Have we conquered Obesity? New Anti-Obesity Medications:

Obesity management is being transformed by glucagon-like peptide-1 (GLP-1) receptor agonists and newer dual incretin agonists. This report synthesizes the latest evidence from randomized controlled trials (RCTs), meta-analyses, and independent reviews on these medications – focusing on semaglutide (Ozempic®/Wegovy®) and tirzepatide (Mounjaro™/Zepbound™) – and compares their performance to traditional interventions. We examine effectiveness, side effects, long-term risk–benefit balance, and issues of pharmaceutical bias and transparency.

1. Effectiveness of GLP-1 Agonists and Dual Agonists

Weight Loss Outcomes: Both weekly semaglutide and tirzepatide have demonstrated unprecedented weight loss efficacy in adults with overweight or obesity (generally BMI ≥30, or ≥27 with comorbidities). In the STEP-1 trial (68-week RCT of semaglutide 2.4 mg plus lifestyle therapy vs placebo), semaglutide produced a −14.9% average body weight reduction from baseline, compared to −2.4% with placebo . This translated to a mean weight loss of ~15 kg on semaglutide vs ~2.6 kg on placebo . Notably, 86% of semaglutide-treated patients achieved ≥5% weight loss (vs 32% on placebo), and 50% achieved ≥15% weight loss (vs 5% on placebo) – an effect size rarely seen with older medications. Similarly, the SURMOUNT-1 trial (72-week RCT of tirzepatide) found dose-dependent weight loss with tirzepatide: at the highest dose (15 mg weekly) −20.9% mean weight reduction vs −3.1% with placebo . About 91% of patients on tirzepatide (15 mg) achieved ≥5% weight loss (vs 35% on placebo), and more than 50% achieved ≥20% weight reduction on the 10 mg and 15 mg doses (vs 3% on placebo) . These results indicate that tirzepatide can induce ~5–10 percentage points greater weight loss than semaglutide at one year, a finding consistent with real-world analyses and head-to-head comparisons .

These incretin-based therapies far outperform older pharmacological options. For context, daily liraglutide 3.0 mg (an earlier GLP-1 RA for obesity) produced ~8% mean weight loss in 1 year . Other approved drugs (e.g. phentermine/topiramate, bupropion/naltrexone) generally induce ~5–10% weight loss in trials. By contrast, weekly semaglutide and tirzepatide routinely produce 15–20% body weight reductions, approaching the efficacy of metabolic surgery. For instance, sleeve gastrectomy results in ~25% weight loss at 1 year (maintaining ~19% at 5 years), while gastric bypass yields ~31% at 1 year (~26% at 5 years) . Thus, tirzepatide’s ~21% weight reduction at 72 weeks rivals the 1-year results of sleeve gastrectomy, albeit long-term durability remains under study. Lifestyle interventions alone are far less effective: in the trials above, even with diet and exercise counseling, placebo groups lost only ~2–3% weight .

Metabolic and Comorbidity Benefits: Beyond weight loss itself, these medications confer improvements in obesity-related comorbidities. Both semaglutide and tirzepatide significantly improve glycemic control. In nondiabetic patients, they markedly lower fasting glucose and HbA1c, and in type 2 diabetes they often enable reduction of other glucose-lowering medications . Importantly, semaglutide and tirzepatide can reverse prediabetes and reduce progression to diabetes: in a 2-year trial, 80% of semaglutide-treated patients with prediabetes reverted to normoglycemia, versus 37% with placebo . Similarly, only 1.4% of initially normoglycemic patients on semaglutide developed prediabetes over 2 years, compared to 13% with placebo .

Cardiometabolic risk factors improve substantially. Patients on semaglutide in STEP trials saw greater reductions in waist circumference, blood pressure, and triglycerides than placebo Tirzepatide produced broad improvements in blood pressure, lipids, and inflammatory markers in SURMOUNT-1 . Perhaps most striking is emerging evidence of cardiovascular outcome benefits. The SELECT trial (semaglutide 2.4 mg vs placebo in ~17,600 adults with obesity and established cardiovascular disease, but without diabetes) found a 20% relative reduction in major adverse cardiac events (heart attack, stroke, CV death) over ~3.3 years . Specifically, 6.5% of semaglutide patients had an event vs 8.0% of placebo (HR 0.80, 95% CI 0.72–0.90) . This is the first trial to demonstrate that weight loss with a GLP-1 RA can translate into fewer hard outcomes in non-diabetic patients. (However, notable dropout occurred: 16.6% on semaglutide discontinued treatment due to adverse events vs 8.2% on placebo – see later sections on tolerability.) While long-term cardiovascular data for tirzepatide are pending, its robust weight and metabolic effects suggest it may yield similar benefits; a cardiovascular outcomes trial for tirzepatide in obesity is underway.

