# Long-Term Diabetes Remission Following Roux-en-Y Gastric Bypass Versus Intensive Medical Therapy in Adults with Type 2 Diabetes and BMI 35–40 kg/m²: A Comprehensive Literature Synthesis

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### Background and Context

Type 2 diabetes mellitus (T2DM) and obesity represent two of the most consequential and intertwined public health crises of the twenty-first century. The International Diabetes Federation estimated a global prevalence of 10.5% (536.6 million people aged 20–79) in 2021, with projections rising to 12.2% (783.2 million) by 2045 (PMC9945737). The burden is not merely epidemiological: T2DM accounts for more than 8.7% of total healthcare expenditure in some national systems, and its complications — cardiovascular disease, nephropathy, neuropathy, and retinopathy — impose enormous morbidity and mortality (PMC9598002). Critically, the relationship between obesity and T2DM is bidirectional and mechanistically intimate: obesity accounts for 80–85% of the risk of developing type 2 diabetes (PMC10222088). The term "diabesity" has been coined to capture this near-inseparable clinical entity (PMC10856683).

The question of whether surgical intervention can achieve durable, long-term remission of T2DM — defined as HbA1c <6.5% off all glucose-lowering medications for a sustained period — has moved from a provocative hypothesis to a central question in metabolic medicine. The 2021 American Diabetes Association consensus statement updated the definition of remission to HbA1c <6.5% measured at least 3 months after cessation of glucose-lowering pharmacotherapy (PMC9945737, PMC10107406). This definition, while promoting standardization, has been critiqued as overly glucocentric, failing to account for cardiovascular risk reduction and the pleiotropic benefits of newer antidiabetic agents (PMC10107406). Nevertheless, it provides the operational framework within which the comparative literature on surgical versus medical management must be interpreted.

The specific BMI range of 35–40 kg/m² occupies a clinically important but undercharacterized niche. Traditional NIH eligibility criteria for bariatric surgery, formulated over three decades ago, set the threshold at BMI ≥40 kg/m² (or ≥35 kg/m² with obesity-related comorbidities), and these criteria have not been formally updated despite dramatic reductions in surgical mortality and morbidity (PMC9945737). Patients with BMI 35–40 kg/m² and T2DM thus sit at the intersection of established surgical eligibility and a population for whom the comparative long-term evidence — particularly at the ≥5-year horizon with the stringent remission criterion of HbA1c <6.5% off all medications — remains incompletely characterized. The landmark STAMPEDE trial, the ARMMS-T2D consortium, and the SLEEVEPASS trial are repeatedly cited in the literature as foundational evidence for surgical superiority, but the specific 5-year remission rates using the HbA1c <6.5% off-medication criterion in the BMI 35–40 subgroup require careful extraction from these broader datasets (PMC12616207). This review synthesizes the available evidence to address this question with the quantitative precision required for clinical and policy decision-making.

Historically, T2DM was conceptualized as a chronic, progressive, and irreversible disease requiring lifelong pharmacological escalation. The observation that glycemic control improved dramatically — often within days of surgery, before significant weight loss had occurred — fundamentally challenged this paradigm (PMC10107406). Early reports from Pories and colleagues in the 1990s documented near-universal resolution of T2DM following gastric bypass, and subsequent decades of evidence have refined our understanding of who benefits most, for how long, and through what mechanisms. The emergence of highly effective pharmacological agents — GLP-1 receptor agonists, SGLT-2 inhibitors, and most recently the dual GIP/GLP-1 agonist tirzepatide — has complicated the comparative landscape. Tirzepatide, for example, resulted in a remission rate of 66% to 81% depending on drug dose over 52 weeks in selected populations (PMC10107406). Against this backdrop, the question of long-term (≥5-year) surgical remission versus intensive medical therapy in the BMI 35–40 range is not merely academic but has direct implications for treatment guidelines, resource allocation, and patient counseling.

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### Molecular and Mechanistic Pathways

#### Weight-Loss-Dependent Mechanisms of Glycemic Improvement

The most intuitive mechanism linking bariatric surgery to T2DM remission is caloric restriction and the consequent reduction in body weight, particularly visceral and ectopic fat. Excessive fat accumulation in the liver and pancreas is mechanistically central to T2DM pathophysiology: hepatic steatosis drives insulin resistance and excess endogenous glucose production, while pancreatic lipid deposition (lipopancreas) impairs beta-cell function and insulin secretion (PMC9945737). Bariatric surgery achieves hypoglycemic effects partly through dramatic weight loss, and the magnitude of weight loss correlates with the likelihood of remission across multiple studies (PMC8127970, PMC9598002). In the large Swedish nationwide cohort of 8,057 RYGB patients, postoperative percentage total weight loss (%TWL) was independently associated with remission at 2 years (adjusted OR 1.04 per 1% TWL, p<0.001), confirming a continuous, linear relationship between weight loss and remission probability (PMC8127970).

Reductions in visceral adiposity following bariatric surgery decrease secretion of pro-inflammatory cytokines (including TNF-α and IL-6) from adipose tissue, improving insulin signaling in skeletal muscle, liver, and adipose tissue; simultaneously, reductions in circulating free fatty acids decrease lipotoxicity, restoring hepatic glucose suppression and peripheral glucose uptake (PMC11857516). Weight loss also improves adipokine profiles, increasing adiponectin (which enhances insulin sensitivity) while reducing leptin resistance. These weight-dependent mechanisms are shared across all bariatric procedures and are not unique to RYGB, which is why sleeve gastrectomy (SG) and one-anastomosis gastric bypass (OAGB) also achieve meaningful remission rates, albeit with different magnitudes and trajectories.

Critically, however, weight loss alone does not fully explain the metabolic benefits of bypass procedures. RYGB achieves higher T2DM remission rates than gastric banding even when controlling for equivalent weight loss, and glycemic improvement begins within days of surgery before meaningful weight loss has occurred, indicating weight-loss-independent mechanisms (PMC10107406). This observation has driven intensive investigation into weight-loss-independent mechanisms, which are particularly relevant to understanding why RYGB may outperform purely restrictive procedures in the BMI 35–40 range.

#### Weight-Loss-Independent Mechanisms: Incretin Enhancement and Gut Hormone Remodeling

The most extensively studied weight-loss-independent mechanism involves dramatic alterations in gut hormone secretion following bypass procedures. Both RYGB and SG raise GLP-1 and PYY levels, promoting satiety, delaying gastric emptying, increasing insulin secretion, and decreasing glucagon production, improving glycemic control even without significant weight loss (PMC11857516). These incretin effects are particularly pronounced after RYGB, which reroutes nutrient flow to deliver incompletely digested nutrients more rapidly to the distal small intestine, stimulating L-cell secretion in the ileum and colon. Individuals with type 2 diabetes often exhibit a diminished incretin effect, meaning their insulin response to oral glucose is impaired compared to non-diabetic individuals, and restoration of this effect through surgical anatomy may be particularly important for glycemic normalization (PMC10856683).

Simultaneously, RYGB reduces circulating ghrelin — the "hunger hormone" produced predominantly in the gastric fundus — though the magnitude of this reduction and its contribution to metabolic improvement relative to GLP-1 enhancement remains debated. Both RYGB and laparoscopic sleeve gastrectomy led to notable reductions in serum ghrelin concentrations one year post-surgery (approximately 0.068 pg/mL for RYGB versus 0.083 pg/mL for LSG), with no statistically significant difference between procedures, suggesting that ghrelin suppression alone does not account for RYGB's metabolic superiority (PMC11416717).

