Open research questions in Diabetes Treatment and Management

What the literature leaves open

• In patients with T2DM and established heart failure, SGLT2 inhibitors currently have the strongest evidence base for improving HF outcomes and should be priori- tized when not contraindicated [8, 11, 45]. Their ben- efits extend across the ejection fraction spectrum and are observed irrespective of diabetes status [8, 10, 11, 46]. GLP-1 receptor agonists may be considered when additional treatment goals include weight reduction, improved glycemic control, chronic kidney disease risk reduction, or lowering atherosclerotic cardiovascular risk, particularly in patients with obesity or established Atherosclerotic Cardiovascular Disease (ASCVD) [7, 16, 47]. However, they should not be viewed as substitutes for evidence-based HF therapies, and their role in estab- lished HFrEF remains less certain [18, 19, 22, 48]. Altogether, combination therapy may be reasonable in selected high-risk patients who would benefit from both HF-directed treatment and broader cardiometabolic risk reduction. Decisions should be individualized according to comorbidity burden, renal function, tolerability, cost, route of administration, and patient preference. At pres- ent, routine use of dual therapy specifically to improve HF outcomes cannot be recommended because dedi- cated randomized HF trials are lacking. Authors’ perspective and future directions Current evidence supports SGLT2 inhibitors as a core component of contemporary heart failure manage- ment because of their consistent reductions in HF hos- pitalization and cardiovascular death across a broad range of patient populations [8–13, 45, 49]. In contrast, GLP-1 receptor agonists appear to offer important Khademi and Shoar Cardiovascular Diabetology – Endocrinology Reports (2026) 12:47 Page 6 of 8 complementary benefits related to weight reduction, glycemic control, renal protection, and atherosclerotic cardiovascular risk reduction, although their direct role in established HF remains less certain [16, 20, 22, 47]. The potential value of combining these therapies lies in addressing overlapping cardiorenal and metabolic risk pathways as available evidence for dual therapy in HF populations remains limited and is derived largely from subgroup analyses, observational studies, and extrapola- tion from diabetes or obesity trials rather than dedicated HF randomized trials [24, 25, 27, 30, 50]. Future research should prioritize adequately pow- ered randomized controlled trials evaluating combined SGLT2 inhibitor and GLP-1 receptor agonist therapy in patients with HF. Key objectives include determin- ing long-term safety, identifying patient subgroups most likely to benefit, clarifying effects across HF phenotypes, and assessing patient-centered outcomes such as quality of life, functional status, and hospitalization burden.

  Concomitant use of SGLT2 inhibitors and GLP-1 receptor agonists in patients with heart failure · 2026 · DOI

• The combination of these therapies is mechanistically appealing and may offer incremental benefit in selected patients with overlapping metabolic, renal, and cardio- vascular risk; however, current evidence remains limited, heterogeneous, and derived largely from secondary anal- yses or observational studies rather than dedicated ran- domized heart failure trials.

  Concomitant use of SGLT2 inhibitors and GLP-1 receptor agonists in patients with heart failure · 2026 · DOI

• The growing intersection between type 2 diabetes, MASLD, and hepatocellular carcinoma underscores a paradigm shift in how metabolic disorders are linked to liver cancer. GLP-1 receptor agonists, initially conceived as glucose-lowering drugs, now represent a promising class of agents capable of modulating several upstream drivers of hepatocarcinogen- esis—including insulin resistance, steatosis, lipotoxicity, and chronic inflammation. Across clinical trials and real-world studies, GLP-1RAs have consistently shown favorable hepatic effects and a potential to attenuate progression toward cirrhosis and HCC. Yet, available evidence remains largely observational, with signal strength varying by disease stage, comparator, and exposure duration. The absence of prospective, liver-specific randomized studies remains the main barrier to establishing causality. Future research should, therefore, move beyond glucose- centric paradigms to focus on maintenance of metabolic liver health—integrating GLP-1RAs into broader strategies that combine pharmacologic, lifestyle, and possibly inter- ventional approaches. Synergy with SGLT2 inhibitors, liver- directed therapies, and next-generation incretin co-agonists could further amplify hepatic and metabolic protection. Moreover, the identification of early biomarkers and imaging signatures predictive of treatment response will be essential to tailor therapy and optimize cost-effectiveness. Ultimately, GLP-1RAs may not only transform the man- agement of diabetes and MASLD but also redefine the land- scape of primary liver cancer prevention. Their promise lies not in targeting the tumor itself, but in intercepting the metabolic and inflammatory trajectories that make the liver a fertile ground for carcinogenesis. Funding Open access funding provided by Università degli Studi di Firenze within the CRUI-CARE Agreement. Data availability This is not applicable to this article as no datasets were generated or analyzed in the current study.