Sustainability of Weight Loss and Post-Cessation Effects: A critical question is whether weight reduction is maintained and what happens after stopping therapy. RCTs with extended follow-up indicate that as long as the drug is continued, weight loss plateaus and is sustained. For example, in the 2-year STEP-5 trial, semaglutide 2.4 mg led to a sustained −15.2% weight change at 104 weeks versus ~−3% with placebo. Over half of semaglutide patients maintained ≥15% loss at 2 years . However, upon discontinuation, weight regain is common. In STEP-4, all participants first received 20 weeks of semaglutide, losing ~10.6% of weight, then were randomized to continue drug or switch to placebo for the next 48 weeks . The difference was dramatic: those who stayed on semaglutide lost an additional 7.9%, whereas those switched to placebo regained 6.9% of body weight. By week 68, the continued-treatment group was ~15% below their original weight, while the withdrawal group had regained most of their initial loss (ending only ~4% below baseline). In other words, stopping the medication led to substantial weight regain, reflecting the chronic, relapsing nature of obesity. Similar patterns are observed with liraglutide and likely with tirzepatide (ongoing SURMOUNT trials are evaluating maintenance). These findings underscore that, like hypertension or diabetes treatments, ongoing therapy is needed to sustain benefits; short-term use (≤20 weeks) is not effective for lasting weight control .

Quality of Life and Functional Improvements: Rapid weight loss with these agents has meaningful clinical benefits for patients’ daily lives. Trials report improved physical function and quality of life scores with treatment. In STEP-1, semaglutide patients had greater gains in patient-reported physical functioning (SF-36 score) than placebo . Other analyses found significant improvement in weight-related quality of life (IWQOL-Lite questionnaire) with semaglutide, including better physical comfort and self-esteem, compared to minimal changes with lifestyle intervention alone . Many patients on GLP-1 RAs report increased mobility, energy, and overall well-being as they shed substantial weight. Of course, some experience side effects (discussed next) that can negatively impact quality of life in the short term, but for those who tolerate therapy, the net effect on daily function is positive. Additionally, remission of comorbidities (e.g. improved glycemic control, blood pressure reduction) can reduce medication burden and health worries, further improving patient satisfaction.

Comparison to Lifestyle and Bariatric Surgery: Lifestyle modification remains fundamental, but its limitations are clear when viewed against these new pharmacotherapies. Diet and exercise typically result in only 3–5% weight loss at 1 year for most individuals (and often less in routine practice) . Moreover, weight regain is common once intensive support is removed . GLP-1 and dual agonist medications, used as adjuncts to lifestyle, enable a large proportion of patients to achieve the ≥10–15% weight loss often needed for significant metabolic improvement. In fact, the degree of weight loss with these drugs begins to overlap with bariatric surgery outcomes, which historically have been considered the gold standard. Bariatric surgery still produces greater absolute weight loss and has the longest track record for durability – for example, gastric bypass patients in a large cohort averaged 26% total weight loss maintained at 5 years, whereas it remains to be seen if pharmacotherapy can safely be continued (or weight maintained) over 5+ years. Surgery also offers benefits like high rates of diabetes remission and long-term mortality reduction in severe obesity. However, surgery entails operative risks, potential complications (anastomotic issues, malabsorption, etc.), and is only accessible to a small fraction of eligible patients. The advent of medications like semaglutide and tirzepatide closes much of the efficacy gap: e.g., a year of tirzepatide 15 mg gave ~21% weight loss , only ~5 percentage points less than gastric bypass at 1 year . While some of the surgical advantage re-emerges over longer follow-up (since pharmacotherapy must be sustained and is subject to adherence issues), these drugs provide a less invasive alternative for substantial weight loss. Indeed, guidelines are beginning to incorporate GLP-1 RAs as a treatment option on par with older surgical approaches for certain patients, especially those who either cannot undergo surgery or prefer medication therapy first .

In summary, GLP-1 receptor agonists (like semaglutide) and dual GLP-1/GIP agonists (like tirzepatide) have demonstrated unprecedented effectiveness in treating obesity, producing clinically significant and potentially life-changing weight loss alongside improvements in comorbid conditions. Their efficacy far exceeds traditional lifestyle intervention alone and approaches that of bariatric procedures, though long-term maintenance and comparative outcomes (vs surgery) are areas of active research.

2. Side Effects and Safety Profile

All potent weight-loss medications must be weighed against their side effect profiles. GLP-1–based therapies are generally considered safe, but they do cause a variety of adverse effects – most commonly gastrointestinal issues – and have some notable rare risks. We summarize side effects observed in trials and post-marketing, ranging from mild and common to severe but infrequent.

Common Adverse Effects: The most frequent side effects of GLP-1 receptor agonists and tirzepatide are gastrointestinal (GI) symptoms. These include: nausea, vomiting, diarrhea, abdominal cramping, and constipation. In trials, a majority of patients experience some GI symptoms, especially during the initial dose-escalation phase as the body adjusts For example, in SURMOUNT-1, nausea occurred in roughly 12–24% of tirzepatide-treated patients (dose-dependent), diarrhea in 12–22%, and vomiting in 5–13%, compared to much lower rates in placebo patients . With semaglutide 2.4 mg, rates of GI effects are similarly high: in a 2-year obesity trial, 82% of semaglutide patients reported at least one GI adverse event vs ~54% on placebo . Nausea was the most common, often affecting ~30–40% of patients on semaglutide during dose escalation, though usually mild or moderate . Diarrhea, constipation, and vomiting are also frequently reported, each in roughly 10–20% of patients . Notably, these effects are typically transient – they tend to occur early (when doses are being increased) and then subside over time in many individuals . Slower titration schedules help improve tolerability. Despite being “mild-to-moderate” in severity for most, GI side effects can impact quality of life and are the leading cause of treatment discontinuation. In STEP-1, 4.5% of semaglutide patients withdrew due to GI adverse events (vs 0.8% on placebo) . In SURMOUNT-1, 6–7% of tirzepatide patients on higher doses discontinued due to side effects (vs ~2.5% placebo) .

