Taken together, the available data suggest that future MASH treatment will likely move toward a more individualized and mechanism-based approach. Patient phenotype, pres- ence of type 2 diabetes, degr

The gap

Consensus across the literature

Supporting evidence — 3 representative gaps

• Controversial effects of metformin on human physiology and pathophysiology (2026) · doi

  7.1 Defining core therapeutic value amid evolving clinical paradigms Metformin remains the foundational first-line pharmacotherapy for type 2 diabetes mellitus (T2DM), valued for its robust, mechanism-based efficacy in suppressing hepatic gluconeogenesis, enhancing peripheral insulin sensitivity, and maintaining weight neutrality—with a near-zero risk of hypoglycemia (Corcoran and Jacobs, 2023). Long-term use is associated with sustained glycemic control, improved endothelial function, and reduced cardiovascular mortality—effects attributable not only to glucose lowering but also and to AMPK-mediated vasoprotective actions (de Jager et al., 2014). The continued use of this drug as a first-line agent is also based on its established safety record and low cost. However, the clinical use of metformin treatment. At warrants consideration beyond present, the major limitations are gastrointestinal intolerance, which affects a considerable proportion of patients, and contraindication in individuals with severe renal impairment, anti-inflammatory, initiation of antioxidant, effects owing to the rare but serious risk of lactic acidosis (Flory and Lipska, 2019; Corcoran and Jacobs, 2023). Importantly, while anticancer are biologically plausible, high-quality randomized trials consistently demonstrate no survival benefit oncologic when metformin regimens—confirming its role as a metabolic adjunct, not a primary antineoplastic agent (Coyle et al., 2016). Likewise, guidelines explicitly advise against metformin monotherapy for weight management, given its modest and highly variable effect size (Liu et al., 2023). standard added to is 7.2 Evidence-driven therapeutic reassessment: Continuation, substitution, or combination? Therefore, reassessment of the role of metformin involves making informed decisions regarding continuation, replacement, or combination therapy. For patients who cannot tolerate the drug or need additional glycemic control with weight reduction, newer agents such as semaglutide (a GLP-1 receptor agonist) serve as an effective alternative or additional option (Ji et al., 2021; Prasad et al., targets both glucose-dependent 2023). Tirzepatide, which insulinotropic polypeptide (GIP) and GLP-1 receptors, has demonstrated even greater effectiveness in reducing glucose levels and preserving β-cell function (Gojani et al., 2025). Cardiovascular indications further refine selection: following myocardial infarction, agents with proven cardiorenal benefits—such as SGLT2 inhibitors or GLP-1 RAs—take precedence over metformin for secondary prevention (Karwi et al., 2019). The VERIFY study further showed that early combination therapy, such as metformin with imiglitazone, provides more sustained glycemic control than metformin alone, supporting an alternative option to the stepwise escalation approach (Matthews et al., 2019; Nishiyama et al., 2023). These findings support a shift from a uniform treatment paradigm toward more flexible and evidence-based therapeutic strategies. 7.3 Rational combination therapy: beyond glycemic synergy Combination regimens are increasingly designed not merely to amplify glucose-lowering potency, but to exploit mechanistic complementarity across disease pathways. The rationale is not merely based on improved glucose control; it also encompasses integrating complementary action mechanisms. Although fixed- dose combinations with sulfonylureas are extensively employed, they must be closely monitored owing to the increased risk of hypoglycemia (Bailey, 2017; Flory and Lipska, 2019). Recent studies have expanded this concept into other disease areas, including cancer. For it has been reported that combining metformin with tangerine considerably inhibits tumor cell energy metabolism, thus enhancing the anticancer effects (Mdkhana et al., 2021). An alternative approach is to limit energy supply to the tumor cells by pairing metformin-mediated inhibition of glycolysis with glucose oxidase, thus creating a metabolism-based approach to cancer therapy (Meng et al., 2022). These observations role of metformin in combination regimens that extend beyond glucose regulation. the evolving instance, indicate