The concept of an "anti-incretin" — a duodenal signal that normally suppresses insulin secretion and whose exclusion following bypass contributes to improved glycemia — has been proposed but remains incompletely characterized. The proximal intestinal nutrient exclusion hypothesis posits that bypassing the duodenum and proximal jejunum removes a signal that promotes insulin resistance, thereby improving glycemic control independently of weight loss (PMC7589837). A duodenal-jejunal bypass liner (DJBL) device, which excludes the proximal intestine without surgery, yielded an additional 1% decrease in HbA1c over controls in a meta-analysis including 105 patients, supporting the proximal intestinal nutrient exclusion hypothesis (PMC11857516). The relative contribution of proximal exclusion versus distal nutrient delivery to the overall metabolic benefit of RYGB remains an active area of investigation.

#### Bile Acid Signaling, Gut Microbiome, and Beta-Cell Reserve

Bile acids have emerged as important metabolic signaling molecules whose circulating levels and composition are substantially altered by bypass surgery. Following RYGB, increased bile acid concentrations in the systemic circulation activate key metabolic receptors, reducing hepatic glucose production and improving insulin sensitivity; RYGB's superiority over SG in dyslipidemia remission was demonstrated in a Thai cohort where 5-year dyslipidemia remission was significantly higher after RYGB than SG (40.9% vs. 18.4%, p=0.048), attributed in part to bile acid-mediated reductions in LDL reabsorption (PMC12942549, PMC11857516).

Changes in gut microbiome composition represent a third weight-loss-independent pathway. Obesity and T2DM are associated with reduced microbial diversity, and bariatric surgery — particularly bypass procedures — is associated with shifts in gut microbial composition that may reduce systemic inflammation and enhance insulin sensitivity (PMC11857516). The gut-brain axis further modulates appetite, hormone regulation, and insulin sensitivity through microbiome-dependent pathways. While these mechanisms are biologically plausible and supported by animal and human observational data, their specific quantitative contribution to T2DM remission in the BMI 35–40 range has not been isolated in controlled human trials.

Perhaps the most clinically important mechanistic consideration is the role of residual pancreatic beta-cell reserve. The probability of achieving and sustaining T2DM remission after any intervention — surgical or medical — is fundamentally constrained by the degree of irreversible beta-cell dysfunction at the time of intervention. Longer diabetes duration is consistently associated with greater beta-cell exhaustion, reduced C-peptide levels, and lower remission rates (PMC9598002, PMC8127970, PMC12942549). Predictive modeling data indicate that patients with a low preoperative Disposition Index had 0% remission at 4 months versus 57% in the high-DI group, rising to 38% vs. 71% at 18 months (PMC11857516). This mechanistic reality explains why diabetes duration is the single most consistent predictor of remission across all studies and all intervention types, and why the BMI 35–40 population — which may include patients with longer-standing, more advanced disease — may have lower remission rates than cohorts with higher BMI and shorter disease duration.

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### Dose-Response and Pharmacokinetics

This section addresses the "dose-response" relationships relevant to the surgical and medical interventions under comparison — specifically, the relationship between the magnitude of weight loss, the degree of metabolic intervention (procedure type), and the probability and durability of T2DM remission.

#### Weight Loss Magnitude and Remission Probability

A consistent finding across the literature is a positive, approximately linear relationship between the magnitude of postoperative weight loss and the probability of T2DM remission. In the Swedish nationwide RYGB cohort (n=8,057), the Spearman correlation between postoperative %TWL and cessation of antidiabetic medication was 0.19 (p<0.001), and the adjusted OR for remission per 1% increase in %TWL was 1.04 (95% CI 1.03–1.04, p<0.001) (PMC8127970). This relationship was linear without an apparent threshold, suggesting that even modest additional weight loss confers incremental remission benefit. In the Swedish nationwide RYGB cohort, postoperative percentage total weight loss (%TWL) was independently associated with T2DM remission at 2 years (adjusted OR 1.04 per 1% TWL, 95% CI 1.03–1.04, p<0.001), with a mean %TWL of 28.4% ± 8.9% and mean BMI loss of 12.0 ± 4.5 kg/m² (PMC8127970).

In the DiRECT trial — a lifestyle intervention study rather than a surgical one — the dose-response relationship between weight loss and remission was even more striking: 86% of patients achieving ≥15 kg weight loss achieved remission at 24 months, compared to 36% overall (PMC10107406). This finding underscores that the metabolic benefits of weight loss are not unique to surgery but that surgery is uniquely effective at achieving and sustaining the magnitude of weight loss required for durable remission. For patients in the BMI 35–40 range, the absolute weight loss achievable through RYGB (typically 25–35% TWL) is generally sufficient to cross the threshold associated with high remission rates, whereas intensive medical therapy rarely achieves or sustains comparable weight loss.

#### Procedure Type as a "Dose" of Metabolic Intervention

The choice of bariatric procedure can be conceptualized as a "dose" of metabolic intervention, with more malabsorptive procedures generally producing greater and more durable glycemic effects. In a randomized controlled trial of 60 patients with T2DM assigned to medical therapy, RYGB, or duodenal switch (DS), diabetes remission (fasting glucose <100 mg/dL and HbA1c <6.5% without pharmacotherapy) was achieved in 0% of the medical group, 75% of the RYGB group, and 95% of the DS group at 2 years (p<0.05) (PMC11857516). This dose-response relationship across procedure types — with DS > RYGB > SG > gastric banding — is consistently observed across the literature, though DS is rarely performed in the BMI 35–40 range due to its complexity and nutritional risks.

For the specific comparison of RYGB versus intensive medical therapy, the systematic review by PMC11682853 summarizes evidence from Panunzi et al. (2016) showing that 64% of the surgical group versus 15% of the medical group achieved diabetes remission (p<0.001), with gastric-only procedures yielding 60% remission and gastric-plus-diversion procedures yielding 76% remission (PMC11682853). The meta-analysis by Zhou and Zeng (2023), which specifically examined patients with BMI <35 kg/m² (a population adjacent to but below the BMI 35–40 range of interest), found that 64.0% (32/50) of surgical patients achieved remission versus 2.8% (7/250) of nonsurgical patients, yielding an OR of 25.06 (95% CI 9.58–65.54, p<0.00001) (PMC9945737). While this population is not identical to the BMI 35–40 group, it demonstrates that the surgical advantage in remission is robust even at lower BMI levels.

#### Intensive Medical Therapy: Achievable Remission Rates

The comparator arm — intensive medical therapy — encompasses a heterogeneous range of interventions in the literature, from structured lifestyle modification programs to combination pharmacotherapy with newer agents. The Look AHEAD study (n=5,145) demonstrated remission prevalence of 11.5% (95% CI 10.1–12.8%) at year 1 and 7.3% (95% CI 6.2–8.4%) at year 4 in the intensive lifestyle arm versus 2.0% in the conventional treatment group (PMC10107406). These rates are substantially lower than those achieved with RYGB and decline over time, reflecting the difficulty of sustaining the weight loss required for durable remission through behavioral means alone. The STAMPEDE trial — the most directly relevant RCT for the question at hand — is referenced multiple times in the literature as demonstrating durable benefits of RYGB over intensive medical management at 5 years, with RYGB often outperforming SG (PMC12616207), though the specific 5-year HbA1c <6.5% off-medication remission rates in the BMI 35–40 subgroup are not directly reported in the papers available for this review.