It’s worth noting that some degree of GI discomfort is almost a feature of this class – indeed, nausea might be intertwined with the mechanisms of weight loss (via reduced appetite and slower gastric emptying) Patients who experience transient nausea often have slightly greater weight loss, suggesting a mediating effect of appetite suppression . Nonetheless, clinicians take GI side effects seriously: guidelines emphasize patient counseling, dose titration, and adjunctive measures (e.g. antiemetics or dietary adjustments) to manage these symptoms.

Beyond the GI tract, other common or intermediate side effects reported with GLP-1 RAs include headache, fatigue, dizziness, and mild increase in heart rate . Semaglutide’s label notes a small increase in resting heart rate (mean ~2–4 beats per minute). Some patients also report injection-site reactions (erythema or discomfort at the injection area), though these are generally minor. Because GLP-1 RAs do not directly cause hypoglycemia (except in conjunction with other diabetes medications), symptomatic hypoglycemia is uncommon in non-diabetic users . However, in people with type 2 diabetes taking insulin or sulfonylureas, adding a GLP-1 RA can increase hypoglycemia risk, so those medications often need dose adjustments .

Gastrointestinal Complications: A subset of GI effects merit special attention as potential long-term or severe complications. GLP-1 agonists slow gastric emptying, which is part of their appetite-suppressing effect, but in some cases this can lead to gastroparesis (delayed gastric emptying) or even gastrointestinal obstruction (ileus). In clinical trials, severe gastroparesis or ileus was rare; most patients adapt to the slowed gastric emptying. However, post-marketing reports have raised concerns that some patients develop persistent vomiting and inability to tolerate food, consistent with gastroparesis, even after discontinuing the drug. In mid-2023, numerous legal claims received media attention where patients on semaglutide or similar drugs reported severe, chronic vomiting (so-called “cyclic vomiting”) and required medical intervention for gastroparesis . It’s unclear how frequently this occurs, but regulators are monitoring it. Physicians now caution that people with known gastroparesis or serious GI motility disorders should likely avoid GLP-1 RAs, and any patient with refractory vomiting on these drugs should be evaluated for possible gastric emptying issues. Furthermore, because of delayed gastric emptying, there are anesthetic considerations – recent guidance warns of higher aspiration risk during surgery, and the need for prolonged fasting before procedures for patients on GLP-1 RAs .

Gallbladder Disease: Rapid weight loss, whether from surgery or medication, can predispose to gallstone formation. Indeed, GLP-1 agonists have been associated with a slight excess of gallbladder-related adverse events (e.g. gallstones, cholecystitis). A meta-analysis of trials found GLP-1 RA treatment carried about a 37% higher relative risk of gallbladder or biliary disease compared to placebo . In semaglutide’s obesity trials, gallbladder disorders were uncommon overall but numerically higher with the drug (e.g. 2.6% vs 1.3% in one 2-year study) . The FDA noted that the risk of gallbladder events appeared greater in patients with larger weight loss, implying that the effect is likely related to weight loss itself as well as possibly a direct effect on biliary motility . Cholelithiasis (gallstones) and cholecystitis now appear in the precautions for these medications. Patients are advised to report symptoms of gallbladder attacks (right upper abdominal pain, etc.), and clinicians stay alert to this risk, especially in those losing weight very rapidly.

Pancreatitis and Pancreatic Concerns: Acute pancreatitis has been observed infrequently in patients on GLP-1 RAs, though establishing causality has been challenging. In early use of this class (e.g. exenatide), case reports of pancreatitis raised alarms, but large trials and observational studies have not conclusively confirmed a significant increased risk. In the semaglutide development program, pancreatitis cases were rare and occurred in both treatment and placebo groups, with no clear excess risk . Nonetheless, because of historical signals, all GLP-1 RA labels (including semaglutide and tirzepatide) list pancreatitis as a potential risk. Post-marketing surveillance continues to monitor for pancreatitis and even pancreatic cancer. To date, no definitive link to pancreatic cancer has been found in humans , but animal studies had noted benign pancreatic growth in some cases. The FDA and EMA consider pancreatitis an “unconfirmed signal” – meaning patients should be aware of symptoms (e.g. severe abdominal pain) and providers should discontinue the drug if pancreatitis is suspected, but the overall benefit still outweighs this very low-frequency risk . In summary, pancreatitis is rare but serious; clinicians typically avoid prescribing GLP-1 RAs to individuals with a history of pancreatitis out of caution.

Thyroid Tumors: A class warning for all GLP-1 receptor agonists (including dual agonists) is the risk of thyroid C-cell tumors. This stems from rodent studies in which lifetime high-dose exposure led to medullary thyroid carcinoma (MTC) in rats. To date, no increase in MTC or thyroid cancer has been observed in human trials . Nonetheless, out of an abundance of caution, these drugs are contraindicated in patients with a personal or family history of MTC or multiple endocrine neoplasia type 2 . Patients are also advised to report any neck masses or persistent hoarseness. It’s important to emphasize that this risk remains theoretical in humans – extensive post-marketing data over 15+ years for other GLP-1 RAs have not shown a thyroid cancer signal. The FDA considers it a “potential risk identified in nonclinical data” and requires it in labeling as a safety guard . So while “thyroid cancer” appears in the warning section, patients should understand it was a rodent-specific finding at very high exposures; routine monitoring of calcitonin levels is not required unless clinical suspicion arises.