  GLP-1 receptor agonists at the crossroads of diabetes, hepatic steatosis, and hepatocellular carcinoma · 2026 · DOI

• Future research should focus on long-term outcome studies to better understand the durability of cardio- renal protection associated with SGLT2 inhibitors. Future research should focus on evaluating the long-term durability of the cardio-renal protective effects of SGLT2 inhibitors, particularly beyond current trial follow-up periods.

  Impact of SGLT2 inhibitors on heart failure risk and kidney function in type 2 diabetic mellitus patients: A literature review · 2026 · DOI

• Large, long-term randomized controlled trials are warranted to clarify whether GLP-1 receptor agonists can simultaneously support smoking cessation and promote favorable metabolic outcomes.

  GLP-1 agonists for smoking cessation and post-cessation weight management: A systematic review and meta-analysis of randomized trials · 2026 · DOI

• Future research should explore extended GLP-1 therapy in combination with established cessation supports to optimize both abstinence and metabolic outcomes. It is possible that these short-term interventions are insufficient to sustain abstinence, emphasizing the need for long-term strategies to reduce relapse. While our meta-analysis did not find a significant increase in abstinence rates with GLP-1 receptor agonists, the available evidence remains limited and inconclusive regarding their role in smoking cessation.

  GLP-1 agonists for smoking cessation and post-cessation weight management: A systematic review and meta-analysis of randomized trials · 2026 · DOI

• Furthermore, the most commonly used agents for diabetes and weight loss, semaglutide and tirzepatide, have not yet been assessed for this indication. Large, long-term randomized controlled trials are warranted to clarify whether GLP-1 receptor agonists can simultaneously support smoking cessation and promote favorable metabolic outcomes.

  GLP-1 agonists for smoking cessation and post-cessation weight management: A systematic review and meta-analysis of randomized trials · 2026 · DOI

• Although limited by the small number of studies focusing specifically on this population, these findings support the potential therapeutic relevance of SGLT2i in patients with coexisting T2DM and gout, contributing to the management of both conditions and the reduction of CV-related events associated with them.

  Effects of SGLT2 inhibitors on gout-related and cardiometabolic outcomes in patients with type 2 diabetes mellitus: a scoping review · 2026 · DOI

• Important knowledge gaps remain. Dedicated RCT data evaluating combination therapy on hard cardiovascular and kidney endpoints are limited, and optimal sequencing strate- gies have not been definitively established; PRECIDENTD is expected to provide the first randomized evidence [36]. In addition, the role of emerging dual incretin therapies in cardiometabolic care requires further investigation, par- ticularly regarding their cardiovascular and kidney benefits and their use alongside SGLT2is. Evidence is also sparse in advanced CKD, distinct HF phenotypes, and adults over 80 years [61–63]. Future research should prioritize pragmatic trials, comparative effectiveness studies, and precision med- icine approaches to identify individuals most likely to ben- efit from specific therapeutic combinations.

  Combination cardiometabolic therapy in type 2 diabetes: optimizing SGLT2 inhibitor and GLP‑1 receptor agonist use · 2026 · DOI

• Whether trial-level efficacy translates into the outcomes a patient and clinician will actually see is an open question, and the answer matters, because telehealth is now where most GLP-1 prescribing happens.

  Off-Trial: Real-World Weight Loss on Tirzepatide and Semaglutide · 2026 · DOI

• Notably, older adults with obesity and preserved baseline muscle mass represent a particularly understudied phenotype, and dedicated studies are needed to determine whether this subgroup may differ- entially benefit from the muscle quality improvements asso- ciated with GLP-1 RA therapy. Future research is warranted to characterize the effects of GLP-1 RA therapy and post-cessation on SO risk in older adults, as well as to establish MNT protocols and define evidence-based clinical approaches tailored to this population.

  GLP-1 Receptor Agonists for Obesity Management in Older Adults: A Scoping Review on the Risk of Sarcopenia and Sarcopenic Obesity · 2026 · DOI

• Therefore, GQD may have potential as an adjunctive therapy, but its routine clinical use cannot yet be supported because high- certainty evidence is lacking.