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### Clinical Evidence and Implications

#### The STAMPEDE Trial and ARMMS-T2D Consortium: Foundational RCT Evidence

The STAMPEDE (Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently) trial is the most frequently cited RCT in the literature addressing the comparison of bariatric surgery versus intensive medical therapy for T2DM. Multiple papers in this review reference STAMPEDE as confirming durable benefits of surgery over intensive medical management, with RYGB often outperforming SG (PMC12616207). The ARMMS-T2D consortium — a pooled analysis of four US randomized trials including STAMPEDE — is cited as reinforcing the long-term metabolic benefits of surgery at 5 years (PMC12616207). While the full text of these trials is not among the papers provided for this review, their findings are consistently characterized in the available literature as demonstrating that RYGB produces superior and more sustained T2DM remission compared to intensive medical therapy, with durable effects at 5 years. The Courcoulas et al. study (included in PMC11682853) reported that HbA1c decreased by 1.6% in the surgery group versus 0.2% in the medical/lifestyle control group at 7 years, with higher diabetes remission rates in the surgical arm, in a randomized trial of 262 participants with mean age 49.9 years and mean BMI 36.4 kg/m² (PMC11682853). This cohort, with a mean BMI of 36.4 kg/m², is directly within the BMI 35–40 range of interest and represents the most directly applicable RCT evidence available in this review.

The Courcoulas et al. finding is particularly important because it demonstrates that the surgical advantage in glycemic control is maintained at 7 years — well beyond the 5-year threshold specified in the user's question — and in a population whose mean BMI falls squarely within the 35–40 range. The 1.4% absolute difference in HbA1c reduction (1.6% vs. 0.2%) between surgical and medical arms at 7 years, while not directly translating to a remission rate using the HbA1c <6.5% off-medication criterion, strongly suggests that a substantially higher proportion of surgical patients would meet this criterion. The study included RYGB, SG, and adjustable gastric banding as surgical options, so RYGB-specific remission rates within this cohort are not separately reported in the available summary.

#### The SLEEVEPASS Trial: 10-Year Comparative Data

The SLEEVEPASS trial, comparing SG and RYGB with 10-year follow-up, is referenced in multiple papers as providing long-term comparative data (PMC12616207, PMC7589837). The available literature characterizes SLEEVEPASS as demonstrating durable long-term remission for both SG and RYGB at 10 years, with RYGB consistently showing a modest advantage. The SLEEVEPASS trial is referenced as reporting a 26% T2DM remission rate at long-term follow-up, substantially lower than the 70.8% reported in the BARI-10-POL Polish multicenter cohort (PMC13123259).

#### Large Cohort Studies: The Swedish Nationwide RYGB Registry

The most methodologically robust large-scale evidence on RYGB-specific remission rates comes from the Swedish nationwide cohort study linking the Scandinavian Obesity Surgery Registry (SOReg) to four national registers, encompassing 8,057 patients with T2DM who underwent primary RYGB between 2007 and 2015 (PMC8127970). In the Swedish nationwide RYGB cohort (n=8,057), at 2-year follow-up 77.1% of patients were off all antidiabetic medication; complete remission (HbA1c ≤42 mmol/mol [≤6.0%] off medication) was achieved in 62.2%, and partial remission (HbA1c ≤48 mmol/mol [≤6.5%] off medication) in an additional 10.6%, for a combined remission rate of 72.8% (PMC8127970). These rates are at 2 years, not 5 years, and the study was restricted to RYGB, precluding direct comparison with medical therapy. Nevertheless, the scale of this cohort (n=8,057) and the quality of the linked registry data make it the most reliable estimate of RYGB-specific remission rates available in the literature.

Critically, the Swedish study demonstrated that the relationship between key predictors and remission was linear and continuous rather than threshold-based. In the Swedish nationwide RYGB cohort, older age (adjusted OR 0.97 per year, p<0.001), longer diabetes duration (adjusted OR 0.89 per year, p<0.001), higher baseline HbA1c (adjusted OR 0.99 per mmol/mol, p<0.001), and insulin use at baseline (adjusted OR 0.26, 95% CI 0.22–0.30, p<0.001) were all independently associated with lower remission rates; approximately 75% of patients on insulin at baseline discontinued insulin by 2 years. BMI was not significant in multivariable analysis after controlling for weight loss (PMC8127970). Approximately 75% of patients on insulin at baseline discontinued insulin use by 2 years, even among those who did not achieve full remission — a clinically meaningful outcome even short of the strict remission criterion.

#### The Iranian Longitudinal Assessment of Bariatric Surgery (LABS): 1- and 3-Year Data

The Iranian LABS study (PMC9598002) provides the largest single-cohort comparison of RYGB, SG, and OAGB for T2DM remission, encompassing 1,351 patients with T2DM and BMI ≥30 kg/m² (mean BMI 44.1 ± 6.9 kg/m²). Complete T2DM remission (HbA1c <6% and FBG <100 mg/dL off all antidiabetic medications, using ASMBS criteria) was achieved in 74.8% at 1 year and 79.4% at 3 years. Remission rates did not differ significantly across surgery types at either time point: RYGB 75.6% vs. OAGB 75.4% vs. SG 70.6% at 1 year (p=0.590); RYGB 79.4% vs. OAGB 80.4% vs. SG 75.8% at 3 years (p=0.695) (PMC9598002). In multivariable logistic regression, surgery type was not an independent predictor of remission after adjustment for patient characteristics. In the Iranian LABS study, the strongest independent predictors of remission were younger age (adjusted OR 0.97 per year, p<0.001), shorter diabetes duration (adjusted OR 0.92 per year, p<0.001), no preoperative insulin use (adjusted OR 0.28, p<0.001), lower preoperative HbA1c (adjusted OR 0.78 per 1%, p<0.001), and absence of family history of obesity (adjusted OR 0.33, p<0.001); surgery type was not an independent predictor after adjustment (PMC9598002).

In the Iranian LABS study, the recurrence rate was 0.22% at 1 year and 1.99% at 3 years, substantially lower than the 17–40% relapse rates reported in some longer-term studies. Mean HbA1c fell from 7.8 ± 1.8% preoperatively to 5.7 ± 1.1% at 1 year and 5.8 ± 1.2% at 3 years; mean BMI fell from 44.1 ± 6.9 to 30.2 ± 5.3 kg/m² at 1 year (PMC9598002).

#### The BARI-10-POL Study: 10-Year Remission Data

The BARI-10-POL multicenter retrospective study (n=113 patients with T2DM; SG 57.5%, RYGB 18.6%, OAGB 23.9%; median preoperative BMI 41.5 kg/m²) found 70.8% T2DM remission (HbA1c <6.5% or fasting glucose <125 mg/dL off antidiabetic medications) at a median follow-up of 10.9 years, with an additional 16.8% experiencing improvement and 12.4% having no change. Median time to remission was 1 month (PMC13123259).

In the BARI-10-POL study, T2DM duration exceeding 10 years was the only statistically significant independent predictor of non-remission (OR 0.043, 95% CI 0.01–0.26, p=0.001), representing a 23-fold reduction in remission odds. OAGB showed a non-significant trend toward higher remission rates (OR 6.424, 95% CI 0.93–44.21, p=0.06). The follow-up rate was only 28.5% of the original 1,703-patient database (PMC13123259). The 70.8% remission rate at 10+ years is remarkably high and suggests that remission achieved after bariatric surgery is substantially more durable than remission achieved through lifestyle or pharmacological means. However, the low follow-up rate introduces substantial selection bias, and the small RYGB subgroup (n=21) precludes procedure-specific conclusions.

#### The Spanish Retrospective Cohort: 5-Year Comparative Data for RYGB, SG, and OAGB in T2DM Patients

The Castro et al. study (cited in PMC10222088 and PMC7589837) provides 5-year comparative data across all three major procedures in a T2DM-specific population. Among 358 T2DM patients (mean BMI 44 ± 9.1 kg/m²; 23.2% on insulin), remission of T2DM (fasting glucose <100 mg/dL and HbA1c <6% off medication) was highest in the OAGB group at all time points: 1 year (OAGB 91.9% vs. RYGB 83.6% vs. SG 81.9%, p=0.038), 2 years (OAGB 91.9% vs. RYGB 83.6% vs. SG 79.5%, p=0.018), and 5 years (OAGB 89.4% vs. RYGB 80.3% vs. SG 75.9%, p=0.029) (PMC10222088). The 5-year RYGB remission rate of 80.3% using the HbA1c <6% criterion (which is more stringent than the HbA1c <6.5% criterion specified in the user's question) is particularly noteworthy, as it suggests that the rate using the less stringent HbA1c <6.5% criterion would be even higher. It should be noted, however, that the actual 5-year complete remission rates in the Castro et al. cohort using the strict HbA1c <6% and FBG <100 mg/dL criterion were 16.7% after SG, 30.8% after RYGB, and 66.7% after OAGB (p=0.0005) among insulin-treated patients (PMC7589837), illustrating that the overall and insulin-user subgroup rates differ substantially and that the figures cited from PMC10222088 reflect the broader cohort including non-insulin users.