Diabetic Retinopathy Complications: Another safety consideration is worsening of diabetic retinopathy in some patients with rapid glycemic improvement. In the semaglutide CV trial for diabetes (SUSTAIN-6), a higher incidence of retinopathy complications was noted in the semaglutide group (likely because rapid drops in blood sugar can transiently worsen retinopathy in susceptible individuals) . In weight-loss trials of semaglutide, most participants are not diabetic, so this wasn’t a major issue; however, for patients with diabetes using high-dose GLP-1 RAs, guidelines recommend retinopathy screening and careful glucose management. The FDA has mandated further evaluation of this risk in diabetic populations . For non-diabetic obese patients, retinopathy is not a concern since their glucose is normal to start with – in fact, many who had prediabetes will have improved glycemia as noted.

Other Rare or Serious Effects: A few other safety signals are being tracked, though current evidence is reassuring:

Kidney injury: Volume depletion from nausea/vomiting can in rare cases lead to acute kidney injury (AKI). There have been case reports of AKI in patients on GLP-1 RAs, often associated with severe dehydration from persistent vomiting or diarrhea. In trials, acute kidney injury was infrequent . Patients with pre-existing kidney disease are monitored closely, and staying hydrated is emphasized.
Heart rate and arrhythmia: GLP-1 RAs cause a small increase in heart rate. The clinical significance of this is unclear, but some worry it could predispose to arrhythmias or exacerbate certain cardiac conditions. However, trials like SELECT showed overall cardiovascular benefits despite the heart rate effect , and there was no signal for arrhythmic events. Ongoing studies (e.g. in heart failure patients) will shed more light.
Psychiatric effects (mood changes, suicidal ideation): There have been scattered reports of mood changes, including depression or increased anxiety in some patients on GLP-1 RAs. More recently, regulators in Europe investigated a possible link between GLP-1 drugs and suicidal thoughts after a few cases were reported. In 2023, the EMA’s Pharmacovigilance Risk Assessment Committee reviewed data and found “no evidence of a causal association” between GLP-1 agonists and suicidal ideation at the population level. Similarly, FDA’s ongoing evaluation has not confirmed a link . Nonetheless, because obesity itself can affect mental health and weight loss might in some cases unmask underlying issues, patients are monitored for any changes in mood. Some regulatory agencies (e.g. in EU) have asked manufacturers to provide additional data on neuropsychiatric effects . For now, no formal warning about suicide risk is in the labeling due to lack of clear signal, but vigilance continues.

Adverse-Effect Profile Summary: Overall, GLP-1 and dual agonists have an “acceptable and manageable” safety profile , especially when compared to older weight-loss drugs that carried serious risks (for instance, fenfluramine’s cardiac valvulopathy or bupropion’s seizure risk at high doses). The most common side effects are gastrointestinal and tend to be mild to moderate, improving with time .

In practice, clinicians find that most side effects are manageable with patient education and symptomatic treatments. For example, taking the medication at night or using anti-nausea medication can help with GI symptoms, and ensuring patients eat smaller, lighter meals can mitigate nausea/vomiting. Adherence to therapy often depends on how well these side effects are handled in the first 1–2 months; once patients get past the initial period, the adverse effects tend to diminish. Indeed, one real-world study noted that by 6–12 months, discontinuation rates due to side effects evened out, and overall GI event rates on semaglutide vs tirzepatide were similar in practice .

Intermediate/Long-Term Considerations: With long-term use of these drugs now a reality, some new considerations are emerging. For example, lean body mass loss has been observed as part of the overall weight loss. Typically, about 25–35% of weight lost with diet or bariatric surgery is lean mass (the rest is fat). Preliminary data suggest a similar proportion of lean mass may be lost with semaglutide-induced weight loss . So if a patient loses 20 kg, perhaps ~5 kg might be muscle. This is not unexpected, but it raises the importance of incorporating resistance exercise and adequate protein intake during pharmacological weight loss to preserve muscle mass. Researchers are even exploring adjunct therapies (like myostatin inhibitors) to mitigate muscle loss in patients on GLP-1 drugs. Another issue is hydration and electrolyte balance – rapid weight loss and reduced food intake can cause dehydration, so patients must maintain fluid intake, especially if experiencing GI side effects.

Finally, reassurance on fertility/teratogenicity: There’s no evidence that these medications affect fertility, but they are not recommended in pregnancy. Animal studies of semaglutide showed some fetal abnormalities (likely related to maternal weight loss and nutrient restriction) . Thus, women of childbearing potential are advised to use contraception and discontinue the medication if planning to conceive.

In conclusion, the safety profile of semaglutide, tirzepatide, and similar agents is favorable, with mostly mild-to-moderate side effects that must be balanced against the significant health benefits of weight loss. Careful patient selection (e.g. avoiding contraindications like MTC, or caution in those with severe GI disease) and proactive management of side effects help maximize the risk–benefit ratio, as discussed next.

