-
Clinical Therapeutics Aug 2023A fixed-dose combination (FDC) product combining dapagliflozin and metformin may increase medication adherence in patients with type 2 diabetes mellitus (T2DM) by... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
A fixed-dose combination (FDC) product combining dapagliflozin and metformin may increase medication adherence in patients with type 2 diabetes mellitus (T2DM) by minimizing pill burden associated with co-administration of individual component (IC) formulations and, consequently, improve cost-efficiency and compliance. This study evaluated the bioequivalence of the dapagliflozin/metformin FDC product versus IC administration in healthy volunteers from a Chinese population and assessed the safety profile of the FDC product. In addition, pharmacokinetic (PK) and safety comparisons of dapagliflozin and metformin across different regions were conducted to evaluate regional differences.
METHODS
This single-center, open-label, parallel-cohort, randomized, 2-period, crossover study enrolled Chinese adults (aged 18-55 years). Volunteers in cohort 1 received either a single FDC tablet of dapagliflozin/metformin extended release (XR) (5/500 mg) or IC tablets (dapagliflozin [5 mg] and metformin XR [500 mg]). Volunteers in cohort 2 received a higher dosage in a similar manner (dapagliflozin [10 mg] and metformin XR [1000 mg]). Volunteers in each cohort were subsequently crossed over to receive the alternate cohort treatment. Plasma concentrations of dapagliflozin and metformin were determined, and bioequivalence analyses were performed under standard fed conditions.
FINDINGS
Eighty healthy Chinese volunteers (89.9% male; mean age, 28.7 years) were randomized into cohort 1 (n = 40) and cohort 2 (n = 39; 1 volunteer withdrew before receiving study treatment). The mean plasma concentration-time profiles of the dapagliflozin and metformin FDC and IC formulations for both doses were found to be nearly superimposable. Dapagliflozin and metformin XR FDC were bioequivalent to the IC tablets, with 90% CIs for each pairwise comparison contained within the 80% to 125% bioequivalence limits. Both the FDC and IC formulations were well tolerated, with no serious adverse events/death. PK parameters for dapagliflozin in the Chinese volunteers were slightly to moderately higher than those from studies conducted in Brazil, Russia, and the United States, and the safety profile of the dapagliflozin/metformin FDC product was consistent with that of other studies. The difference in PK parameters among the 4 regions was not clinically meaningful.
IMPLICATIONS
The bioequivalence of the dapagliflozin/metformin FDC and IC formulations in healthy Chinese adults was established without any new safety concerns. Notably, the observed bioequivalence may be extrapolated to patients with T2DM as the PK parameters of dapagliflozin and metformin in healthy adults are similar to those reported in patients with T2DM.
CLINICALTRIALS
gov identifier: NCT04856007.
Topics: Adult; Female; Humans; Male; Area Under Curve; Cross-Over Studies; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Drug Combinations; East Asian People; Healthy Volunteers; Hypoglycemic Agents; Metformin; Tablets; Therapeutic Equivalency; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 37442656
DOI: 10.1016/j.clinthera.2023.06.012 -
Frontiers in Immunology 2023Cancer is a major global health concern, and immune checkpoint inhibitors (ICIs) offer a promising treatment option for cancer patients. However, the efficacy of ICIs...
INTRODUCTION
Cancer is a major global health concern, and immune checkpoint inhibitors (ICIs) offer a promising treatment option for cancer patients. However, the efficacy of ICIs can be influenced by various factors, including the use of concomitant medications.
METHODS
We searched databases (PubMed, Embase, Cochrane Library, Web of Science) for systematic reviews and meta-analyses for systematic reviews and meta-analyses on the impact of concomitant medications on ICIs efficacy, published from inception to January 1, 2023. We evaluated the methodological quality of the included meta-analyses, and re-synthesized data using a random-effects model and evidence stratification.