Among insulin-treated patients specifically, complete T2DM remission at 5 years was 16.7% after SG, 30.8% after RYGB, and 66.7% after OAGB (p=0.0005) (PMC7589837). This dramatic difference in remission rates among insulin users across procedures highlights the importance of procedure selection for patients with more advanced disease. Patients not requiring insulin preoperatively had substantially higher remission rates across all procedures, and the difference between RYGB and OAGB was not statistically significant in the non-insulin subgroup, suggesting that OAGB's advantage may be most pronounced in patients with more severe disease.

#### The UAE Single-Center Cohort: 3-Year Data in BMI ≥35 Population

The Cleveland Clinic Abu Dhabi retrospective cohort (PMC12616207) is the most directly relevant study to the user's question, as it specifically enrolled adults with BMI ≥35 and T2DM who underwent SG (n=84) or RYGB (n=78) with at least 3 years of follow-up. At the three-year follow-up, 33 (39.3%) of SG patients achieved complete diabetes remission compared with 41 (52.6%) of RYGB patients. Although the absolute remission difference of 13.3% favored RYGB, this was not statistically significant (p=0.12) (PMC12616207). The non-significant p-value likely reflects the study's limited statistical power (n=162 total), as the authors acknowledge. Among baseline insulin users, remission was achieved in 9/30 (30.0%) after SG versus 11/29 (37.9%) after RYGB (p=0.71). Importantly, by three years, half of the insulin users in both groups were able to discontinue insulin and continue on oral therapy alone (SG: 15/30, 50.0%; RYGB: 14/29, 48.3%), representing a clinically meaningful reduction in treatment burden even among non-remitters (PMC12616207).

The 3-year remission rates in this BMI ≥35 cohort (39.3% for SG, 52.6% for RYGB) are lower than those reported in many other studies, which may reflect the Middle Eastern patient population, the absence of baseline HbA1c and diabetes duration data (limiting characterization of disease severity), and the relatively short follow-up. The authors note that these rates are consistent with the STAMPEDE trial findings and align with global data suggesting RYGB may provide superior metabolic benefits compared with SG (PMC12616207).

#### The Thai Propensity-Score-Matched Cohort: Long-Term Metabolic Remission

The Thai retrospective cohort (PMC12942549) enrolled 581 patients (median BMI 45.54 kg/m²; 32.9% with T2DM) who underwent SG (78.1%) or RYGB (21.9%) between 2012 and 2022. T2DM remission was achieved in 79.1% of patients overall, with T2DM duration <3 years being the strongest independent predictor (HR 2.40, 95% CI 1.41–4.07, p=0.001). After propensity score matching (n=254), no statistically significant difference in T2DM remission was observed between SG and RYGB at 3 years (64.1% vs. 61.7%, p=0.491) (PMC12942549). The 5-year follow-up rate was only 46.6%, limiting the precision of longer-term estimates. Notably, RYGB's superiority over SG in dyslipidemia remission was demonstrated in a Thai cohort where 5-year dyslipidemia remission was significantly higher after RYGB than SG (40.9% vs. 18.4%, p=0.048), attributed in part to bile acid-mediated reductions in LDL reabsorption (PMC12942549).

#### The Moradi et al. Cohort: Largest Three-Procedure Comparison

The Moradi et al. retrospective study (n=1,351; cited in PMC10222088 and PMC11682853) found no statistically significant difference between RYGB, OAGB, and SG in T2DM remission at 1 year (RYGB 75.6%, OAGB 75.4%, SG 70.6%) or 3 years (RYGB 79.4%, OAGB 80.4%, SG 75.8%), with overall complete remission of 74.8% at 1 year and 79.4% at 3 years. This is the largest cohort comparing all three procedures and provides the most statistically robust evidence that procedure type — at least among RYGB, OAGB, and SG — is not the primary determinant of remission when patient characteristics are comparable.

#### Intensive Medical Therapy Remission Rates: The Comparator Arm

The available literature provides several estimates of T2DM remission rates with intensive medical therapy. The Look AHEAD study demonstrated 11.5% remission at year 1 and 7.3% at year 4 with intensive lifestyle modification (1,200–1,800 kcal/day plus 175 minutes/week of moderate-to-intense exercise) versus 2.0% in the conventional treatment group (PMC10107406). The DiRECT trial achieved 36% remission at 24 months overall, rising to 86% in patients achieving ≥15 kg weight loss, using a very-low-calorie diet (825–853 kcal/day) with total diet replacement (PMC10107406). The DIADEM-I study showed 61% T2DM remission at 12 months with a low-calorie dietary intervention versus 12% in standard care, in patients with recently diagnosed T2DM (duration <3 years) (PMC10107406). These lifestyle-based remission rates, while impressive in selected populations, are substantially lower than the 60–80% rates achieved with RYGB in comparable populations, and they decline over time as weight is regained.

For pharmacological intensive medical therapy specifically, the REMIT-sita and REMIT-dapa studies — using combination regimens of sitagliptin/metformin/glargine and dapagliflozin/metformin/glargine, respectively — found no statistically significant difference between intensive drug regimens and control groups in achieving remission (PMC10107406). Tirzepatide, the dual GIP/GLP-1 agonist, resulted in a remission rate of 66% to 81% depending on drug dose over 52 weeks (PMC10107406), but these are short-term data in patients with relatively mild disease (short duration, low baseline HbA1c), and long-term (≥5-year) remission data for pharmacological approaches are not available in the current literature.

The meta-analysis by Zhou and Zeng (2023) — examining patients with BMI <35 kg/m², the population immediately below the range of interest — found that 64.0% of surgical patients achieved remission versus 2.8% of nonsurgical patients (OR 25.06, 95% CI 9.58–65.54, p<0.00001) (PMC9945737). While this population is not identical to the BMI 35–40 group, the magnitude of the surgical advantage is striking and consistent with the broader literature.

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### Comparative Effectiveness

#### RYGB Versus Intensive Medical Therapy: Synthesized Estimates

Synthesizing across the available evidence, the following estimates can be constructed for the BMI 35–40 range:

**RYGB at ≥5 years (HbA1c <6.5% off all medications):** The most directly applicable data come from the Castro et al. 5-year cohort (80.3% using the more stringent HbA1c <6% criterion in the overall cohort, suggesting ≥80% using HbA1c <6.5%), the BARI-10-POL 10-year cohort (70.8% using HbA1c <6.5% or FBG <125 mg/dL), and the Moradi et al. 3-year cohort (79.4% complete remission). The Swedish nationwide cohort provides 2-year data of 72.8% (complete + partial remission using HbA1c <6.5%). Taken together, these data suggest that RYGB achieves ≥5-year T2DM remission (HbA1c <6.5% off all medications) in approximately 50–80% of appropriately selected patients with BMI 35–40 kg/m², with the wide range reflecting heterogeneity in patient selection (particularly diabetes duration and insulin use), remission definitions, and follow-up methodology.

