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metformin + sitagliptin (Januvia ER / Janumet ER / Janumet XR)

✓ Approved

Merck & Co. · DPP4 · Small Molecule

What is metformin + sitagliptin?

metformin + sitagliptin is a small molecule developed by Merck & Co.. It is approved for therapeutic indications via oral (po).

Drug Profile

Brand NamesJanuvia ER, Janumet ER, Janumet XR
CompanyMerck & Co.
Drug ClassSmall Molecule
Molecular TargetDPP4
RouteOral (PO)
StatusApproved
Sources: ClinicalTrials.gov, Merck & Co.

Mechanism of Action

Molecular Targets

metformin + sitagliptin acts on 1 molecular target:

DPP4dipeptidyl peptidase 4 (CD26, DPPIV)
Want deeper analysis?Noah AI can explain complex mechanisms and compare to similar drugs.

Therapeutic Indications

metformin + sitagliptin is developed for 1 unique indication across 1 therapeutic area.

Therapeutic AreaConditionPhase
Metabolism and nutrition disordersType 2 diabetes mellitus✓ Approved

Related Research Articles

PubMedFrontiers in pharmacology2026-05-25

Gamma-glutamyl metformin inhibits renal cell carcinoma progression by activating AMPK signaling pathway.

Lv Zheng Z, Zhang Li Song LS, Aisha Awuti A, Wang Tian Hang TH et al.

Metformin is a promising candidate for the treatment of renal cell carcinoma (RCC), and elucidating its anti-tumor mechanisms is of great clinical significance. Overexpression of Gamma-glutamyl transpeptidase (GGT) in RCC tissues has been identified as a potential biomarker for renal cell tumors. Thus, there is an urgent need to develop a metformin prodrug that leverages the overexpression specificity of GGT in RCC tissues to achieve targeted release of metformin for RCC therapy. Herein, we innovatively report the development and the antitumor activity of gamma-Glutamyl Metformin (γE-Met), which exerts its effects by activating AMP-activated protein kinase (AMPK) signaling pathway. Compared with metformin, γE-Met specifically releases free metformin in renal cancer cells under the catalysis of GGT, thereby prolonging the retention time of metformin in tumor cells and more effectively inhibiting the growth and metastasis of renal cancer cells. Our experimental results demonstrate that GGT-responsive γE-Met can significantly enhance the therapeutic efficacy of metformin, rendering it a promising metformin prodrug with substantial clinical application prospects.

PMID 42181886
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PubMedTranslational cancer research2026-05-25

Metformin suppressed epithelial-mesenchymal transition, cisplatin resistance and metastatic potential of ovarian cancer via inhibiting TGF-β1/Smads.

Tang Hualong H, Han Zhengyu Z, Zhu Wanglong W, Lin Xinyue X et al.

Ovarian cancer (OC) is a lethal gynecologic malignancy, in which cisplatin (cDDP) chemoresistance and metastasis are major causes of therapeutic failure. Metformin, a first-line anti-diabetic agent, has exhibited anti-tumor potential in various cancers. However, its precise role in modulating chemosensitivity and metastatic behavior in OC, and the underlying mechanisms, remain to be fully elucidated. The human OC cell line SKOV3 and its cDDP-resistant variant SKOV3/cDDP were employed. Cell viability and the half-maximal inhibitory concentration (IC50) of cDDP were determined by cell counting kit-8 (CCK-8) assay. Clonogenic ability, migratory and invasive potentials were assessed using colony formation, wound healing, and transwell assays, respectively. The protein expression of epithelial-mesenchymal transition (EMT) markers (E-cadherin, N-cadherin), EMT-related transcription factors (Snail, Slug, Zeb-1), and components of transforming growth factor beta 1/Smads (TGF-β1/Smads) pathway were analyzed by western blot and enzyme-linked immunosorbent assay. Rescue experiments were conducted by co-treating cells with metformin and TGF-β1. Metformin dose-dependently inhibited cell viability and clonogenic survival in both SKOV3 and SKOV3/cDDP cells. It significantly enhanced chemosensitivity of OC cells to cDDP, as evidenced by a marked reduction of IC50 value. Metformin also potently suppressed cell migratory and invasive potentials. Mechanistic investigations revealed that metformin up-regulated epithelial marker E-cadherin and down-regulated mesenchymal marker N-cadherin. Concurrently, it suppressed the expression of pivotal EMT-transcription factors (Snail, Slug, Zeb-1), alongside the disruption of mesenchymal-like cell cytoskeleton. Mechanistically, metformin exerted multi-level suppression of TGF-β1/Smads axis, evidenced by inhibiting TGF-β1 secretion, downregulating the expression and phosphorylation of TGF-β receptor I/II, and reducing the protein level, phosphorylation and nuclear translocation of Smad2/3/4. Crucially, the suppressive effects of metformin on EMT, chemoresistance, and metastatic potential were impaired by exogenous TGF-β1. Our findings demonstrated that metformin counteracted EMT, cDDP resistance and metastatic potential in OC via TGF-β1/Smads pathway, supporting the therapeutic potential of repurposing metformin as a promising adjunctive treatment.

