semaglutide dramatically reduces the risk of major adverse cardiovascular events (MACEs) in addition to its obesity benefits. This is bolstered by the results of another trial, STEP-1, which also suggested significant reduction in future cardiovascular events. These results have captured the attention of researchers, who commented in Nature that they could change the practice of cardiology.

Semaglutide, sold in the US for the treatment of both obesity (Wegovy) and diabetes (Ozempic), is an agonist for glucagon-like peptide 1 (GLP-1), a hormone associated with appetite.

”It’s hard to think of other [drugs], apart from statins, that have shown such a profound effect,” says Martha Gulati, director of preventive cardiology at Cedars-Sinai Medical Center in Los Angeles, USA.

It was expected that semaglutide would have cardiovascular benefits through promoting weight loss, but evidence shows that drugs mimicking GLP-1 can improve fatty-acid metabolism and reduce inflammation, for example, says Gulati. “This is what’s so fascinating about these drugs. They work on the brain, the pancreas, the cardiovascular system, the gastrointestinal tract … There’s more to them than simply weight loss.”

Recent studies have been encouraging in terms of semaglutide’s benefits for reducing cardiovascular disease risk. Earlier this month, Novo Nordisk announced the headline results from the SELECT cardiovascular outcomes trial. The double-blinded trial compared subcutaneous once-weekly semaglutide 2.4mg with placebo as an adjunct to standard of care for prevention of MACEs over a period of up to five years. The trial enrolled 17 604 adults aged 45 years or older with overweight or obesity and established cardiovascular disease (CVD) with no prior history of diabetes.

The trial showed 20% reduction in MACEs for people treated with semaglutide 2.4mg compared to placebo. The primary endpoint was a composite outcome of the first occurrence of MACE cardiovascular death, non-fatal myocardial infarction or non-fatal stroke. All three of these components contributed to the MACE reduction. 1270 first MACEs were accrued.

Expanding GLP-1 analogues to cardiovascular disease prevention may not be without challenges, as the European Medicines Agency opened investigations into semaglutide and liraglutide over reports of suicidal thoughts and self-harm.

A separate study based on the STEP 1 trial data found that 93 million adults in the US could benefit from semaglutide, from a combination of weight loss and reduced cardiovascular benefits. They estimate a reduction in relative risk of 18% with the drug.

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Safety and Efficacy of Oral Semaglutide Shown in Clinical Trial Success

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Participants taking a daily 50mg dose of oral semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, lost more weight than those taking placebo, according to results announced by the manufacturer, Norvo Nordisk.

Novo Nordisk announced headline results from phase 3a trial in a statement. The OASIS 1 trial is a 68-week, efficacy and safety trial comparing once-daily oral semaglutide 50mg for weight management to placebo in 667 adults with obesity or overweight with one or more comorbidities. Participants also undertook lifestyle interventions.

When evaluating the effects of treatment if all people adhered to treatment from a mean baseline body weight of 105.4 kg, people treated with oral semaglutide 50mg achieved a statistically significant weight loss of 17.4% after 68 weeks compared to a 1.8% reduction with placebo. In addition, 89.2% of those who received oral semaglutide 50mg, reached a weight loss of 5% or more after 68 weeks, compared to 24.5% with placebo.

When applying the treatment policy estimand, people treated with oral semaglutide 50 mg achieved a superior weight loss of 15.1% compared to a reduction of 2.4% with placebo and 84.9% achieved a weight loss of 5% or more, compared to 25.8% with placebo.

“We are very pleased with the weight loss demonstrated by the once-daily oral formulation of semaglutide in obesity. The results show comparable weight loss as in the STEP 1 trial with injectable semaglutide 2.4mg in obesity branded as Wegovy®”, said Martin Holst Lange, executive vice president for Development at Novo Nordisk. ”The choice between a daily tablet or weekly injection for obesity has the potential to offer patients and healthcare providers the opportunity to choose what best suits individual treatment preferences”.

Oral semaglutide 50 mg also appeared be safe and was well tolerated, with the most common adverse events being mostly mild to moderate gastrointestinal ones consistent with the GLP-1 receptor agonist class. Gastrointestinal adverse events were most prominent during dose escalation.

Novo Nordisk expects to file for regulatory approval in the US and the EU in 2023. The global launch of oral semaglutide 50mg is contingent on portfolio prioritisations and manufacturing capacity.

Source: Novo Nordisk

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Quarter of Teens with Obesity Treated with Semaglutide Fell to Normal Weight

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A secondary analysis of a trial of 2.4mg semaglutide (Wegovy) found nearly half of the teenage participants with obesity returned to normal weight or fell below the obesity threshold. The trial, results of which were published in Obesity, added semaglutide to dietary advice and a daily goal of 60 minutes of moderate- to high-intensity physical activity.

During the 68-week STEP TEENS trial, 44.9% of participants (aged 12–18 with obesity) returned to either normal weight or went down to the overweight category while on treatment compared with only 12.1% of those on placebo. At the end of the trial, 25% of the treatment group dropped to normal weight compared to just 2% for placebo.

“These results underscore the high degree of clinical effectiveness of semaglutide in adolescents with obesity,” said first author Aaron S. Kelly, PhD, in a statement. “In a practical sense, we see that semaglutide reduced weight to a level below what is defined as clinical obesity in nearly 50% of the teens in our trial, which is historically unprecedented with treatments other than bariatric surgery.”

An ‘important piece to the puzzle’ of the obesity problem

“A question I get a lot is, ‘Is this going to solve the obesity problem? Should we just give it to everybody’?” said Kelly, who is at the University of Minesota. “No and no. It’s not going to solve the obesity problem, but it’s an important piece to the puzzle in helping to solve it, especially for those who already have obesity.”

The trial’s initial results saw a an average BMI reduction 16.1% with semaglutide compared with a 0.6% increase with placebo at week 68. On average, participants on semaglutide lost 15.3 kg, while those on placebo gained 2.4 kg.

“The degree of body weight reduction is unprecedented,” lead study author Daniel Weghuber, MD, of Paracelsus Medical University, told MedPage Today at the ObesityWeek meeting, when the results were presented. “After years of frustration, all of a sudden patients were actually losing weight. They’d never seen that before.”

These results led to the approval for ages 12 and older by the FDA in December 2022, after being approved for adults in June 2021. The study also found a slightly superior but non-significant effect in females than males, despite not being set up to measure sex differences. The same was true for ages 12–14 vs 15–18.

Source: MedPage Today