**Intensive medical therapy at ≥5 years (HbA1c <6.5% off all medications):** The available evidence suggests remission rates of approximately 5–15% with intensive lifestyle modification at 4–5 years (Look AHEAD: 7.3% at year 4), declining from higher early rates. Pharmacological intensive therapy has not demonstrated statistically significant remission rates in controlled trials. The DiRECT trial achieved 36% at 24 months but with a very-low-calorie diet intervention that is difficult to sustain long-term, and 5-year data are not available in the papers reviewed.

**The surgical advantage:** The absolute difference in ≥5-year remission rates between RYGB and intensive medical therapy in the BMI 35–40 range is therefore approximately 40–70 percentage points, representing a 5- to 15-fold higher remission rate with surgery. This estimate is consistent with the OR of 25.06 (95% CI 9.58–65.54) reported in the meta-analysis of surgical versus nonsurgical treatment in the adjacent BMI <35 population (PMC9945737), and with the Panunzi et al. finding of 64% surgical versus 15% medical remission summarized in PMC11682853.

#### RYGB Versus Sleeve Gastrectomy: Procedure-Specific Comparisons

Multiple studies compare RYGB and SG directly, with generally consistent findings of RYGB superiority, though the magnitude of the difference varies and is not always statistically significant. The Borgeraas et al. RCT (n=705) found RYGB T2DM remission rates of 57% versus SG 47% at 1 year (RR 1.20, p=0.047), with no significant difference at 2–5 years (RR 1.06, p=0.34) (PMC11682853). The Hofsø et al. single-center triple-blind RCT (n=109) found a 27% risk difference favoring gastric bypass over SG for diabetes remission at 1 year (RR 1.57, p=0.0054) (PMC11682853). The Murphy et al. single-center double-blind RCT (n=114, BMI 35–65 kg/m²) found T2DM remission in 47% of SR-LRYGB versus 33% of LSG patients at 5 years (adjusted OR 4.5, p=0.009), using HbA1c <6% without glucose-lowering medications as the criterion (PMC11682853). The Madsen et al. cohort study found 74% T2DM remission at 1 year after RYGB with 27% relapse at 5 years, and a reduced risk of microvascular complications (HR 0.53) (PMC11682853).

The UAE cohort (PMC12616207) found 52.6% RYGB versus 39.3% SG remission at 3 years in BMI ≥35 patients (p=0.12, non-significant due to sample size). The Thai propensity-matched cohort found no significant difference between RYGB and SG for T2DM remission at 3 years (61.7% vs. 64.1%, p=0.491) (PMC12942549). The Italian SG vs. OAGB cohort found that patients off antidiabetic agents at 36 months were 82% in the SG group and 93% in the OAGB group (p=0.059), with the overall odds ratio for DMII remission across the entire follow-up favoring OAGB (OR 0.51, 95% CI 0.27–0.96, p=0.03) (PMC10856683).

The systematic review comparing all three procedures (PMC10222088) concluded that no single procedure demonstrates a clearly superior outcome, and that patient-level factors — age, baseline HbA1c, insulin use, and diabetes duration — are at least as important as procedure type in predicting remission. This conclusion is supported by the multivariable analyses in the Iranian LABS study (PMC9598002) and the Swedish nationwide cohort (PMC8127970), both of which found that surgery type was not an independent predictor of remission after adjustment for patient characteristics.

#### Predictors of Remission: Implications for Patient Selection in BMI 35–40

The consistent predictors of T2DM remission across all studies and all intervention types are: shorter diabetes duration, younger age, lower preoperative HbA1c, absence of insulin use, higher preoperative BMI (within the surgical range), and preserved beta-cell function (higher C-peptide). These predictors have been formalized into scoring systems including the DiaRem score (range 0–22, incorporating HbA1c, insulin use, age, and other diabetes medications), the Advanced DiaRem (range 0–21, adding diabetes duration and number of medications), the ABCD score (incorporating age, BMI, C-peptide, and diabetes duration), and the IMS (Individualized Metabolic Surgery) score. Predictors of T2DM remission have been formalized into scoring systems including the DiaRem score (range 0–22), the Advanced DiaRem (range 0–21), the ABCD score, and the IMS score. The IMS score demonstrated remission rates of 60%, 45.5%, and 0% for mild, moderate, and severe disease categories, respectively, in a small ESG cohort (n=20). The Robert et al. score showed remission rates of 68% vs. 38% for RYGB vs. SG at a score of 3, 77% vs. 50% at a score of 4, and 100% vs. 71% at a score of 5 (PMC11857516, PMC10222088).

For patients in the BMI 35–40 range specifically, the preoperative BMI is generally sufficient to qualify for surgery under current guidelines, but the other predictors — particularly diabetes duration and insulin use — will substantially modulate the expected remission rate. A patient with BMI 38 kg/m², diabetes duration <5 years, HbA1c 7.5%, and no insulin use would be expected to have a substantially higher remission rate than a patient with the same BMI but 15 years of diabetes, HbA1c 9.5%, and insulin dependence. The BARI-10-POL study found that T2DM duration >10 years reduced remission odds by a factor of 23 (OR 0.043, p=0.001) (PMC13123259), while the Iranian LABS study found that each additional year of diabetes duration reduced remission odds by 8% (adjusted OR 0.92 per year, p<0.001) (PMC9598002).

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### Safety Profile and Adverse Events

#### Perioperative Mortality and Major Complications

Bariatric surgery carries a well-characterized perioperative risk profile that must be weighed against its metabolic benefits. Perioperative mortality is very low, ranging between 0.03% and 0.2% across the literature (PMC10222088). The BARI-10-POL study reported no postoperative deaths among 113 patients, with an overall complication rate of 9.7% and Clavien-Dindo grade III complications in 3.5% (PMC13123259). The Spanish 5-year cohort reported postoperative complications including 2 staple line leaks after SG, 1 gastrojejunal anastomotic leak and 1 hemoperitoneum after RYGB, and 1 anastomotic leak and 2 intraperitoneal bleedings after OAGB (PMC7589837). The systematic review of three procedures found that RYGB consistently showed the highest complication rates, while SG had the lowest (PMC10222088). The Soong et al. study of superobese patients found that the overall complication rate for RYGB was 17.7%, with a statistically significant major complication rate of 4.8% compared to OAGB (0.8%) and SG (0.5%) (PMC10222088).

For patients with BMI <35 kg/m² — the population immediately below the range of interest — the complication rate for bariatric surgery was reported as 6–20%, compared to 2–6% for major complications in patients with BMI >35 kg/m² (PMC9945737). This suggests that the BMI 35–40 range may carry a complication profile closer to the higher-BMI population than to the lower-BMI population, though this comparison is imprecise. The 30-day complication rate for RYGB and SG combined was approximately 3–5% in the systematic review by PMC11682853, consistent with the broader literature.

#### Nutritional Deficiencies and Long-Term Metabolic Complications

RYGB is associated with well-characterized nutritional deficiencies requiring lifelong supplementation. The most clinically significant include vitamin B12 deficiency (requiring supplementation due to reduced intrinsic factor production from the bypassed stomach), vitamin D deficiency (66% in the RYGB group in the Pakistani cohort, PMC11571033), iron deficiency (38.8% in the RYGB group, PMC11571033), and folate deficiency (8.0% in the RYGB group vs. 30.8% in the OAGB group, p=0.028, PMC11571033). In a Pakistani cohort comparing RYGB and OAGB, vitamin D deficiency was present in 66% of the RYGB group, iron deficiency in 38.8%, and folate deficiency in 8.0% of the RYGB group versus 30.8% in the OAGB group (p=0.028) (PMC11571033). The comparison between RYGB and OAGB for nutritional deficiencies is nuanced: the YOMEGA trial reported greater serious adverse events and nutritional complications with OAGB (PMC7589837), while the Spanish 5-year cohort found no significant differences in nutritional deficiencies between RYGB and OAGB except for lower iron deficiency after SG (PMC7589837). The Italian SG vs. OAGB cohort found significantly higher rates of vitamin D deficiency (12.3% vs. 3.9%, p=0.03), iron deficiency (15.7% vs. 9.3%, p<0.001), and riboflavin deficiency (8.7% vs. 2.3%, p=0.043) after OAGB compared to SG (PMC10856683).

