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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

PubMedDrugs2026-10-15

Metformin Lowers Fasting Hyperglycemia by Increasing Glucose Clearance in People with Moderately Controlled Type 2 Diabetes.

Kahl Sabine S, LaMoia Traci E TE, Jonuscheit Marc M, Heilmann Geronimo G et al.

Metformin is the most frequently prescribed antidiabetic drug worldwide; however, the mechanism by which it lowers blood glucose remains incompletely understood. The objective of this study was to examine the effects of metformin on whole-body and specifically on hepatic glucose and energy metabolism in type 2 diabetes. This open repeated-measures pilot study examined this question using Positional Isotopomer NMR Tracer Analysis (PINTA) to assess rates of endogenous glucose production (VEGP), hepatic pyruvate carboxylase flux (VPC), and citrate synthase (VCS) flux in 16 men with moderately controlled type 2 diabetes (T2D; BMI 30 ± 3 kg/m2, HbA1c 8.4 ± 1.4%) undergoing two examination days with (M+; 1 g twice daily) and without metformin (M-) treatment. Hepatic ATP and glycogen concentrations were quantified by 31P/13C magnetic resonance spectroscopy. M+ reduced fasting glycemia by 18%, which could mostly be attributed to a 24% increase in rates of whole-body glucose clearance. Surprisingly, these changes were accompanied by a 58% increase in VPC and a 34% increase in VCS, due to a 26% increase in plasma glucagon concentrations. The increase in VPC was offset by reductions in the contributions of glycerol conversion to glucose resulting in no change in VEGP. Metformin decreased hepatic ATP content by 16% and increased plasma GDF-15 concentrations, but did not alter rates of net hepatic glycogenolysis. Metformin treatment in male individuals of European ancestry with moderately controlled T2D decreases blood glucose concentrations by increasing rates of whole-body glucose clearance. Metformin further inhibits glycerol-derived gluconeogenesis, which is consistent with complex IV, not complex I, being the molecular target of metformin action. ClinicalTrials.gov ( https://clinicaltrials.gov/ ): NCT04088851.

PMID 42875657
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PubMedProstate cancer and prostatic diseases2026-10-15

Metabolic and oncological effects of metformin added to ADT in prostate cancer: systematic review and meta-analysis including STAMPEDE.

Fakhri Farah F, Alkhairi Zeid Z, Sarhan Talal T, Imran Gozeel G et al.

Androgen-deprivation therapy (ADT) is the cornerstone of advanced prostate cancer treatment but induces a metabolic syndrome phenotype that heightens cardiovascular risk. Metformin, an insulin-sensitising biguanide with emerging anticancer properties, is a rational ADT adjunct. Following STAMPEDE's 2025 publication, we aimed to quantify metformin's metabolic benefit and characterise its oncological signal by disease volume. This PRISMA 2020-guided review (PROSPERO CRD420261384520) searched five databases through 12 May 2026. Eligible RCTs compared metformin plus ADT versus ADT alone in prostate cancer. Primary metabolic outcomes were body weight, waist circumference, HbA1c, fasting glucose, and LDL cholesterol. Secondary (exploratory) oncological outcomes were overall survival (OS) and castration-resistant prostate cancer-free survival (CRPC-FS), derived predominantly from a single trial. Random-effects models with Hartung-Knapp correction were used; GRADE assessed certainty. Six trials enroling 2415 participants (78% from STAMPEDE) were included: STAMPEDE (n = 1 874), PRIME (n = 166), PREMIUM (n = 83), MANSMED (n = 124), Mahalingam (n = 36), and Alagizy (n = 132). Disease status ranged from metastatic (STAMPEDE, Alagizy, majority MANSMED) to locally advanced or biochemically recurrent (PREMIUM, PRIME, Mahalingam); all excluded diabetes mellitus except MANSMED ( ~ 20%). At 12 months, metformin significantly reduced waist circumference (MD -1.12 cm; p = 0.014), HbA1c (MD -0.070%; p = 0.029), and fasting glucose (MD -0.100 mmol/L; p = 0.031). Body weight and LDL cholesterol reductions were non-significant (MD -1.60 kg; p = 0.090 and MD -0.130 mmol/L; p = 0.343, respectively). In STAMPEDE, metformin did not improve OS (HR 0.91; p = 0.15); the high-volume subgroup showed a survival benefit (HR 0.79; p = 0.007; volume interaction p = 0.12, non-significant). In MANSMED, CRPC-free survival was significantly prolonged (HR 0.50; p = 0.01), though this signal derives from a single small, open-label trial. Metformin added to ADT produces moderate-certainty reductions in waist circumference and HbA1c. Oncological benefit in unselected patients was not demonstrated; the hypothesis-generating STAMPEDE high-volume subgroup signal, derived from a single trial, warrants evaluation in a prospective, volume-stratified RCT.