3. Long-Term Risk–Benefit Balance

Considering the profound benefits alongside the side effects and costs, what is the overall risk–benefit calculus for these new anti-obesity medications, especially for non-diabetic individuals with obesity? Here we assess their impact on health outcomes, quality of life, mortality, cost-effectiveness, and adherence, to judge whether the long-term benefits justify any risks.

Health Benefits vs Risks: The health benefits of achieving and maintaining substantial weight loss are extensive. High-quality evidence now shows that GLP-1 RAs not only improve surrogate measures (blood sugar, blood pressure, lipid levels) but also can reduce incidence of serious outcomes like progression to diabetes and cardiovascular events . For an individual with obesity (and related comorbidities such as hypertension or prediabetes), losing 15–20% of body weight can significantly reduce the risk of developing type 2 diabetes, lower blood pressure, improve obstructive sleep apnea, and even reduce liver fat (benefiting conditions like NASH). Semaglutide’s SELECT trial suggests a tangible mortality benefit in high-risk patients, given fewer heart attacks and strokes occurred . On the other hand, the risks of these medications are generally low probability and manageable – mostly GI discomfort and rare events as detailed above. No chronic organ toxicity has emerged; for instance, no signal of heart valve damage (as seen with older appetite suppressants) and no evidence of cancer risk in humans (thyroid or otherwise) so far . The theoretical thyroid tumor issue remains just that – theoretical – and pancreatitis or gallbladder events occur at low rates. Regulatory agencies, after reviewing trial data, have concluded that the benefit–risk balance is strongly in favor of these drugs for their indicated populations. The FDA’s approval summary for semaglutide 2.4 mg stated: “the weight-loss benefit … outweighs the potential risks in the intended population. The treatment effect on weight loss is clinically meaningful and expected to improve health outcomes… The most common adverse reactions primarily impact tolerability. Other risks, including less common but serious safety issues, are adequately mitigated with labeling.”. This encapsulates the consensus that for individuals with obesity, the reduction in health risks due to weight loss (e.g. better cardiometabolic health) outweighs the mostly mild or rare medication side effects.

Quality of Life: Weight loss of the magnitude achieved by semaglutide or tirzepatide often results in marked improvement in quality of life (QoL). Patients report better physical function, mobility, and energy, along with psychological benefits from improved self-image and confidence. Clinical studies have documented significant gains in QoL metrics on treatment, as mentioned earlier – for example, improvements in SF-36 physical component scores and IWQOL-Lite total scores with semaglutide vs placebo . Importantly, these drugs do not cause the kind of neuropsychiatric side effects or cognitive impairment that some older weight-loss drugs did (e.g. no stimulant effects like phentermine or mood swings as with some past medications). The main detractor from QoL would be the GI side effects; a patient experiencing frequent nausea or vomiting may temporarily feel worse. However, for the majority who tolerate the medication after the initial period, daily life is enhanced by weight loss. People can move with less pain, fit in chairs or clothes more easily, and participate in activities that obesity may have hindered. Many also see improvement in obesity-related depression or anxiety as their health and body image improve (though rigorous data on mental health outcomes are still being gathered). One must also note that if medication is stopped and weight is regained, some QoL gains will be lost – highlighting the chronic nature of obesity treatment.

Longevity and Mortality: Does treating obesity with these drugs help people live longer? While weight loss in general is associated with reduced mortality in observational studies (particularly in those with obesity-related health issues), we now have direct evidence in support: the SELECT trial with semaglutide demonstrated a significant reduction in cardiovascular death and nonfatal MI/stroke . Though it was not powered to detect an all-cause mortality drop in the timeframe, a 20% decrease in major cardiac events should translate to improved survival over time. Bariatric surgery studies have shown surgery extends life (patients have lower long-term mortality compared to matched obese patients who don’t have surgery). We anticipate that if patients can maintain substantial weight loss with medication, they too may enjoy a longevity benefit. This will need confirmation through long-term follow-up of cohorts on medical therapy. It’s also important to ensure that any subtle long-term risks of the drugs themselves do not offset gains – so far, none have emerged, but continued vigilance (for cancer, etc.) is warranted as millions of people use these medications for many years.

Adherence and Persistence: One real-world challenge is long-term adherence. The need for weekly injections (or daily for some drugs) and dealing with side effects can affect how many patients stay on therapy. Real-world data from large healthcare systems in 2022–2023 show that around half of patients discontinued semaglutide or tirzepatide within one year. Discontinuation rates of ~50% by 1 year sound high, but many of these were due to insurance and cost issues (discussed below) or patients reaching a personal goal and stopping (often followed by regain). Among those who can afford and tolerate the medication, persistence is higher. Improving tolerability (through gentle titration and side effect management) can reduce dropouts due to side effects. From a risk–benefit perspective, non-adherence is a risk in itself – stopping the drug typically leads to weight regain and loss of health benefits, as demonstrated in STEP-4 . Thus, the long-term benefit is heavily tied to keeping patients on therapy, or at least on some form of weight maintenance strategy. This is why some experts compare obesity to hypertension – if the “blood pressure medication” (in this case, weight-loss drug) is stopped, the condition relapses. The onus is on healthcare systems to make continued treatment feasible.