Dumping syndrome is a common complication of RYGB, with a Danish questionnaire-based study finding that 52.4% of 1,429 RYGB patients reported one or more dumping syndrome-related symptoms at a mean of 4.7 years post-surgery (PMC11416717). Bone demineralization and increased fracture risk are additional long-term concerns, as RYGB impairs calcium and vitamin D absorption, potentially leading to osteoporosis and osteopenia with prolonged follow-up (PMC11416717). Anemia affects approximately 12% of patients at baseline and may worsen postoperatively due to iron and vitamin B12 malabsorption (PMC11416717). Postprandial hypoglycemia can also occur, especially in Roux-en-Y gastric bypass surgery, as a consequence of exaggerated GLP-1 responses and hyperinsulinemia (PMC9945737).

#### Revision Surgery and Long-Term Durability

In a 7-year Turkish cohort, SG was significantly associated with a higher need for revision surgery compared to RYGB and MGB (p=0.0372) (PMC11943842). The most common reasons for revision after OAGB and RYGB are malnutrition and weight regain, while GERD and weight regain are the primary drivers for SG revision. Weight regain is a recognized phenomenon after all bariatric procedures, with the characteristic trajectory of rapid weight loss in the first 1–2 years, nadir at 12–24 months, and partial regain thereafter (PMC12942549). In the Spanish 5-year cohort, the weight curve showed clear weight regain at 5 years after surgery in the RYGB and SG groups, while the OAGB group maintained a mean BMI of 25.9 kg/m² at 5 years (PMC7589837). Weight regain is associated with diabetes relapse, and the long-term durability of remission is therefore partly dependent on the durability of weight loss.

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### Unresolved Controversies and Disagreements

#### Procedure Superiority: RYGB Versus SG Versus OAGB

The most prominent controversy in the literature concerns whether RYGB, SG, or OAGB is superior for T2DM remission. The evidence is genuinely conflicting. On one side, multiple studies demonstrate RYGB superiority: the Borgeraas et al. RCT found RYGB remission rates of 57% versus SG 47% at 1 year (RR 1.20, p=0.047) (PMC11682853); the Hofsø et al. RCT found a 27% risk difference favoring gastric bypass (RR 1.57, p=0.0054) (PMC11682853); the Murphy et al. RCT found adjusted OR 4.5 favoring SR-LRYGB over LSG at 5 years (p=0.009) (PMC11682853); and the Hage et al. study found RYGB more effective than SG regardless of baseline characteristics (PMC11416717). On the other side, the Moradi et al. cohort (n=1,351) found no statistically significant difference between RYGB, OAGB, and SG at 1 or 3 years (PMC9598002, PMC10222088); the Thai propensity-matched cohort found no significant difference between RYGB and SG for T2DM remission (PMC12942549); and the SM-BOSS randomized clinical trial found no statistically significant difference in glycemic control between SG and RYGB (PMC10856683).

The Castro et al. 5-year cohort found OAGB superior to both RYGB and SG (PMC10222088, PMC7589837), while the BARI-10-POL study found a non-significant trend toward OAGB superiority (OR 6.424, p=0.06) (PMC13123259). The Italian SG vs. OAGB cohort found the overall OR favoring OAGB (OR 0.51, p=0.03) but no significant difference in the proportion of patients off antidiabetic agents at 24 or 36 months (PMC10856683). These discrepancies likely reflect differences in patient selection (particularly diabetes duration and insulin use), surgical technique (especially OAGB biliopancreatic limb length), follow-up duration, and remission definitions. The systematic review by PMC10222088 concluded that no single procedure demonstrates a clearly superior outcome, and that patient-level factors are at least as important as procedure type.

#### The Role of Weight Loss Versus Weight-Loss-Independent Mechanisms

A second major controversy concerns the relative contributions of weight loss and weight-loss-independent mechanisms to T2DM remission after bariatric surgery. The observation that glycemic improvement begins within days of surgery — before significant weight loss — has been interpreted as evidence for weight-loss-independent mechanisms (PMC10107406, PMC7589837). However, more recent studies comparing the metabolic benefits of dietary intervention alone versus surgery have not found significant differences when caloric restriction is matched, suggesting that reduced caloric intake and subsequent weight loss may act independently in determining glycemic improvement (PMC10107406). The Spanish 5-year cohort found no significant association between %TWL or %EWL and T2DM remission (PMC13123259), while the Swedish nationwide cohort found a significant positive association between %TWL and remission (adjusted OR 1.04 per 1% TWL, p<0.001) (PMC8127970). These conflicting findings may reflect differences in the range of weight loss achieved across cohorts and the statistical power to detect modest associations.

#### Long-Term Remission Durability and Relapse Rates

The durability of T2DM remission after bariatric surgery is a third area of genuine uncertainty. The BARI-10-POL study reported 70.8% remission at 10+ years (PMC13123259), while the Madsen et al. cohort found 27% relapse at 5 years after initial remission (PMC11682853). The Iranian LABS study found only 1.99% recurrence at 3 years (PMC9598002), while other studies have reported relapse rates of 17–40% in longer-term follow-up (PMC9598002). The wide range of reported relapse rates reflects differences in remission definitions, follow-up duration, patient selection, and the degree of weight regain. The SLEEVEPASS trial is referenced as showing durable long-term remission for both SG and RYGB at 10 years (PMC12616207), but the specific remission rates using the HbA1c <6.5% off-medication criterion at 10 years are not reported in the available papers.

#### The Glucocentric Remission Definition and Cardiovascular Risk

A fourth controversy concerns whether the HbA1c <6.5% off-medication remission criterion is the appropriate endpoint for evaluating the success of metabolic interventions. The critical appraisal by PMC10107406 argues that this definition is overly glucocentric, fails to account for cardiovascular risk reduction, and may generate false security in patients who achieve glycemic remission but retain substantial cardiometabolic risk. The withdrawal of newer antidiabetic agents with proven cardiovascular and renal benefits (GLP-1 receptor agonists, SGLT-2 inhibitors) to achieve "remission" may paradoxically increase cardiovascular risk in some patients. This perspective challenges the framing of the user's question and suggests that the appropriate endpoint for comparing RYGB versus intensive medical therapy may need to incorporate cardiovascular outcomes rather than glycemic remission alone.

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### Limitations of the Evidence Base

The evidence base for long-term T2DM remission following RYGB versus intensive medical therapy in the BMI 35–40 range is subject to numerous methodological limitations that constrain the precision and generalizability of the available estimates.

**Follow-up duration.** The most critical limitation is the scarcity of data meeting the ≥5-year follow-up criterion specified in the user's question. Most large cohort studies report 1- to 3-year outcomes, and the few studies with ≥5-year data (Castro et al., BARI-10-POL, SLEEVEPASS) have important methodological limitations of their own. The BARI-10-POL study had a follow-up rate of only 28.5%, introducing substantial selection bias (PMC13123259). The Castro et al. study had follow-up rates exceeding 83% at 5 years but was conducted at a single institution with highly selected patients (PMC7589837).

**Remission definition heterogeneity.** A systematic review of the literature has identified nearly 100 different definitions of remission in type 2 diabetes, creating heterogeneity in published studies that affects comparability and reproducibility of results (PMC10107406). The studies reviewed here use at least four distinct criteria: HbA1c <6.0% and FBG <100 mg/dL (ASMBS complete remission), HbA1c <6.5% off medication (ADA 2021 consensus), HbA1c <6.5% or FBG <125 mg/dL (BARI-10-POL), and FBG <7 mmol/L or HbA1c <6.5% (Wasir et al.). This heterogeneity makes cross-study comparisons unreliable and inflates the apparent range of remission rates.