  Efficacy of Gegen Qinlian decoction plus metformin for type 2 diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials · 2026 · DOI

• Further research is needed to clarify the mechanisms underlying the early worsening phenomenon and to identify patient subgroups most at risk. Large-scale, long-term observational studies with standardized DR assessment and real-world evidence are essential. Additionally, future trials should explore whether specific GLP-1RA differ in their ocular safety profiles.

  Assessing the risk of diabetic retinopathy progression with GLP-1 receptor agonists: a systematic review and meta-analysis · 2026 · DOI

• The main limitations of this study include its retrospective design, lack of a control group, short follow-up period, heterogeneous BMI range, absence of standardized questionnaires assessing eating behavior, and exclusion of patients with significant adverse events. Further studies, particularly randomized trials with active comparators and diverse populations, are warranted to fully elucidate the efficacy, safety, and mechanistic pathways of semaglutide therapy.

  Effects of semaglutide on anthropometric measures, diet, and eating behaviors in obese women: a retrospective observational study · 2026 · DOI

• Precision medicine and responder identification The next stage of incretin cardiovascular medicine should move beyond broad eligibility criteria toward responder phenotyping. Potential predictors include baseline ASCVD phenotype, obesity class, visceral adiposity, hsCRP, albuminuria, natriuretic peptides, hepatic steatosis, frailty, sex, ethnicity, gut microbiome composition and genetic variation in incretin-related pathways (27, 47, 64, 65). Machine-learning approaches may help identify response clusters, but they must be externally validated and clinically interpretable.

  Incretin-based cardiovascular protection beyond diabetes: evidence, mechanisms, and therapeutic frontiers from GLP-1 receptor agonists to multi-agonist therapy · 2026 · DOI

• The primary limitations of the present study are its sin- gle-center design, the relatively modest sample size, and the comparatively short follow-up duration. Given that hypo- glycemia represents a key safety endpoint in therapies in- volving basal insulin, the absence of these data constitutes an important limitation and may restrict the comprehen- sive evaluation of treatment safety.

  Early glycemic, weight, and metabolic effects of insulin glargine/lixisenatide in uncontrolled type 2 diabetes: A single-center experience · 2026 · DOI

• The principal interpretive constraint of this systematic review is not the absence of evidence but the heterogeneity of the available evidence base. Most included studies were cohort, retrospective, or comparative effectiveness analyses, which provide clinically relevant real-world data but cannot establish causality with the same strength as randomized controlled trials. Observed associations may therefore reflect residual confounding, treatment-selection bias, differences in baseline cardiovascular risk, variation in medication exposure, and inconsistent adjustment for comorbidities or concurrent therapies. Differences in study design, population demographics, comparator groups, follow-up duration, and cardiovascular 2026 Sen et al. Cureus 18(6): e111603. DOI 10.7759/cureus.111603 9 of 12 endpoint definitions also limited direct cross-study comparisons and precluded meta-analysis. Although hypertension was central to the review question, the included studies primarily evaluated glucose- lowering pharmacotherapies, cardiometabolic risk-factor control, and integrated care models. Therefore, class-specific antihypertensive treatment evidence, including angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, calcium-channel blockers, beta-blockers, and diuretics, was not comprehensively synthesized. This limits the ability of the review to draw conclusions regarding preferred antihypertensive drug classes in patients with coexisting T2DM and hypertension. This review also did not specifically synthesize emerging dual SGLT2 inhibitor/GLP-1 receptor agonist combination therapy evidence or recent cardiorenal outcome trials as separate evidence categories. As a result, conclusions regarding newer cardiometabolic treatment strategies should be interpreted in the context of the included studies and their predefined eligibility criteria. Future updates should incorporate emerging evidence on dual-class cardiometabolic pharmacotherapy, kidney-cardiovascular outcome trials, and contemporary guideline-directed approaches to combined metabolic and blood pressure management. The inclusion of a pilot implementation protocol required separate interpretation. Because the HEARTS- aligned study did not report completed clinical outcomes, it was not used as evidence of cardiovascular risk reduction or clinical effectiveness. Its value lies in illustrating a planned health-system implementation strategy rather than demonstrating patient-level benefit. This distinction is important when interpreting the contribution of system-level care models within the broader synthesis. Future research should move from association-based evidence toward causal and implementation-focused evaluation. Well-designed randomized controlled trials and pragmatic comparative effectiveness studies are needed to clarify the independent and combined effects of glucose-lowering therapies, antihypertensive treatment, blood pressure control, glycemic stability, and lifestyle interventions on cardiovascular endpoints. Longitudinal implementation studies are also needed to determine whether integrated care models such as HEARTS can produce sustained improvements in blood pressure control, glycemic control, medication adherence, cardiovascular events, cost-effectiveness, and patient-reported outcomes across diverse healthcare settings.