RESULTS
We included 23 publications, comprising 11 concomitant medications and 112 associations. Class II-IV evidence suggested that antibiotics have a negative impact on ICIs efficacy. However, ICIs efficacy against melanoma, hepatocellular carcinoma, and esophageal squamous cell carcinoma was not affected, this effect was related to the exposure window (class IV). Class III evidence suggested that proton pump inhibitors have a negative impact on ICIs efficacy; nevertheless, the efficacy against melanoma and renal cell carcinoma was not affected, and the effect was related to exposure before the initiation of ICIs therapy (class II). Although class II/III evidence suggested that steroids have a negative impact, this effect was not observed when used for non-cancer indications and immune-related adverse events (class IV). Class IV evidence suggested that opioids reduce ICIs efficacy, whereas statins and probiotics may improve ICIs efficacy. ICIs efficacy was not affected by histamine 2 receptor antagonists, aspirin, metformin, β-blockers, and nonsteroidal anti-inflammatory agents.
CONCLUSION
Current evidence suggests that the use of antibiotics, PPIs, steroids, and opioids has a negative impact on the efficacy of ICIs. However, this effect may vary depending on the type of tumor, the timing of exposure, and the intended application. Weak evidence suggests that statins and probiotics may enhance the efficacy of ICIs. Aspirin, metformin, β-blockers, and NSAIDs do not appear to affect the efficacy of ICIs. However, caution is advised in interpreting these results due to methodological limitations.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/PROSPERO,identifier, CRD42022328681.
Topics: Humans; Analgesics, Opioid; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Esophageal Neoplasms; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immune Checkpoint Inhibitors; Kidney Neoplasms; Liver Neoplasms; Melanoma; Metformin; Steroids; Systematic Reviews as Topic; Meta-Analysis as Topic
PubMed: 37841249
DOI: 10.3389/fimmu.2023.1218386 -
Diabetes Care Dec 2023To identify predictors of body weight (BW) reduction of ≥15% with tirzepatide treatment and to describe associated clinical parameters of participants with type 2...
OBJECTIVE
To identify predictors of body weight (BW) reduction of ≥15% with tirzepatide treatment and to describe associated clinical parameters of participants with type 2 diabetes (T2D) who achieved different categorical measures of BW reduction (<5%, ≥5 to <10%, ≥10 to <15%, and ≥15%) across four studies from the phase 3 SURPASS clinical trial program for T2D.
RESEARCH DESIGN AND METHODS
The multivariate model for predictor of a BW reduction of ≥15% included age, sex, race, BW, HbA1c, tirzepatide dose and baseline metformin use, fasting serum glucose, and non-HDL cholesterol. Baseline characteristics and change from baseline to week 40/42 for efficacy parameters were described and analyzed in treatment-adherent participants (≥75% doses administered and on treatment at week 40/42) receiving once weekly tirzepatide (5 mg, 10 mg, or 15 mg) (N = 3,188).
RESULTS
Factors significantly associated with achieving a BW reduction of ≥15% with tirzepatide were higher tirzepatide doses, female sex, White or Asian race, younger age, metformin background therapy, and lower HbA1c, fasting serum glucose, and non-HDL cholesterol at baseline. With higher categorical BW reduction, there were greater reductions in HbA1c, triglycerides, ALT, waist circumference, and blood pressure.
CONCLUSIONS
Baseline factors associated with a higher likelihood of achieving a BW reduction of ≥15% with tirzepatide were higher tirzepatide doses, female sex, White or Asian race, younger age, metformin background therapy, better glycemic status, and lower non-HDL cholesterol. With greater BW reduction, participants with T2D achieved larger improvements in glycemia and cardiometabolic risk parameters. These findings help inform which people with T2D are most likely to achieve greater BW reduction with improved cardiometabolic risk factors with tirzepatide.
Topics: Adult; Female; Humans; Blood Glucose; Body Weight; Cardiometabolic Risk Factors; Cholesterol; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Hypoglycemic Agents; Metformin; Overweight; Weight Loss
PubMed: 37824793
DOI: 10.2337/dc23-1135 -
Meta-analysis of factors associated with antidiabetic drug prescribing for type 2 diabetes mellitus.European Journal of Clinical... Aug 2023There is a lack of consensus on prescribing alternatives to initial metformin therapy and intensification therapy for type 2 diabetes mellitus (T2DM) management. This... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
There is a lack of consensus on prescribing alternatives to initial metformin therapy and intensification therapy for type 2 diabetes mellitus (T2DM) management. This review aimed to identify/quantify factors associated with prescribing of specific antidiabetic drug classes for T2DM.