**Selection bias and retrospective design.** The majority of available studies are retrospective cohort analyses, which are subject to selection bias, information bias, and confounding by indication. Patients selected for surgery may differ systematically from those managed medically in ways that are not fully captured by available covariates (PMC9945737, PMC13123259). The high loss-to-follow-up rates in several studies (31–61% by years 2–4 in the prediabetes cohort, PMC10782579; 43.1% in the Pakistani micronutrient study, PMC11571033) introduce attrition bias that likely inflates reported remission rates.

**BMI subgroup specificity.** None of the available studies specifically enrolled patients with BMI 35–40 kg/m² as the primary inclusion criterion. The UAE cohort (PMC12616207) enrolled patients with BMI ≥35 without an upper limit, and the mean BMI in most other cohorts is substantially above the 35–40 range of interest. The relationship between BMI and remission is complex: higher BMI is associated with greater weight loss potential but also with more severe metabolic disease, and the net effect on remission in the 35–40 range specifically is not well characterized.

**Absence of C-peptide data.** C-peptide — a direct measure of residual beta-cell function and one of the strongest predictors of remission — was not available in the Swedish nationwide cohort (PMC8127970) or the BARI-10-POL study (PMC13123259), limiting the robustness of the predictive models in these large datasets.

**Comparator arm heterogeneity.** The "intensive medical therapy" comparator encompasses a wide range of interventions across studies, from structured lifestyle modification programs (Look AHEAD, DiRECT) to combination pharmacotherapy (REMIT-sita, REMIT-dapa) to standard care. The absence of a standardized, contemporary intensive medical therapy comparator — incorporating GLP-1 receptor agonists and SGLT-2 inhibitors — in most surgical trials means that the surgical advantage may be overstated relative to what would be observed against modern pharmacological management.

**Generalizability across populations.** The available studies span diverse populations including Swedish, Iranian, Polish, Thai, Italian, UAE, and Pakistani cohorts, with substantial differences in ethnicity, dietary patterns, healthcare systems, and surgical technique. The Thai cohort had a notably high mean BMI (47.3 kg/m²) despite lower Asian BMI thresholds for surgery (PMC12942549), while the Iranian cohort had a predominance of OAGB (50%) reflecting local surgical practice patterns (PMC9598002). These population-specific factors limit the generalizability of any single study's findings to the BMI 35–40 Western population.

**Publication bias.** The systematic review by PMC11682853 acknowledges that studies with negative results may be underrepresented, potentially leading to overestimation of surgical efficacy. The funnel plot asymmetry noted in the meta-analysis by PMC9945737 suggests potential publication bias in the surgical remission literature.

**Lack of standardized intensive medical therapy.** The comparator arm in most surgical trials predates the widespread availability of GLP-1 receptor agonists and SGLT-2 inhibitors. Future trials comparing RYGB against contemporary intensive pharmacotherapy — including these newer agents — are needed to establish the current comparative advantage of surgery.

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### Special Populations

#### Patients with Long-Standing Diabetes and Insulin Dependence

Patients with diabetes duration >10 years and preoperative insulin dependence represent a subgroup with substantially lower remission rates after RYGB. The BARI-10-POL study found that T2DM duration >10 years reduced remission odds by a factor of 23 (OR 0.043, p=0.001) (PMC13123259). Among insulin-treated patients in the Castro et al. cohort, complete T2DM remission at 5 years was 16.7% after SG, 30.8% after RYGB, and 66.7% after OAGB (p=0.0005) (PMC7589837). In the Swedish nationwide RYGB cohort, older age (adjusted OR 0.97 per year, p<0.001), longer diabetes duration (adjusted OR 0.89 per year, p<0.001), higher baseline HbA1c (adjusted OR 0.99 per mmol/mol, p<0.001), and insulin use at baseline (adjusted OR 0.26, 95% CI 0.22–0.30, p<0.001) were all independently associated with lower remission rates; approximately 75% of patients on insulin at baseline discontinued insulin by 2 years. BMI was not significant in multivariable analysis after controlling for weight loss (PMC8127970). For this subgroup, RYGB may still provide meaningful clinical benefit — particularly in reducing insulin requirements — even when full remission is not achieved.

#### Younger Patients with Short Diabetes Duration

Younger patients with recently diagnosed T2DM represent the subgroup most likely to achieve and sustain remission after RYGB. The Thai cohort found T2DM duration <3 years to be the strongest independent predictor of remission (HR 2.40, 95% CI 1.41–4.07, p=0.001) (PMC12942549). The Iranian LABS study found that each additional year of age reduced remission odds by 3% (adjusted OR 0.97 per year, p<0.001) (PMC9598002). Across multiple studies, shorter diabetes duration and younger age consistently emerge as the strongest patient-level predictors of durable remission after bariatric surgery (PMC9598002, PMC8127970, PMC12942549, PMC13123259). For patients in the BMI 35–40 range with short diabetes duration and no insulin use, RYGB remission rates at 5 years may approach or exceed 80%.

#### Socioeconomic and Ethnic Subgroups

The Swedish nationwide RYGB cohort identified first-generation immigrant status (adjusted OR 0.66, 95% CI 0.57–0.77, p<0.001) and large-city residence (associated with lower remission compared to smaller towns, p<0.001) as independent predictors of lower T2DM remission rates after RYGB (PMC8127970). These socioeconomic factors likely reflect differences in healthcare access, dietary environment, follow-up adherence, and chronic stress — factors that are not captured by clinical predictors alone. South Asian populations have distinct metabolic characteristics, including greater predisposition to central obesity and diabetes at lower BMI, which may affect both the indication for surgery and the metabolic response (PMC11571033).

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### Conclusions and Future Directions

#### What the Evidence Supports

The available evidence consistently and robustly supports the conclusion that Roux-en-Y gastric bypass achieves substantially higher rates of long-term T2DM remission (HbA1c <6.5% off all glucose-lowering medications) compared to intensive medical therapy in adults with T2DM and BMI in the 35–40 kg/m² range. The best available estimates suggest that RYGB achieves ≥5-year remission in approximately 50–80% of appropriately selected patients in this BMI range, compared to approximately 5–15% with intensive lifestyle modification and even lower rates with pharmacological intensive therapy alone. The absolute difference in remission rates is approximately 40–70 percentage points, representing a 5- to 15-fold higher remission rate with surgery. This advantage is supported by multiple RCTs (Courcoulas et al. at 7 years in BMI 36.4 kg/m², Murphy et al. at 5 years in BMI 35–65 kg/m², Hofsø et al. at 1 year), large cohort studies (Swedish nationwide n=8,057; Iranian LABS n=1,351; Spanish 5-year n=358), and meta-analyses (OR 25.06 for surgery vs. nonsurgery in adjacent BMI population).

The evidence also supports the conclusion that patient-level factors — particularly diabetes duration, preoperative HbA1c, insulin use, age, and beta-cell reserve — are at least as important as procedure type in predicting remission. Patients with BMI 35–40 kg/m², diabetes duration <5 years, HbA1c <8%, and no insulin use are the most likely to achieve durable remission after RYGB. The evidence supports early surgical intervention — before beta-cell exhaustion becomes irreversible — as the strategy most likely to maximize long-term remission rates.

The evidence further supports that RYGB achieves remission through both weight-loss-dependent mechanisms (caloric restriction, visceral fat reduction, improved insulin sensitivity) and weight-loss-independent mechanisms (GLP-1 enhancement, bile acid signaling, gut microbiome remodeling, proximal intestinal exclusion), and that these mechanisms are more pronounced with bypass procedures than with purely restrictive procedures such as SG.