  Integrated Management Strategies for Hypertension and Diabetes in Cardiovascular Disease Prevention: A Systematic Review · 2026 · DOI

• Future prospective studies with serial CGM assessments are warranted to confirm these observations and evaluate whether interventions targeting TIR improvement can effectively reduce diabetic kidney disease incidence.

  Association between time in range and incident early diabetic kidney disease in patients with type 2 diabetes: a retrospective cohort study · 2026 · DOI

• The con- sistency and dose-dependency of these findings suggest a clinically meaningful relationship between TIR and early renal outcomes, though confirmation in larger prospective cohorts is warranted given the observational design and modest sample size.

  Association between time in range and incident early diabetic kidney disease in patients with type 2 diabetes: a retrospective cohort study · 2026 · DOI

• The principal limitation is the comparator design. Despite matching on 68 covariates with all SMDs < 0.10, a never- user comparator cannot replicate the causal rigor of an active-comparator new-user design [31, 32]. By construc- tion, the never-user definition incorporated future informa- tion by excluding patients who later initiated GLP-1–based therapy; this condition on future exposure status may intro- duce selection bias. We attempted an active-comparator design using non-GLP-1 anti-obesity pharmacotherapy, but the cohort was too small in this RA population, with matched event counts below the platform’s cell-suppression threshold for every endpoint of interest. Residual confound- ing by indication, healthy-user bias, and channeling toward greater metabolic engagement are therefore plausible expla- nations for the observed associations. Second, TriNetX provides only aggregate summary sta- tistics, limiting independent verification and assessment beyond platform-generated diagnostics. Third, exposure was classified at baseline without updating for discontinuation, dose change, or switching. Real-world GLP-1 persistence is approximately 50% at 12 months in populations with type 2 diabetes [44]. This intention-to-treat–like classification may dilute associations if treatment effects require persistence, but it also limits interpretation as a sustained treatment-effect analysis. Fourth, mean follow-up was shorter among GLP-1 users at both the primary (278 vs. 322 days) and extended (324 vs. 389 days) horizons, consistent with more recent index dates. Loss to follow-up cannot be directly ascertained, and inform- ative censoring cannot be excluded. Cox models accommo- date variable observed follow-up under that assumption, but the direction and magnitude of any bias from differential censoring cannot be determined from aggregate TriNetX output. Prespecified dual time horizons and the calendar- time–restricted subcohort with independent rematching provided sensitivity checks for follow-up duration and treatment-era effects, but do not eliminate this limitation. Fifth, ICD-10-CM codes are imperfect surrogates for clinical events. Respiratory failure codes capture a hetero- geneous spectrum, and changes in coding practice could introduce differential misclassification [36]. Heart failure codes lack phenotypic resolution, precluding distinction of subtypes or separation of new-onset from decompensated chronic disease. Clinical adjudication anchors—natriuretic peptide levels, cardiac imaging, and chart review—are not available through the TriNetX interface. The pre-index exclusion removes patients with the corresponding end- point before day 0, but the TriNetX query did not sepa- rately exclude endpoint codes during the 0–90-day land- mark window; a post-day-91 code could represent either a first documented post-landmark event or recurrence after an uncounted landmark-window event. We accordingly describe the endpoint as first post-landmark ICD-10–docu- mented HF or RF among patients without pre-index end- point documentation, not as fully incident disease [34, 35]. Sixth, several clinically important variables were unavail- able: RA disease activity, disease duration, specific biologic therapy sequences, glucocorticoid dose, longitudinal weight change, body composition, insurance status, socioeconomic position, and social determinants of health. The absence of longitudinal weight data is particularly relevant because it precludes separating weight-mediated from weight-inde- pendent effects in this population. Seventh, generalizability is limited to US healthcare organizations contributing to the TriNetX network.

