{"id":530957,"date":"2026-04-14T21:01:08","date_gmt":"2026-04-14T21:01:08","guid":{"rendered":"https:\/\/www.newsbeep.com\/uk\/530957\/"},"modified":"2026-04-14T21:01:08","modified_gmt":"2026-04-14T21:01:08","slug":"why-glp-1-drugs-dont-work-for-everyone","status":"publish","type":"post","link":"https:\/\/www.newsbeep.com\/uk\/530957\/","title":{"rendered":"Why GLP-1 Drugs Don’t Work for Everyone"},"content":{"rendered":"

\"GLP-1Share on Pinterest<\/a>Research has found that the effectiveness of GLP-1 drugs may vary based on a person\u2019s genetics. Image Credit: Indranil MUKHERJEE \/ AFP via Getty ImagesGLP-1 medications may not always be effective for everyone. New research suggests that around 10% of people carry genetic variations that explain why. A new review suggests that certain combination approaches for obesity pharmacotherapy may be effective when GLP-1 drugs are not. Experts share recommendations for alternative weight loss strategies.<\/p>\n

GLP-1 medications have exploded in popularity to manage type 2 diabetes and treat obesity.<\/p>\n

The popularity of this class of medications, which includes Ozempic<\/a> and Wegovy<\/a>, is partly due to their widespread success for weight loss.<\/p>\n

However, new research published in Genome Medicine<\/a> shows that GLP-1 drugs<\/a> may not be effective for everyone. The findings suggest that certain genetic factors may offer an explanation.<\/p>\n

Around 10% of people carry genetic variations linked to \u201cGLP-1 resistance.\u201d These individuals appear to have higher-than-normal levels of the hormone glucagon-like peptide-1 (GLP-1). GLP-1 helps to regulate blood sugar. In contrast, the hormone appears less effective despite higher GLP-1 levels.<\/p>\n

\u201cThis aligns with my clinical experience, where I frequently see a variable response to GLP-1 medications,\u201d said Mir Ali<\/a>, MD, bariatric surgeon and medical director of MemorialCare Surgical Weight Loss Center at Orange Coast Medical Center in Fountain Valley, CA. Ali wasn\u2019t involved in the study. <\/p>\n

It\u2019s unclear whether these genetic variations influence weight loss. GLP-1 drugs are generally prescribed at higher doses for weight loss than for diabetes management. The current study focused on how GLP-1s and these genetic variants influence blood sugar levels.<\/p>\n

The study focused on two genetic variants that affect the enzyme peptidyl-glycine alpha-amidating monooxygenase (PAM). <\/p>\n

PAM plays a role in activating various hormones, including GLP-1. <\/p>\n

Certain variants of PAM are more common in those with diabetes and may impair the release of insulin from the pancreas. The research team sought to determine whether these variants also disrupt GLP-1. <\/p>\n

In addition to helping regulate blood sugar, GLP-1 also stimulates insulin release after meals, slows stomach emptying, and reduces appetite. GLP-1 drugs are made to mimic the effects of this hormone. <\/p>\n

When the research team analyzed individuals with a PAM variant called p.S539W, they expected to find lower GLP-1 levels. However, they found elevated levels of GLP-1 in these individuals. <\/p>\n

They also found that, even with higher GLP-1 levels, participants did not reduce their blood sugar levels more quickly. More GLP-1 was needed to achieve the same biological effect, indicating the participants were GLP-1-resistant. <\/p>\n

\u201cThese findings support the idea that some patients may have partial biologic resistance to incretin-based therapies,\u201d said Robert Glatter<\/a>, MD, attending physician in the Department of Emergency Medicine at Lenox Hill Hospital in New York City, and Assistant Professor of Emergency Medicine at Zucker School of Medicine at Hofstra\/ Northwell. Glatter wasn\u2019t involved in the study. <\/p>\n

\u201cStill, genetics explains only a portion of treatment heterogeneity, and routine pharmacogenomic screening is not yet ready for widespread clinical use,\u201d he added. <\/p>\n

More research is needed to verify the effects genetic variations can have on weight loss with GLP-1s. Still, the findings show promise for the future of obesity treatment. <\/p>\n

\u201cThe broader lesson from recent research is that obesity treatment is entering a precision-medicine era,\u201d Glatter said. \u201cInstead of asking whether GLP-1 medications work, clinicians are beginning to ask for whom they work best \u2014 and what alternative pathways should be considered when responses are incomplete.\u201d<\/p>\n

We asked our experts to explain why GLP-1s don\u2019t always work for weight loss and what alternatives are available. These interviews have been lightly edited for clarity.<\/p>\n