#### What the Evidence Does NOT Support

The evidence does not support the conclusion that RYGB is uniformly superior to SG for T2DM remission in the BMI 35–40 range. While multiple RCTs and cohort studies demonstrate RYGB superiority, others find no significant difference, and the systematic review of three-procedure comparisons concluded that no single procedure demonstrates a clearly superior outcome. The evidence does not support the use of a single remission rate estimate for all patients in the BMI 35–40 range, as the range of expected outcomes is wide (50–80%) and highly dependent on patient-level predictors.

The evidence does not support the conclusion that intensive medical therapy — even with contemporary agents including GLP-1 receptor agonists and SGLT-2 inhibitors — achieves comparable ≥5-year remission rates to RYGB in the BMI 35–40 range. While tirzepatide achieves remission rates of 66–81% over 52 weeks in selected populations (PMC10107406), long-term (≥5-year) data for pharmacological remission are not available, and the populations studied (short diabetes duration, low baseline HbA1c) are more favorable than the typical BMI 35–40 surgical candidate.

The evidence does not support the conclusion that the HbA1c <6.5% off-medication remission criterion is the only clinically meaningful endpoint for comparing RYGB versus intensive medical therapy. Cardiovascular outcomes, medication burden reduction, quality of life, and complication prevention are equally important endpoints that are not fully captured by the remission criterion alone.

#### Future Research Directions

1. **Randomized controlled trials with ≥5-year follow-up specifically in the BMI 35–40 range** are urgently needed. The STAMPEDE and ARMMS-T2D trials provide the closest available evidence but do not report BMI-stratified remission rates using the HbA1c <6.5% off-medication criterion at 5 years. A dedicated RCT enrolling only patients with BMI 35–40 kg/m² and T2DM, comparing RYGB against contemporary intensive medical therapy (including GLP-1 receptor agonists and SGLT-2 inhibitors), with ≥5-year follow-up and standardized remission assessment, would directly address the user's question.

2. **Head-to-head comparison of RYGB versus contemporary pharmacotherapy** (tirzepatide, semaglutide, SGLT-2 inhibitors) with ≥5-year follow-up is needed to establish the current comparative advantage of surgery against the best available medical alternatives. Most existing surgical trials used comparators that predate the availability of these highly effective agents.

3. **Standardization of remission definitions** across future trials is essential. The adoption of the 2021 ADA consensus definition (HbA1c <6.5% for ≥3 months off all glucose-lowering pharmacotherapy) as the universal standard would enable meaningful cross-study comparisons and meta-analyses.

4. **Incorporation of C-peptide and beta-cell function measures** into preoperative assessment and predictive models would improve patient selection and allow more precise estimation of expected remission rates for individual patients. The absence of C-peptide data from the largest available cohorts (Swedish nationwide, BARI-10-POL) represents a significant gap.

5. **Long-term cardiovascular outcome data** from surgical trials are needed to establish whether the glycemic remission achieved by RYGB translates into reductions in cardiovascular events, mortality, and microvascular complications in the BMI 35–40 range. The meta-analysis cited in PMC10107406 (RR 0.43 for macrovascular complications, RR 0.40 for myocardial infarction) provides encouraging evidence but is based on a mix of RCTs and cohort studies with heterogeneous populations.

6. **Comparative effectiveness research on RYGB versus OAGB** in the BMI 35–40 range with ≥5-year follow-up is needed. The available evidence suggests OAGB may achieve higher remission rates than RYGB in some populations, particularly among insulin-treated patients, but the evidence base is limited by small sample sizes, retrospective designs, and heterogeneous biliopancreatic limb lengths.

7. **Investigation of relapse predictors and prevention strategies** is needed to understand why some patients who achieve initial remission after RYGB subsequently relapse, and what interventions (pharmacological, behavioral, or revisional surgical) can prevent or reverse relapse. The reported relapse rates range from 1.99% at 3 years (PMC9598002) to 27% at 5 years (PMC11682853), and the determinants of this wide range are incompletely understood.

8. **Socioeconomic and ethnic subgroup analyses** are needed to understand why first-generation immigrants and large-city residents have lower remission rates after RYGB (PMC8127970), and to develop targeted interventions to reduce these disparities. The mechanisms underlying these associations — whether related to dietary patterns, follow-up adherence, chronic stress, or other factors — remain unknown.

9. **Integration of continuous glucose monitoring (CGM) metrics** — particularly time in range (TIR) — into remission assessment would provide a more sensitive and clinically meaningful measure of glycemic normalization than HbA1c alone, as advocated by the critical appraisal in PMC10107406.

10. **Economic analyses** comparing the long-term cost-effectiveness of RYGB versus intensive medical therapy in the BMI 35–40 range are needed to inform healthcare policy decisions. While the initial costs of surgery are substantial, the subsequent reduction in diabetes medication, complications, and healthcare utilization may result in net cost savings over a 10–20 year horizon, particularly given the high and growing cost of newer pharmacological agents.

In summary, the available evidence strongly supports the conclusion that RYGB achieves substantially higher rates of long-term T2DM remission compared to intensive medical therapy in adults with BMI 35–40 kg/m², with best estimates of approximately 50–80% versus 5–15% at ≥5 years. However, the precision of these estimates is limited by the absence of studies specifically designed to address this question, the heterogeneity of remission definitions and patient populations, and the rapid evolution of both surgical techniques and pharmacological alternatives. The clinical decision to pursue RYGB in this population should be individualized based on diabetes duration, beta-cell reserve, insulin use, patient preference, and the availability of contemporary pharmacological alternatives, with the understanding that the surgical advantage is most pronounced in patients with shorter disease duration and preserved beta-cell function.

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*This review synthesizes evidence from the following primary sources: PMC13123259, PMC11857516, PMC10856683, PMC10782579, PMC9945737, PMC10222088, PMC12942549, PMC12616207, PMC9598002, PMC8127970, PMC11682853, PMC7589837, PMC11571033, PMC11943842, PMC10107406, PMC11416717.*

## References

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2. **pmc:PMC11857516** *(cited in 7 claims)* — Ghusn W, Zeineddine J, Betancourt R, et al. (2025). *Advances in Metabolic Bariatric Surgeries and Endoscopic Therapies: A Comprehensive Narrative Review of Diabetes Remission Outcomes.* doi:10.3390/medicina61020350
3. **pmc:PMC11682853** *(cited in 6 claims)* — Mohamed A, Aljabal H, Alalawi A, et al. (2024). *The Impact of Bariatric Surgery on Type 2 Diabetes Mellitus Remission: A Systematic Review.* doi:10.7759/cureus.74755
4. **pmc:PMC13123259** *(cited in 6 claims)* — Jaworski P, Dowgiałło-Gornowicz N, Orłowski M, et al. (2026). *Type 2 diabetes mellitus remission 10 years after metabolic and bariatric surgery: a multicenter retrospective study in Poland (BARI‑10‑POL).* Videosurgery and other Miniinvasive Techniques. doi:10.20452/wiitm.2026.18020
5. **pmc:PMC8127970** *(cited in 5 claims)* — Stenberg E, Olbers T, Cao Y, et al. (2021). *Factors determining chance of type 2 diabetes remission after Roux-en-Y gastric bypass surgery: a nationwide cohort study in 8057 Swedish patients.* doi:10.1136/bmjdrc-2020-002033
6. **pmc:PMC10222088** *(cited in 4 claims)* — Balasubaramaniam V, Pouwels S (2023). *Remission of Type 2 Diabetes Mellitus (T2DM) after Sleeve Gastrectomy (SG), One-Anastomosis Gastric Bypass (OAGB), and Roux-en-Y Gastric Bypass (RYGB): A Systematic Review.* doi:10.3390/medicina59050985
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