Cost and Value Considerations: A crucial aspect of long-term use is cost. These medications are expensive (U.S. list prices often exceed $1,000 per month). For many patients without diabetes, insurance coverage for anti-obesity drugs is limited. As a result, cost is a significant factor leading to discontinuation in practice – patients may start on samples or short-term coverage, lose weight, but then have to stop when they can no longer afford it. This raises an equity issue, as obesity is prevalent in lower-income populations who may not have coverage. Independent health economics analyses have questioned the cost-effectiveness of these drugs at current prices. The Institute for Clinical and Economic Review (ICER) concluded in 2022 that semaglutide provides a net health benefit vs lifestyle alone (high efficacy), but at its list price it represents “low long-term value for money” . ICER estimated semaglutide would need to be priced around $7,500–$9,800 per year (after rebates) to meet typical cost-effectiveness thresholds ; actual U.S. pricing is roughly double that, making it not cost-effective by standard metrics. They voted unanimously that the clinical benefit is substantial, but the high price is a barrier . Tirzepatide’s pricing for obesity (branded Zepbound, approved late 2023) is expected to be similar; if so, the same value concerns apply. The cost issue can indirectly become a safety issue if patients ration their medication or stop abruptly due to loss of coverage, leading to weight cycling. Policymakers and payers are actively debating how to improve access (some have called for government negotiation or even patent overrides to bring prices down . In the long run, competition (e.g. new drugs or eventual generics) may reduce cost, improving the overall risk–benefit by making sustained treatment accessible.

Comparisons to Surgery – Risk/Benefit: When counseling patients, doctors often compare these medications to bariatric surgery in terms of expected benefits and risks. Bariatric surgery has higher upfront risk (about 0.1–0.3% perioperative mortality, risk of complications like leaks or clots), but after recovery, surgery doesn’t cause ongoing side effects for most (aside from nutritional deficiencies requiring supplements). GLP-1 agonists have virtually no acute mortality risk and can be stopped if not tolerated, but they cause chronic side effects in some patients and require adherence. Surgery usually results in permanent anatomical changes that sustain weight loss, whereas drug-induced weight loss is reversible (which is a double-edged sword – easier to relapse, but also easier to “stop” treatment if needed). In high-risk patients (e.g. extremely obese with multiple comorbidities), one might do both: use medication to lose weight prior to surgery (“bridge” therapy) to reduce surgical risk. Or vice versa, use medication after surgery if weight regain occurs. The encouraging aspect is that for many patients, these medications can significantly delay or avoid the need for surgery, achieving health improvements with fewer serious risks. As one commentary put it, GLP-1 RAs for obesity represent “the end of the beginning” in obesity therapeutics – a new era where effective medical therapy can complement the existing surgical tools.

Population-Level Considerations: On a population scale, obesity carries enormous health burden and costs (hundreds of billions annually in the U.S. alone) . Effective treatment could yield societal benefits like reduced healthcare expenditures for diabetes, heart disease, etc. But those benefits will only be realized if the treatments are broadly implemented and sustained. There is some concern that only treating obesity pharmacologically without addressing diet, exercise, and social determinants is a missed opportunity – ideally, these drugs are used as part of a comprehensive approach including lifestyle changes, behavior therapy, and environmental interventions. Long-term benefit is maximized when patients not only lose weight, but also adopt healthier habits; the medication can make that easier by reducing hunger, but it’s not a standalone cure for unhealthy lifestyle.

In summary, from a long-term perspective, the benefits of GLP-1 and dual agonist therapies (substantial, sustained weight loss and reduction in obesity-related complications) clearly outweigh the manageable risks for most patients with obesity . Quality of life tends to improve, and emerging data suggest reductions in morbidity and mortality. The principal challenges to reaping these long-term benefits are ensuring patient adherence and making therapy accessible and affordable for those who need it. With appropriate patient monitoring and management, the risk–benefit profile remains highly favorable.

4. Pharmaceutical Bias and Transparency

With the dramatic success and lucrative market of these drugs, it is important to scrutinize the evidence for any industry influence, trial design biases, or suppression of negative data. Semaglutide (Wegovy) is produced by Novo Nordisk, and tirzepatide (Mounjaro/Zepbound) by Eli Lilly – both are among the largest pharma companies, raising questions about trial independence and result reporting. Here we investigate whether the data on new anti-obesity meds are trustworthy and what oversight exists from regulators and independent watchdogs.

Industry Sponsorship and Trial Design: All the major trials (STEP for semaglutide, SURMOUNT for tirzepatide) were funded and run by the manufacturers. Company involvement in trial design, data analysis, and writing of publications has been disclosed. For example, the STEP program publications note that Novo Nordisk employees were investigators and that medical writing support was funded by Novo Nordisk . In the STEP-4 trial (semaglutide withdrawal study), Novo Nordisk representatives were involved in “design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript” . This level of sponsor involvement is not unusual in industry-funded trials, but it does mean the findings should be interpreted with that potential conflict in mind. However, it’s worth noting that investigators and academic centers also participated, and sponsors did not have unilateral control to block publication of unfavorable results according to the disclosures .