METHODS
Five databases (Medline/PubMed, Embase, Scopus, Web of Science) were searched using the synonyms of each concept (patients with T2DM, antidiabetic drugs and factors influencing prescribing) in both free text and Medical Subject Heading (MeSH) forms. Quantitative observational studies evaluating factors associated with antidiabetic prescribing of metformin, sulfonylurea, thiazolidinedione, Dipeptidyl-peptidase 4 inhibitors (DPP4-I), sodium glucose transporter 2 inhibitors (SGLT2-I), Glucagon-Like peptide receptor agonist (GLP1-RA) and insulin in outpatient settings and published from January 2009 to January 2021 were included. Quality assessment was performed using a Newcastle-Ottawa scale. The validation was done for 20% of identified studies. The pooled estimate was measured using a three-level random-effect meta-analysis model based on odds ratio [95% confidence interval]. Age, sex, body mass index (BMI), glycaemic control (HbA1c) and kidney-related problems were quantified.
RESULTS
Of 2331 identified studies, 40 met the selection criteria. Of which, 36 and 31 studies included sex and age, respectively, while 20 studies examined baseline BMI, HbA1c and kidney-related problems. The majority of studies (77.5%, 31/40) were rated as good and despite that the overall heterogeneity for each studied factor was more than 75%, it is mostly related to within-study variance. Older age was significantly associated with higher sulfonylurea prescription (1.51 [1.29-1.76]), yet lower prescribing of metformin (0.70 [0.60-0.82]), SGLT2-I (0.57 [0.42-0.79]) and GLP1-RA (0.52 [0.40-0.69]); while higher baseline BMI showed opposite significant results (sulfonylurea: 0.76 [0.62-0.93], metformin: 1.22 [1.08-1.37], SGLT2-I: 1.88 [1.33-2.68], and GLP1-RA: 2.35 [1.54-3.59]). Both higher baseline HbA1c and having kidney-related problems were significantly associated with lower metformin prescription (0.74 [0.57-0.97], 0.39 [0.25-0.61]), but more insulin prescriptions (2.41 [1.87-3.10], 1.52 [1.10-2.10]). Also, DPP4-I prescriptions were higher for patients with kidney-related problems (1.37 [1.06-1.79]) yet lower among patients with higher HbA1c (0.82 [0.68-0.99]). Sex was significantly associated with GLP1-RA and thiazolidinedione prescribing (F:M; 1.38 [1.19-1.60] and 0.91 [0.84-0.98]).
CONCLUSION
Several factors were identified as potential determinants of antidiabetic drug prescribing. The magnitude and significance of each factor differed by antidiabetic class. Patient's age and baseline BMI had the most significant association with the choice of four out of the seven studied antidiabetic drugs followed by the baseline HbA1c and kidney-related problems which had an impact on three studied antidiabetic drugs, whereas sex had the least impact on prescribing decision as it was associated with GLP1-RA and thiazolidinedione only.
Topics: Humans; Hypoglycemic Agents; Diabetes Mellitus, Type 2; Sodium-Glucose Transporter 2; Glycated Hemoglobin; Dipeptidyl Peptidase 4; Metformin; Sulfonylurea Compounds; Dipeptidyl-Peptidase IV Inhibitors; Insulin; Thiazolidinediones
PubMed: 37002856
DOI: 10.1111/eci.13997 -
Advanced Science (Weinheim,... May 2024Complete remission of colorectal cancer (CRC) is still unachievable in the majority of patients by common fractionated radiotherapy, leaving risks of tumor metastasis...
Complete remission of colorectal cancer (CRC) is still unachievable in the majority of patients by common fractionated radiotherapy, leaving risks of tumor metastasis and recurrence. Herein, clinical CRC samples demonstrated a difference in the phosphorylation of translation initiation factor eIF2α (p-eIF2α) and the activating transcription factor 4 (ATF4), whose increased expression by initial X-ray irradiation led to the resistance to subsequent radiotherapy. The underlying mechanism is studied in radio-resistant CT26 cells, revealing that the incomplete mitochondrial outer membrane permeabilization (iMOMP) triggered by X-ray irradiation is key for the elevated expression of p-eIF2α and ATF4, and therefore radio-resistance. This finding guided to discover that metformin and 2-DG are synergistic in reversing radio resistance by inhibiting p-eIF2α and ATF4. Liposomes loaded with metformin and 2-DG (M/D-Lipo) are thus prepared for enhancing fractionated radiotherapy of CRC, which achieved satisfactory therapeutic efficacy in both local and metastatic CRC tumors by reversing radio-resistance and preventing T lymphocyte exhaustion.