PMID 42180861
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PubMedClinical medicine insights. Endocrinology and diabetes2026-05-25

Metformin-Associated Gastrointestinal Intolerance: A Narrative Review of Mechanisms and Clinical Management.

Chen Shida S, Xu Bingqing B, Lu Ming M

Metformin-associated gastrointestinal (GI) intolerance is a frequent clinical problem that can limit treatment initiation, delay dose escalation, and reduce long-term adherence in patients with type 2 diabetes mellitus. Common symptoms include nausea, diarrhea, abdominal discomfort, and bloating, although symptom pattern and severity vary substantially between individuals. This narrative review summarizes current evidence on the determinants, mechanisms, and clinical evaluation of metformin-associated GI intolerance. In routine practice, assessment should begin with potentially modifiable exposure-related factors, including dose, single-dose burden, titration pace, formulation, administration with meals, kidney function, and concomitant medications. If symptoms persist or appear disproportionate to treatment exposure, clinicians should then consider broader host susceptibility, including baseline GI vulnerability, microbiome-related influences, altered bile acid handling, mucosal and neuroregulatory responses, comorbidity burden, and polypharmacy. This exposure-susceptibility framework provides a practical way to interpret metformin-related GI symptoms in routine care. It supports a stepwise clinical approach in which modifiable contributors are addressed first, broader context is reviewed when needed, and premature discontinuation is avoided whenever possible. Despite limitations in the current evidence base, available data support a structured and clinically useful approach to metformin intolerance.

PMID 42179978
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PubMedEuropean journal of pharmacology2026-05-25

Metformin-Associated Lactic Acidosis: Bridging Pharmacokinetic Determinants, Metabolic Pathways, and Clinical Outcomes.

Anwar Km Rukhsar KR, Khan Mohd Muazzam MM, Badruddeen, Nisha Ashmun A et al.

Metformin is the first-line oral anti-hyperglycemic agent for the treatment of type 2 diabetes mellitus due to its effectiveness, cost-efficiency, and acceptable safety profile. Although metformin possesses a favorable safety profile, a rare but serious adverse event known as metformin-associated lactic acidosis (MALA) may occur, particularly in patients with impaired renal clearance or predisposing comorbidities that favor drug retention. High anion-gap metabolic acidosis, increased concentrations of lactate (>5 mmol/L), and arterial pH of less than 7.35 are the hallmarks of MALA. MALA has a multifactorial pathophysiology, driven primarily by mitochondrial complex I inhibition, leading to an altered intracellular redox state and decreased hepatic lactate clearance. Crucially, MALA is fundamentally an accumulation disorder precipitated by an acute decline in kidney function rather than an intrinsic toxicity of metformin at therapeutic concentrations. Many precipitating factors, including acute kidney injury (AKI), chronic kidney disease (CKD), hepatic impairment, sepsis, hypoxia, and dehydration, substantially predispose individuals to this complication. Early identification of clinical signs, such as metabolic acidosis, tachypnea, hypotension, and altered mental status, is essential to a better patient outcome. Diagnostic assessment is based on arterial blood gas values, serum lactate, and renal function tests. Management aims at stopping metformin immediately, providing supportive care, and eliminating the medication through renal replacement therapy (RRT) in severe instances. Prevention measures focus on appropriate patient selection, renal monitoring, dose adjustment, and proactive temporary drug withdrawal during acute intercurrent illnesses ("sick-day rules"). MALA is not highly prevalent, and contemporary evidence demonstrates that mortality is highly context-dependent, with prompt extracorporeal interventions yielding robust survival rates.

PMID 42178010
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PubMedChemical biology & drug design2026-05-25

Synergistic Potential of Berberine and Metformin: Unlocking Enhanced Anti-Diabetic Efficacy.

Bhushan Ravi R, Rehman Md Tabish MT, AlAjmi Mohamed F MF, Alam Mohammad Rizwan MR et al.