One might ask: Were the trials “stacked” to show the drugs in the best light? In general, the RCTs were well-designed, placebo-controlled studies in appropriate populations. The placebo groups received lifestyle counseling, which some critics say is a low bar (since we know lifestyle alone yields minimal weight loss), but that is the standard to isolate the drug’s effect. A subtle design choice was evident in trials like STEP-4: a run-in period was used, where all patients first took semaglutide for 20 weeks, and only those who tolerated it and reached target dose were randomized. This effectively excluded those with early intolerance, thereby enriching the trial with tolerators and maximizing the apparent efficacy among those who stayed on drug. While this design was meant to answer a specific question about maintenance, it does highlight how industry trials may employ strategies to demonstrate efficacy under ideal conditions (adherent patients) which might exceed effectiveness in a real-world mix of patients. Nevertheless, such designs are openly reported and recognized. The FDA, in its review, actually commended the overall trial quality and noted “low proportions of missing data” in the phase 3 trials , indicating the results were robust and not overly affected by dropout – an assurance that the efficacy signals are credible.

Selective Outcome Reporting: We looked for any evidence that companies have withheld negative findings. Thus far, no major safety findings have been kept secret – issues like retinopathy, gallbladder events, and heart rate increases were reported in publications or discussed in regulatory reviews ). In fact, Novo Nordisk’s trials revealed the retinopathy signal in diabetes, which they duly reported. Both Novo and Lilly have large post-marketing surveillance programs and are required to report adverse events to regulators. It appears that any known risks (pancreatitis, thyroid tumors in animals, etc.) have been transparently disclosed either in journal articles or drug labels. Independent meta-analyses (e.g. on gallbladder risk or GI side effects) have largely confirmed what was reported in individual trials. It is unlikely, for instance, that either company would fail to report a serious adverse event like cancer occurring in trials, given regulatory scrutiny.

One area of potential bias is that no head-to-head trials between semaglutide and tirzepatide were initially done by the companies – each sponsored placebo-controlled trials for their own drug. This leaves a gap filled by independent comparative analyses. A 2024 analysis of EHR data (noted above) found tirzepatide had greater weight loss than semaglutide in practice , aligning with expectations from separate trials. There’s no indication that Novo Nordisk or Lilly suppressed any direct comparison; rather, it’s typical that companies don’t fund trials pitting their drug against a competitor’s. We now rely on academic or payer-funded studies for those comparisons. Fortunately, the consensus of such studies supports the conclusion that both drugs are highly effective, with tirzepatide perhaps ~5% more effective in weight loss terms .

Regulatory Oversight: The FDA and European Medicines Agency (EMA) conducted thorough reviews of these medications’ data before approval. FDA advisory committees publicly vetted semaglutide 2.4 mg’s efficacy and safety. The FDA review documents (which are public) clearly discuss limitations and require post-marketing studies for certain questions (e.g. a cardiovascular outcomes trial, which became SELECT). The FDA did express concern that short-term use is not meaningful (hence labeling indicates chronic use), and it acknowledged that only patients who reached the full dose were evaluated for efficacy (implicitly suggesting that real-world results might include those who can’t tolerate full dose) . These candid assessments indicate regulators were not blindly accepting sponsor interpretations – they critically evaluated the data and included safeguards (like contraindications for MTC, warnings for pancreatitis, etc.). The EMA similarly required a warning about the potential risk of suicidal ideation until it could complete a review (which in 2023 concluded no proven link) . The transparency of regulatory processes has helped validate that no major safety issue was hidden. For example, EMA’s public report on Wegovy notes the small imbalance in gallstones and recommends routine monitoring, showing they picked up even on infrequent events.

Pharmaceutical Marketing and Spin: One potential bias is in how the results are framed to the public and physicians. Novo Nordisk and Lilly have invested heavily in marketing these drugs, which could sometimes lead to oversimplified messaging (e.g. calling them “game changers” without nuance). Independent experts caution that while the drugs are excellent tools, they are not a panacea and require long-term commitment. There is also concern about off-label promotion – for instance, the massive popularity of semaglutide for cosmetic weight loss or minor obesity could be partly driven by hype. Regulators like FDA have strict rules against off-label marketing, but social media and word-of-mouth have fueled demand in ways beyond the companies’ direct control. Still, both Novo and Lilly clearly benefit from the “viral” popularity of Ozempic/Wegovy on social media, which some critics argue the companies have passively encouraged.

Another area to watch is publication of negative studies – so far, most trials have been positive (the drugs work very well). If a trial were to find a serious harm or lesser efficacy in a subgroup, transparency demands it be published. There is currently no known trial of these agents with negative results that remains unpublished, but ongoing outcome studies (e.g. tirzepatide’s cardiovascular trial) will be important to publish regardless of outcome. The companies’ track record with GLP-1 drugs in diabetes suggests they do publish major trial results (for example, Lilly published unfavorable results of an Alzheimer’s trial of a different drug, showing a willingness to report failures).

Independent Watchdogs and Critiques: Organizations like Public Citizen have weighed in, especially on pricing and access. Public Citizen has not accused the companies of data suppression, but rather of profiteering. In a 2023 statement, they highlighted Novo Nordisk’s massive revenue (~$50 billion) from semaglutide drugs and how that far outstrips their R&D investment, arguing that the public is paying exorbitant prices . They called on the U.S. government to intervene to allow generic competition due to “outrageous prices” . This is a critique of business practices, not the scientific data per se. However, it does indirectly point to a potential bias in how trials are conducted – cost-effectiveness is not a focus of industry trials. Trials showed the drug works, but didn’t answer “is it worth the price?”, a question taken up by independent groups like ICER (which concluded current pricing is not aligned with value) . Public Citizen’s stance is that the government should “unlock generic competition” because Novo’s pricing forces payers to ration treatment and even state health plans have said they cannot afford broad coverage .