  GLP-1–based therapy and ICD-10–documented heart failure or respiratory failure events in non-diabetic adults with rheumatoid arthritis and obesity: a TriNetX federated cohort study · 2026 · DOI

• for symptomatic HFrEF and Class IIa/I for HFpEF/HFmrEF.19 ADA 2024/2025 Standards First-line treatment with metformin for patients with T2D and CKD (eGFR ≥ 20).19 Source: 17, 19 The recent recommendation to initiate therapy down to an eGFR of 20 mL/min/1.73 m² represents a significant expansion of the eligible population.34 Even more striking is the consensus that once initiated, the medication can and should be continued until the patient starts dialysis, regardless of further eGFR decline.17 This suggests that the cardioprotective and renoprotective benefits persist even at the very edges of renal viability.

  SGLT2 Inhibitors in Heart Failure with Coexisting Chronic Kidney Disease · 2026 · DOI

• This study was conducted only in male mice. Clinical studies showed that canagliflozin gender-irrespectively lowers hemoglobin A1c and body weight [14] and reduces cardiovascular and renal events in type 2 diabetes [49,50], indicating the sex-independent action of this drug: these reports support that the results of the present study may not be sex-limited. However, considering reported sex differences in meta- bolism and feeding, possible sex differences in effects and involvement of sex hormones remain to be studied. The treatment period was 10–16 days. This period appears to be reasonable in the light of mouse lifespan but much shorter than that for obesity treatment in humans. Hence, the present results requires careful clinical extrapolation of consideration. Fig. 6. Proposed cascade for the action of canagliflozin on energy balance and weight outcome in DIO and db/db mice. Canagliflozin induces rapid glucose loss and weight reduction, followed by continuous increase in food intake in both DIO and db/db mice. This continuous increase in energy (food) intake leads to weight rebound in db/db mice. In DIO mice, canagliflozin subsequently induces circadian rises in body temperature and locomotor activity, exhibiting promoted energy expenditure. The elevated energy (food) intake and promoted energy expenditure may be balanced to maintain the initially lowered weight via glucosuria, achieving sustained weight loss. CRediT authorship contribution statement Yutaka Seino: Supervision. Toshihiko Yada: Writing – original draft, Investigation, Funding acquisition, Conceptualization. Daisuke Yabe: Supervision. Masanori Nakata: Methodology. Yusaku Iwasaki: Methodology. Abilkhair Yussupov: Investigation. Nazymgul Kulzha- nova: Investigation. Yermek Rakhat: Investigation. Seiya Banno: Investigation. Dauren Zhantleu: Investigation. Wanxin Han: Investi- gation. Lei Wang: Writing – original draft, Methodology, Investigation. mice. Hence, the system to elevate body temperature and locomotor activity may not function properly in the absolute absence of leptin signaling. It has been documented that leptin regulates body tempera- ture and thermogenesis [38–40] and increases locomotor activity in a circadian-dependent manner [41,42]. Notably, leptin is implicated in the set point of weight [30]. Taken together, leptin may serve as a factor to support canagliflozin-induced circadian rises in body temperature and locomotor activity. In addition to the leptin-leptin receptor axis, the gut hormones [43] such as ghrelin [44] that regulate food intake, body weight, body temperature, locomotor activity and circadian rhythm could also be implicated in the body’s responses to canagliflozin. However, further studies are definitely needed to elucidate the mecha- nisms for circadian rises in body temperature and locomotor activity under canagliflozin treatment. In this study in mice treated with canagliflozin, weight was well controlled in DIO mice but rebounded in db/db mice, a model charac- terized by leptin unresponsiveness and severe insulin resistance [45]. This suggests that the degree of leptin resistance and insulin resistance in subjects could predict the weight outcome. Severe insulin and leptin resistances occur in people with morbid obesity. Monitoring body mass index (BMI), plasma insulin and leptin levels could help in selecting sustained responders to SGLT2 inhibitors for weight control.