PMID 42875601
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PubMedDiabetologia2026-10-15

Efficacy and safety of HRS-7535, a novel oral small-molecule glucagon-like peptide-1 receptor agonist, in participants with type 2 diabetes mellitus inadequately controlled by metformin and sodium-glucose co-transporter 2 inhibitors: a multicentre, randomised, double-blind, placebo-controlled, parallel-group Phase II trial.

Xu Mingtong M, Song Weihong W, Lv Fang F, Fu Yanqin Y et al.

This study aimed to evaluate the efficacy and safety of HRS-7535, an oral small-molecule glucagon-like peptide-1 receptor agonist (GLP-1RA), in Chinese participants with type 2 diabetes mellitus inadequately managed by metformin and sodium-glucose co-transporter 2 inhibitors (SGLT2i). This multicentre, randomised, double-blind, placebo-controlled, Phase II study included participants aged 18-75 years with type 2 diabetes, HbA1c 58-97 mmol/mol (7.5-11.0%) and BMI 20.0-35.0 kg/m2 and on stable-dose metformin and sodium-glucose co-transporter 2 (SGLT2) inhibitor therapy for ≥8 weeks prior to screening. Participants were assigned in a 1:1:1 ratio to receive HRS-7535 30 mg, HRS-7535 60 mg or visually matching placebo tablets once daily using a stratified block randomisation method, with treatment assignments concealed until study completion. The primary endpoint was the change in HbA1c from baseline to week 16. Secondary efficacy outcomes included the proportions of participants achieving HbA1c targets of <53 mmol/mol (7.0%) and ≤48 mmol/mol (6.5%), and changes from baseline in fasting body weight to week 16. A total of 155 participants with a mean baseline HbA1c of 69 mmol/mol (8.5%) were randomly assigned to HRS-7535 30 mg (n=51), HRS-7535 60 mg (n=53) or placebo (n=51). At week 16, the least‑squares mean differences in HbA1c from baseline for the HRS-7535 30 mg, HRS-7535 60 mg and placebo groups were -16 mmol/mol (95% CI -19, -14) (-1.5% [95% CI -1.7, -1.3]), -20 mmol/mol (95% CI -22, -17) (-1.8% [95% CI -2.0, -1.6]) and -4 mmol/mol (95% CI -7, -2) (-0.4% [95% CI -0.6, -0.2]), respectively (p<0.0001 for both HRS-7535 doses vs placebo). The proportions of participants achieving HbA1c <53 mmol/mol (7.0%) were 51.0% in the HRS‑7535 30 mg group, 66.0% in the HRS‑7535 60 mg group, and 9.8% in the placebo group; the corresponding proportions for HbA1c ≤48 mmol/mol (6.5%) were 35.3%, 37.7% and 3.9%, respectively. Body weight loss was -2.4% in the HRS-7535 60 mg group vs -0.7% in the placebo group. Most treatment-emergent adverse events (TEAEs) were mild to moderate, and gastrointestinal adverse events were the most common. No severe hypoglycaemia was reported. The only TEAE that led to treatment discontinuation occurred in the placebo group. Treatment with HRS-7535 resulted in significant improvements in glycaemic management in participants with type 2 diabetes, and the drug exhibited a favourable safety profile. To address a significant clinical data void, this research focused on the addition of HRS‑7535 to the background regimen of metformin and SGLT2i for glycaemic management in participants with type 2 diabetes. Trial registration ClinicalTrials.gov NCT06393348. Funding This study was funded by Jiangsu Hengrui Pharmaceuticals.

PMID 42875600
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PubMedAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2026-10-15

Mitochondrial Quality Control in Degenerative Musculoskeletal Diseases: Signaling Networks and Therapeutic Landscapes.

Gao Haiyang H, Cheng Zhangrong Z, Chen Xianglong X, Wu Wenbo W et al.

Degenerative musculoskeletal disorders, including osteoarthritis (OA), intervertebral disc degeneration (IVDD), and osteoporosis (OP), are increasingly viewed as disorders of mitochondrial quality control (MQC) rather than passive mechanical wear. The MQC network, comprising mitochondrial dynamics, mitophagy-biogenesis coupling, and inter-organelle communication, organizes the aging-inflammation-metabolism axis. Its collapse releases mtDNA fragments that act as damage-associated molecular patterns (DAMPs) activating innate immunity via cGAS-STING, and metabolic intermediates that remodel the epigenome through histone lactylation, potentially locking acute stress into a "metabolic memory", although the mtDNA-methylation component remains hypothesis-level. Multi-omics and cell-free mtDNA liquid biopsy underpin a proposed subtyping into bioenergetic failure, immuno-inflammatory activation, and senescent cell accumulation, still a within-OA hypothesis pending independent and cross-disease validation. Therapy is shifting from symptom management toward organelle medicine, including cardiolipin stabilizers, PROTAC-mediated protein degradation, mitochondrial base editing, and engineered mitochondrial transplantation. Metformin has randomized trial evidence in knee OA pending confirmation, NAD+ precursors are in early clinical testing, and SS-31 holds accelerated approval only for Barth syndrome; other strategies remain preclinical. Delivery barriers and disease heterogeneity require precision stratification, biomimetic models, and AI-driven decision-making. This review delineates the shared molecular logic of the three diseases and proposes a prototype subtyping-to-treatment roadmap pending validation.