  Keywords: metformin glucose combination based glycemic control therapy therapeutic weight risk effects beyond regimens role alternative
• SGLT2 inhibitors and incretin-based therapies for metabolic dysfunction-associated steatohepatitis: a systematic review (2026) · doi

  Taken together, the available data suggest that future MASH treatment will likely move toward a more individualized and mechanism-based approach. Patient phenotype, pres- ence of type 2 diabetes, degree of obesity, cardiovascular and renal risk, baseline fibrosis stage, and likelihood of sus- tained weight loss may influence therapeutic selection. In this context, incretin-based therapies may be particularly relevant for patients in whom obesity and inflammatory dis- ease activity predominate, whereas SGLT2 inhibitors may be especially attractive in individuals with type 2 diabetes, cardiovascular disease, heart failure, or chronic kidney dis- ease risk. Combination strategies may also become increasingly relevant, as MASH results from overlapping metabolic, Page 11 of 13 166 inflammatory, and fibrogenic pathways. Future trials should clarify whether combining systemic metabolic therapies, weight-loss-promoting agents, and liver-directed therapies can produce additive or synergistic effects on steatohepatitis resolution, fibrosis regression, and long-term clinical out- comes. Longer follow-up, paired histological assessment, standardized noninvasive biomarkers, and clinically mean- ingful endpoints will be essential to define the definitive position of these pharmacological classes in the manage- ment of MASH.

  Keywords: mash therapies future based type diabetes obesity cardiovascular risk fibrosis weight loss relevant inflammatory ease
• Glycemic management in critically ill and surgical patients with type 2 diabetes: safety signals and medication-related problems in a hospital-based study (2026) · doi

  Limitations include lack of baseline patient char- acteristics prior to insulin therapy initiation, ab- sence of long-term follow-up, and variability in in- sulin protocols across centers. Additionally, the use of RBS as the primary glyce- mic outcome does not capture glycemic variability Romanian medical JouRnal – Volume 73, no. 1, 202694 or time-in-range, which are increasingly recognized as important metrics. Overall, these results highlight an ongoing chal- lenge in balancing the benefits of strict glucose con- trol against the risks of hypoglycemia in surgical and critically ill patients with T2DM. While some evidence favors moderate glycemic targets (<140 mg/dL) to prevent complications such as wound in- fections and myocardial events, increased rates of hypoglycemia with intensive regimens support the need for individualized targets based on patient risk [19–25]. The study also demonstrates the value of standardized approaches such as the PCNE classifi- cation and interdisciplinary, pharmacist-led inter- ventions in optimizing drug therapy, particularly in complex tertiary care settings where clinician time is limited. Future large-scale, multicenter research could help define optimal glycemic targets for dif- ferent patient groups and reinforce the role of clini- cal pharmacists in supporting best practices in gly- cemic management in Indian hospitals. This study did not include formal measures of illness severity such as APACHE II or SOFA scores, nor surrogate clinical indicators of disease severity. As a result, differences in baseline severity between critically ill and surgical patients, as well as between those receiving intensive insulin therapy and liberal insulin therapy, could not be accounted for. This may have influenced glycemic outcomes and the oc- currence of drug-related problems, thus limiting a definitive causal interpretation of between-group comparisons. coNcLuSIoN The present study emphasizes the importance of ensuring adequate glycemic control in critically ill and surgical patients in India. Given its observational nature, the findings highlight patterns and associa- tions in glycemic management rather than establish- ing causal relationships. From this analysis, it can be observed that timely insulin titration and monitoring were associated with improved glycemic control in critically ill patients with T2DM without a dispropor- tionate increase in hypoglycemia; however, these ob- servations do not confirm the effectiveness or safety of specific insulin strategies. Furthermore, the findings underline the need for individualized insulin approaches, which may be as- sociated with better glycemic outcomes in these set- tings, warranting further investigation rather than immediate practice-changing conclusions, while con- tributing to the development of the concept of i

  Keywords: glycemic insulin therapy critically patients patient hypoglycemia surgical targets severity include baseline variability time highlight