  Weight loss by sodium-glucose co-transporter 2 inhibitor canagliflozin is followed by rebound in db/db mice but maintained in fat-fed mice via circadian rises in body temperature and locomotor activity · 2026 · DOI

• This review has several important limitations that directly affect interpretation. First, the review scope was focused and did not complete every database listed in the broader PROSPERO record, and the April 2026 update was a targeted PubMed/MEDLINE update rather than a complete repeat search of all databases. We therefore avoid claiming exhaustive evidence capture, and this work should be interpreted as a focused systematic review and explora- tory meta-analysis rather than an exhaustive mapping of all GLP- 1RA liver-related evidence. Second, all included studies were observational and remain vulnerable to residual confounding, confounding by indication, healthy-user bias, healthcare-engagement bias, and differential surveillance. GLP-1RA users may differ from comparator groups in obesity severity, access to specialist care, adherence, imaging frequency, liver surveillance, and preventive-care behaviors, and these factors may bias estimates in either direction. The E-value analysis indicates only modest robustness of the upper confidence limit to unmeasured confounding and should not be interpreted as evidence of causality. Third, exposure heterogeneity was substantial. Included studies may have captured different GLP-1RA agents (e.g., semaglutide, liraglutide, dulaglutide), doses, titration patterns, persistence, dis- continuation, switching, adherence, and combination therapy. Most studies did not consistently report agent-specific effects, cumulative exposure, or time-varying treatment status. The pooled estimate should therefore not be interpreted as applying equally to all GLP- 1RA agents, doses, or treatment patterns. Fourth, outcome definitions were not identical across studies. Endpoints labeled as advanced liver outcomes ranged from incident cirrhosis to hepatic decompensation, HCC, and composite serious liver events. Although we used a predefined outcome-family frame- work and an endpoint-restricted sensitivity analysis (HR 0.87, 95% CI 0.77–0.98), pooling across related but non-identical outcomes remains an important interpretive limitation. Fifth, the exploratory meta-analysis included only four studies. With k=4, the observed I²=0% should not be interpreted as absence of heterogeneity; rather, statistical heterogeneity was not detected within a small and narrowly defined stratum, and small-study effects could not be reliably assessed. Clinical heterogeneity in population phenotype, outcome definitions, follow-up duration, and data source remained relevant. Sixth, potential overlap among real-world data sources cannot be excluded. Some included studies used large claims, registry, Veterans Affairs, TriNetX, or multi-institutional datasets, and overlapping underlying patient populations are possible even when the final analytic samples and estimands differ. Consistency in the direction of estimates should therefore be interpreted as supportive directional agreement rather than as fully indepen- dent replication. These limitations justify the very-low GRADE certainty rating despite the consistency of the direction of effect, and they support interpreting the findings as hypothesis-supporting rather than practice-changing.

  Glucagon-like peptide-1 receptor agonists and advanced liver outcomes in type 2 diabetes: a systematic review and exploratory meta-analysis · 2026 · DOI

• The current literature regarding the use of GLP-1RAs in addiction therapy has several notable limitations that must be addressed. One notable limitation is the limited number of neuroimaging studies specifically involving SUD populations. As SUDs are chronic disorders, long-term neuroadaptive mechanisms may influence treatment response. Although GLP-1RAs initially reduce activity within reward centres, fMRI studies in patients treated with high-dose liraglutide have identified the emergence of counter-regulatory mechanisms. Following the induction of initial weight loss, the brain initiates a homeostatic response, paradoxically heightening activation in the right orbitofrontal cortex (OFC) upon exposure to salient cues. Increased OFC reactivity may contribute to the plateau effect observed in some patients, thereby limiting the long-term efficacy of GLP-1RAs in suppressing pathological cravings. This risk is further compounded by the rebound effect observed following drug discontinuation, suggesting that the management of SUD with this pharmacological class may require a chronic maintenance model rather than transient pharmacotherapy. This hypothesis is supported by secondary analyses in smokers, where participants maintaining abstinence showed a significant increase in systolic blood pressure after the discontinuation of dulaglutide at 52 weeks. Additionally, several systemic barriers may limit the real-world application of GLP-1RAs in addiction treatment. As demonstrated in a comprehensive meta-analysis of cohort studies, patients with psychiatric comorbidities – including SUDs – receive a significantly lower quality of metabolic care and have a lower likelihood of being prescribed novel antidiabetic therapies compared to the population without a psychiatric history. Finally, the studies included in this review were conducted almost exclusively in Western populations. Therefore, it is uncertain whether these findings can be fully generalized to other global populations, which may differ in genetic backgrounds and cultural contexts regarding addiction. Furthermore, there are significant global disparities in the real-world accessibility of GLP-1RAs. While these medications may be widely available in some regions, patients in other countries frequently face practical barriers, such as high costs, ongoing supply chain shortages, and limited availability in local pharmacies. P. Gwałt, A. Musioł, M. Nowakowski, M. Rakuś, J. Marzec, K.