PMID 42875857
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PubMedEuropean journal of pharmacology2026-10-14

Effects of Sitagliptin Combined with GTS-21 on Improving Glycemic Control and Diabetic Nephropathy by Anti-Apoptosis in Leprdb/db Mice.

Tian Weikun W, Wang Wenzhao W, Tang Shuo S, Su Liye L et al.

Activation of α7 nicotinic acetylcholine receptor (α7nAChR) by GTS-21 engages the cholinergic anti-inflammatory pathway (CAP). This study investigated adding GTS-21 to sitagliptin, a DPP-4 inhibitor used to increase endogenous GLP-1, confers additional benefit over sitagliptin monotherapy on glycemic control and diabetic nephropathy (DN) in Leprdb/db mice, focusing on anti-apoptotic mechanisms. Leptin receptor-deficient (Leprdb/db, 8-week-old) mice were randomized into control (saline), sitagliptin (20 mg/kg), or combination (sitagliptin 20 mg/kg + GTS-21 4 mg/kg) groups for 4 weeks. Oral glucose tolerance test (OGTT), serum creatinine (Scr), blood urea nitrogen (BUN), and IL-6 were measured. Renal histology was evaluated by H&E staining. Apoptosis was assessed by TUNEL staining and cleaved caspase-3 expression. In vitro, HK-2 cells exposed to high glucose (30 mM) were treated with liraglutide (100 nM) and/or GTS-21 (20 nM) to examine apoptosis. Combination therapy significantly improved glucose tolerance at weeks 1 and 4 (AUC reduction, P=0.0366 and P=0.0435 vs control), whereas sitagliptin alone showed no effect. Both treatments reduced Scr (P=0.0002 for combination; P=0.0101 for monotherapy), but only combination therapy attenuated renal histological injury (P=0.002) and decreased IL-6 in serum and kidney (P=0.0433 and P=0.0041). Renal apoptosis was also suppressed, with reduced TUNEL-positive cells (P=0.0043) and cleaved caspase-3 (P=0.0122). In HK-2 cells, high glucose increased cleaved caspase-3 (P=0.0324), which was attenuated by liraglutide plus GTS-21 (P=0.0320). Add-on GTS-21 to sitagliptin improved glycemic control and attenuated diabetic nephropathy beyond sitagliptin monotherapy in Leprdb/db mice, with reduced renal inflammation and suppressed apoptosis. These findings suggest that combined activation of GLP-1 receptor and α7nAChR signaling warrants further investigation as a renoprotective strategy in diabetic nephropathy.

PMID 42874910
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PubMedFrontiers in pharmacology2026-10-14

The role of sitagliptin in modifying metabolic, hormonal and clinical parameters in polycystic ovarian syndrome patients: a randomized controlled trial.

Altyar Ahmed E AE, Dessouky Dina Y DY, Mohamed Salem Sara Abdallah SA, Salem Heba F HF et al.

Polycystic ovarian syndrome (PCOS) is a disease that is not limited to reproductive symptoms; it is also significantly linked to metabolic problems such as obesity, insulin resistance, and dyslipidemia. Sitagliptin, a DPP-4 inhibitor, may play a significant role in metabolic, inflammatory, and hormonal abnormalities in PCOS patients. This randomized clinical trial aimed to investigate the impact of sitagliptin on metabolic disturbances, hormonal abnormalities, and clinical outcomes in patients with PCOS. The study is registered on Clinicaltrials.gov with an ID of (NCT05972928). This randomized controlled trial was conducted at Beni-Suef University Hospital, involving 80 women diagnosed with PCOS based on the Rotterdam criteria. Participants were equally allocated into either a sitagliptin group, receiving 100 mg daily, or a control group, with a follow-up period of 3 months. Changes in body weight served as the sole primary outcome of the study. Meanwhile, changes in BMI, HOMA-IR, lipid profile, and hormonal indicators, along with clinical improvements in infertility, hirsutism, acne, and menstrual irregularity, were evaluated as secondary outcomes. Regarding the primary outcome, a highly significant reduction in body weight was observed within the sitagliptin group (p < 0.001). Similarly, secondary outcomes including BMI, HOMA-IR, DHEA, HbA1c, total and free testosterone, and LH levels, all demonstrated significant decreases (p < 0.05). Clinical secondary outcomes also showed potential improvements, with menstrual regularity increasing significantly (p = 0.006), alongside visible reductions in hirsutism (p = 0.006) and exploratory reduction in the infertility rates (p = 0.031), that needs further confirmation. Furthermore, the intervention was well-tolerated, as recorded side effects were both rare and mild in intensity. Sitagliptin has potential impact on the hormonal, metabolic and clinical aspects of PCOS, and an exploratory effect on reproductive function. This makes it a potentially promising option for managing this complex condition. https://clinicaltrials.gov/study/NCT05972928, identifier NCT05972928.

PMID 42871447
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