Another concern is over-reliance on industry data for long-term effects. Since these drugs are new for obesity, we only have at most 2-year trial data (except semaglutide’s SELECT at ~3.3 years). Independent academia is calling for long-term (>5 year) studies and registry data to see what happens with prolonged use or after stopping. No evidence of suppression of such data exists – it’s simply not available yet. Regulatory agencies did require follow-up: for instance, FDA asked Novo to conduct an outcomes trial (which became SELECT) to definitively show CV safety/benefit, precisely to ensure transparency on long-term outcomes. Now that SELECT is positive, Novo will surely use it in marketing; had it been negative, FDA would have likely made that known and possibly restricted use.

Bias in interpretation: One might also consider that most publications on these drugs involve authors with ties to the companies (many obesity experts have consulted for Novo or Lilly, as disclosed in papers. This could subtly bias the optimistic tone of some articles. To counter that, independent editorials (in NEJM, Lancet, etc.) and guidelines try to provide balanced views. For example, an editorial in The Lancet in 2022 noted that GLP-1 RAs “effectively reduce weight… particularly in the initial years of treatment” but emphasized the need for “robust long-term data on safety and maintenance” . Such independent voices ensure that excitement is tempered with caution. The medical community remains aware that these drugs are not magic – if a patient stops them, weight returns; if a patient doesn’t tolerate them, other options are needed; and lifestyle improvements remain essential.

In summary, we find no credible evidence of trial result suppression or overt manipulation by the pharmaceutical companies, beyond the inherent biases of industry-sponsored research (which are mitigated by regulatory oversight and independent analysis). The efficacy outcomes have been so strong that results speak for themselves, and safety issues identified in trials have been openly acknowledged. Regulatory agencies (FDA, EMA) have imposed transparency through required trials and detailed labeling. Independent watchdogs have focused criticism on pricing and access rather than on data integrity. Still, it remains crucial to continue independent post-marketing studies and surveillance. As millions more patients use these medications, any unexpected adverse effect trends should be promptly published – the current surveillance (like FDA’s FAERS analysis of tirzepatide showing some signals like “injection site pain” and even an unexpected one like “starvation ketoacidosis” in rare cases indicates that the safety net is working and such signals are investigated transparently.

Pharmaceutical Transparency Initiatives: Both Novo Nordisk and Eli Lilly have registered all their obesity trials in public databases (ClinicalTrials.gov) and many trial results are posted there. The companies also have data-sharing policies for researchers, indicating a degree of openness. Of course, one must remain vigilant. The incredible commercial success (Novo’s combined sales of Ozempic/Wegovy nearing $50 billion since launch) provides a motive to expand indications and usage – for instance, there is heavy promotion for using GLP-1 RAs in broader overweight populations and even in adolescents (semaglutide is now approved for teens with obesity, based on recent trials). Each new population should be evaluated independently. Thus far, adolescent trials showed similar efficacy and no new safety issues, which is reassuring, and those were also published in NEJM.

In conclusion, while pharmaceutical companies clearly shape the research agenda and have reaped enormous profits, the scientific evidence for GLP-1 and dual agonist drugs has undergone rigorous scrutiny by independent experts and regulators, making it reliable. Ongoing monitoring by agencies and independent groups will help catch any attempts at downplaying negatives, but at this point the weight of evidence is that these drugs perform as reported. The main controversies lie not in hidden dangers, but in how to ensure those benefits reach patients in an equitable and cost-effective way without excessive influence from the profit motive.

References:

This report is based on evidence from peer-reviewed journals, regulatory documents, and meta-analyses. Below is a selection of cited sources for further reading:

Wilding JPH et al. NEJM. 2021 – STEP 1 trial of semaglutide in obesity (Once-Weekly Semaglutide in Adults with Overweight or Obesity - PubMed) (Once-Weekly Semaglutide in Adults with Overweight or Obesity - PubMed).
Jastreboff AM et al. NEJM. 2022 – SURMOUNT-1 trial of tirzepatide in obesity (Tirzepatide Once Weekly for the Treatment of Obesity - PubMed) (Tirzepatide Once Weekly for the Treatment of Obesity - PubMed).
Garvey WT et al. Nat. Med. 2022 – STEP 5 trial 2-year results (semaglutide) ( Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial - PMC ) ( Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial - PMC ).
ADA 2023 – SELECT trial results (semaglutide CV outcomes) (Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes - PubMed) (Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes - PubMed).
FDA CDER Summary Review, Wegovy (semaglutide 2.4 mg), 2021 (Review) (Review).
ICER Final Evidence Report on Obesity Management, 2022 (ICER Publishes Final Evidence Report and Policy Recommendations on Treatments for Obesity Management - ICER) (ICER Publishes Final Evidence Report and Policy Recommendations on Treatments for Obesity Management - ICER).
Public Citizen statement on Novo Nordisk, 2023 (Novo Nordisk’s $50 billion in Ozempic & Wegovy Sales Comes at the Expense of Healthcare Solvency - Public Citizen) (Novo Nordisk’s $50 billion in Ozempic & Wegovy Sales Comes at the Expense of Healthcare Solvency - Public Citizen).

Apendix. AI thought process.

Systematic Review of New Obesity Drugs and Their Risk-Benefit ProfilesChatGPT

Analyzing anti-obesity treatments

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