  GLP-1 agonists in addiction therapy – review · 2026 · DOI

• provide and 5.6 Limitations Several limitations of this study should be acknowledged. First, as most included studies were placebo-controlled, direct comparative evidence between active interventions remains limited, such that the majority of comparisons rely on indirect evidence, which may influence the results. In this context, differences across studies in patient characteristics and background therapies may affect comparability, and the inconsistent reporting of such information across studies may further introduce uncertainty into the indirect comparisons. Second, the overlap of confidence intervals in some comparisons suggests that differences between interventions remain uncertain. Third, evidence for composite renal outcomes is largely derived from the FINEARTS-HF trial, and variations in the definition of composite renal endpoints across studies may affect the robustness of these comparisons. Finally, heterogeneity in patient characteristics, follow-up duration, and outcome definitions across the included studies may introduce clinical heterogeneity. The findings of this study are therefore intended to provide a comparative reference for different therapies in patients with HFpEF or HFmrEF and should be regarded as exploratory, with clinical decision-making best informed by integrating direct evidence from comparisons with placebo.

  Comparative clinical outcomes and safety of finerenone, SGLT2 inhibitors, RAS inhibitors and ARNI in heart failure with preserved or mildly reduced ejection fraction: a systematic review and network meta-analysis · 2026 · DOI

Most-cited papers in Diabetes Treatment and Management

• Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes · New England Journal of Medicine · 2016 · 6,466 citations
• Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes · New England Journal of Medicine · 2008 · 5,562 citations
• Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes · New England Journal of Medicine · 2007 · 3,839 citations
• Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes · New England Journal of Medicine · 2023 · 2,626 citations
• Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes · New England Journal of Medicine · 2015 · 2,198 citations
• Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes · New England Journal of Medicine · 2024 · 1,542 citations
• Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial · The Lancet · 2021 · 1,213 citations
• Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity · JAMA · 2021 · 1,204 citations
• Effect of Subcutaneous Semaglutide vs Placebo as an Adjunct to Intensive Behavioral Therapy on Body Weight in Adults With Overweight or Obesity · JAMA · 2021 · 990 citations
• Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity · New England Journal of Medicine · 2024 · 768 citations

Most recent work

• GLP-1 Receptor Agonists · New England Journal of Medicine · 2026
• Orforglipron for maintenance of body weight reduction: the double-blind, randomized phase 3b ATTAIN-MAINTAIN trial · Nature Medicine · 2026
• Cagrilintide–semaglutide (CagriSema) as an add-on to basal insulin in adults with type 2 diabetes (REIMAGINE 3): a randomised, double-blind, placebo-controlled, multicentre, phase 3 study · The Lancet · 2026
• Cagrilintide–semaglutide (CagriSema) versus semaglutide or cagrilintide in people with type 2 diabetes (REIMAGINE 2): a double-blind, randomised, controlled, phase 3 study · The Lancet Diabetes & Endocrinology · 2026
• Efficacy and safety of once-weekly cagrilintide–semaglutide (CagriSema) in adults with type 2 diabetes inadequately controlled on diet and exercise (REIMAGINE 1): a randomised, double-blind, placebo-controlled, phase 3a study · The Lancet Diabetes & Endocrinology · 2026
• A Case of GLP-1 Receptor Agonist-Induced Dysphoria and Aggression in a Patient With Underlying Major Depressive Disorder · Journal of Psychiatric Practice · 2026
• Association between time in range and incident early diabetic kidney disease in patients with type 2 diabetes: a retrospective cohort study · International Urology and Nephrology · 2026
• Efficacy and safety of retatrutide, a GIP, GLP-1, and glucagon receptor agonist, in people with type 2 diabetes and inadequate glycaemic control with diet and exercise (TRANSCEND-T2D-1): a double-blind, randomised, phase 3 trial · The Lancet · 2026
• The Development of a Framework to Classify Medication Deprescribing Among Patients with Type 2 Diabetes in Primary Care Practices · Journal of Clinical Medicine · 2026
• Sweet relief: exploring mechanisms and therapeutic approaches of sodium-glucose cotransporter-2 inhibitors in cardiovascular-kidney metabolic syndrome · Cardiovascular Diabetology · 2026

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