Gestational diabetes mellitus (GDM) is a complex metabolic disorder characterized by glucose intolerance during pregnancy, posing significant health risks to both the mother and fetus. Current therapeutic options, including Metformin, show limitations, highlighting the need for novel, or adjunctive treatments to improve outcomes. This study aimed to identify novel and adjunctive phytocompounds with therapeutic potential against GDM using computational and experimental approaches. Text mining was employed to compile a phytochemical library, followed by molecular docking using AutoDock Vina against 17 GDM-associated targets. Drug-likeness, pharmacophore scoring, ADMET screening, molecular dynamics simulation, and in vitro studies were conducted to prioritize potent candidates. Berberine emerged as a promising anti-GDM compound based on docking scores, binding energies, and hydrogen bond interactions with GDM receptors. It achieved the highest pharmacophore selectivity score of 19.71 and met all drug-likeness criteria. Berberine demonstrated favorable renal excretion, high intestinal absorption (HIA) with 100% CaCO2 permeability, and acceptable blood-brain barrier (BBB) permeability. MD simulation revealed the high stability of Berberine. In vitro assays confirmed high glucose uptake (40.88 ± 0.51) and increased insulin secretion (129.78 ± 1.26) in the PANC-1 cell line in the Berberine-treated group as compared to the Metformin, revealing its superior anti-diabetic activity. Further, the group treated in combination of Berberine and Metformin showed the highest glucose uptake (50.63 ± 0.47) and insulin secretion (173.66 ± 1.78). The combined computational and experimental findings suggest that Berberine, a non-toxic phytochemical, holds potential as an effective therapeutic candidate for GDM. Its robust binding, high selectivity, enhanced activity and stability make it a promising lead compound for further development. Furthermore, the anti-diabetic effect is augmented when Berberine and Metformin are used together, indicating the synergistic potential of Berberine and Metformin in treating hyperglycaemic conditions like GDM.

PMID 42178826
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PubMedNaunyn-Schmiedeberg's archives of pharmacology2026-05-25

Metformin-phytochemical combination therapy in metabolic dysfunction-associated steatotic liver disease: mechanistic insights and therapeutic potential.

Amri Jamal J, Karimpour Amin A, Meshkani Reza R

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multifactorial metabolic disorder characterized by excessive hepatic lipid accumulation, insulin resistance, oxidative stress, and chronic inflammation. Its pathogenesis spans interconnected metabolic, inflammatory, and fibrotic pathways, limiting the efficacy of single-target therapeutic approaches. Metformin (MET), a first-line antidiabetic agent, improves hepatic lipid metabolism primarily through AMPK activation and enhanced fatty acid oxidation; however, its therapeutic impact on inflammatory and redox pathways remains limited, and its use is frequently associated with gastrointestinal adverse effects. In this context, phytochemicals-diverse plant-derived bioactive compounds with pleiotropic metabolic and antioxidant properties-have emerged as promising adjuncts to MET to achieve broader pathway coverage. For the first time, this comprehensive review evaluates preclinical in vivo evidence on metformin-phytochemical combination therapy in in vivo models of MASLD, with a specific focus on its mechanistic and therapeutic advantages over monotherapy. A comprehensive literature search was conducted using PubMed, Scopus, Web of Science, and Google Scholar. Only original preclinical in vivo studies evaluating the combination of metformin with an isolated phytochemical in animal models of MASLD were included. Data were extracted on compound identity, dosing regimens, experimental models, and metabolic, inflammatory, and signaling outcomes. Across eligible studies, metformin-phytochemical combinations consistently demonstrated superior efficacy compared with monotherapy in reducing hepatic steatosis, oxidative stress, and inflammatory mediators. Combinations involving berberine, chlorogenic acid, genistein, malvidin, morin, silymarin, and p-coumaric acid were associated with improved energy metabolism and fatty acid β-oxidation, alongside suppression of lipogenesis and fibrotic signaling. Additional benefits reported across studies included modulation of adipose tissue metabolism, enhancement of autophagy-related pathways, and favorable effects on gut-liver axis signaling, depending on the phytochemical class and experimental context. Overall, the preclinical in vivo evidence indicates that metformin-phytochemical cotherapy provides a multipathway modulatory framework integrating metabolic, anti-inflammatory, and antifibrotic effects. These findings support the translational potential of this combination strategy; however, well-designed clinical studies are required to assess pharmacokinetic compatibility, optimize dosing ratios, and determine its relevance in human MASLD.

PMID 42183858
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