What other factors influence GLP-1 effectiveness?<\/p>\n

Ali: Other factors can include underlying medical conditions or the patient not using the medications exactly as prescribed.<\/p>\n

Glatter: In practice, many patients labeled \u201cnon-responders\u201d to GLP-1 therapy are experiencing incomplete dosing, early discontinuation because of gastrointestinal side effects<\/a>, insufficient treatment duration, or competing metabolic drivers such as severe insulin resistance<\/a>, sleep disruption, sarcopenia<\/a>, or medication-associated weight gain. <\/p>\n

Addressing these contributors often restores treatment effectiveness.<\/p>\n

What other options do people have if GLP-1s don\u2019t work?<\/p>\n

Ali: If a patient meets the criteria, surgical weight loss<\/a> remains the most effective long-term solution. <\/p>\n

Glatter: Another important option that deserves earlier consideration\u2014not later referral\u2014is metabolic and bariatric surgery<\/a>. Too often framed as a last resort after medication failure, surgery is better understood as a parallel therapeutic strategy within the same treatment continuum. <\/p>\n

Procedures such as sleeve gastrectomy<\/a> and Roux-en-Y gastric bypass produce average weight reductions of 25 to 35%<\/a> and remain the most durable interventions available for severe obesity<\/a> and obesity-related metabolic disease. <\/p>\n

Importantly, surgery also alters incretin signaling itself, increasing GLP-1 activity and improving insulin sensitivity in ways that complement pharmacologic therapies.<\/p>\n

Is combination pharmacotherapy an option? <\/p>\n

Glatter: When response remains limited despite optimization, clinicians should consider moving beyond monotherapy. <\/p>\n

Obesity is a network disease involving appetite regulation, reward signaling, gut-brain hormones, and energy expenditure pathways. <\/p>\n

Combination pharmacotherapy<\/a> \u2014 such as pairing incretin agents with phentermine<\/a>, topiramate<\/a>, or bupropion-naltrexone<\/a> \u2014 targets complementary mechanisms and is increasingly supported by mechanistic and clinical evidence. Rather than representing treatment escalation alone, combination therapy reflects a broader shift toward multimodal metabolic care.<\/p>\n

Ali: If surgery is not an option, we can try medications that stimulate more than one receptor (such as Zepbound<\/a>) or a combination of different medications.<\/p>\n

What are some other proven weight loss strategies?<\/p>\n

Ali: The majority of weight loss is driven by dietary modifications\u2014primarily reducing carbohydrate<\/a> and sugar intake while emphasizing proteins<\/a> and vegetables. Adding both aerobic<\/a> and resistance exercise further helps burn calories and mitigate muscle loss.<\/p>\n

Glatter: Additional approaches to lose weight and manage cardiometabolic aspects of obesity include adherence to the Mediterranean<\/a>, DASH<\/a>, or MIND<\/a> diet, along with adequate strength training<\/a>, close monitoring of hydration status, and caloric intake to maintain and prevent muscle loss, particularly while taking a GLP-1. <\/p>\n

Even if one chooses not to take a GLP-1 to manage weight loss, adherence to a Mediterranean-style diet, adequate hydration, and resistance training combined with aerobic exercise is recommended for weight loss and preservation of muscle mass. <\/p>\n","protected":false},"excerpt":{"rendered":"Share on PinterestResearch has found that the effectiveness of GLP-1 drugs may vary based on a person\u2019s genetics.…\n","protected":false},"author":2,"featured_media":530958,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[42],"tags":[102,6591,56,54,55],"class_list":{"0":"post-530957","1":"post","2":"type-post","3":"status-publish","4":"format-standard","5":"has-post-thumbnail","7":"category-medication","8":"tag-health","9":"tag-medication","10":"tag-uk","11":"tag-united-kingdom","12":"tag-unitedkingdom"},"_links":{"self":[{"href":"https:\/\/www.newsbeep.com\/uk\/wp-json\/wp\/v2\/posts\/530957","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.newsbeep.com\/uk\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.newsbeep.com\/uk\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/uk\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/uk\/wp-json\/wp\/v2\/comments?post=530957"}],"version-history":[{"count":0,"href":"https:\/\/www.newsbeep.com\/uk\/wp-json\/wp\/v2\/posts\/530957\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/uk\/wp-json\/wp\/v2\/media\/530958"}],"wp:attachment":[{"href":"https:\/\/www.newsbeep.com\/uk\/wp-json\/wp\/v2\/media?parent=530957"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newsbeep.com\/uk\/wp-json\/wp\/v2\/categories?post=530957"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newsbeep.com\/uk\/wp-json\/wp\/v2\/tags?post=530957"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}