Topics: Colorectal Neoplasms; Mice; Animals; Humans; Mitochondria; Liposomes; Metformin; Radiation Tolerance; Cell Line, Tumor; Disease Models, Animal; Activating Transcription Factor 4
PubMed: 38520732
DOI: 10.1002/advs.202400845 -
Endocrine Reviews Mar 2024The decline in cognitive function and the prevalence of neurodegenerative disorders are among the most serious threats to health in old age. The prevalence of dementia... (Review)
Review
The decline in cognitive function and the prevalence of neurodegenerative disorders are among the most serious threats to health in old age. The prevalence of dementia has reached 50 million people worldwide and has become a major public health problem. The causes of age-related cognitive impairment are multiple, complex, and difficult to determine. However, type 2 diabetes (T2D) is linked to an enhanced risk of cognitive impairment and dementia. Human studies have shown that patients with T2D exhibit dysbiosis of the gut microbiota. This dysbiosis may contribute to the development of insulin resistance and increased plasma lipopolysaccharide concentrations. Metformin medication mimics some of the benefits of calorie restriction and physical activity, such as greater insulin sensitivity and decreased cholesterol levels, and hence may also have a positive impact on aging in humans. According to recent human investigations, metformin might partially restore gut dysbiosis related to T2D. Likewise, some studies showed that metformin reduced the risk of dementia and improved cognition, although not all studies are concordant. Therefore, this review focused on those human studies describing the effects of metformin on the gut microbiome (specifically the changes in taxonomy, function, and circulating metabolomics), the changes in cognitive function, and their possible bidirectional implications.
Topics: Humans; Metformin; Diabetes Mellitus, Type 2; Gastrointestinal Microbiome; Dysbiosis; Insulin Resistance; Cognition; Dementia
PubMed: 37603460
DOI: 10.1210/endrev/bnad029 -
Scientific Reports Oct 2023Type 2 diabetes and thyroid function disorders are two common chronic endocrine disorders with the high prevalence in various populations. Metformin is well established... (Meta-Analysis)
Meta-Analysis
Type 2 diabetes and thyroid function disorders are two common chronic endocrine disorders with the high prevalence in various populations. Metformin is well established as the first-line drug therapy for managing diabetes mellitus. In this meta-analysis, we aimed to determine the effect of metformin on serum TSH and FT4 concentrations in patients with type 2 diabetes. We searched PubMed, Scopus, web of science, Cochrane library, and google scholar to collect information on the effect of metformin on serum TSH and FT4 levels. Demographic and clinical information and serum TSH and FT4 concentrations before and after metformin treatment were extracted. Studies on patients over 18 years of age were included. A total of 11 studies including 1147 patients were selected for the final analysis. In hypothyroid patients, the TSH level decreased significantly after treatment with metformin (Hedges's g:1.55, 95%CI 0.93-2.16, p-value < 0.001); FT4 level increased slightly after taking metformin, but the increase was not significant (Heddges's g: - 0.30, 95%CI - 0.90,0.31, p-value = 0.34). In euthyroid subjects, the slight decrease found in TSH and FT4 concentrations was not statistically significant. Metformin reduces TSH levels in hypothyroid patients; however, it has no effect on TSH levels in euthyroid patients. Metformin does not affect serum FT4 levels in euthyroid and hypothyroid patients.
Topics: Humans; Adolescent; Adult; Metformin; Diabetes Mellitus, Type 2; Thyroxine; Thyrotropin; Thyroid Hormones; Hypothyroidism; Triiodothyronine
PubMed: 37907510
DOI: 10.1038/s41598-023-43266-9 -
International Journal of Molecular... Aug 2023The tumor microenvironment (TME) plays a pivotal role in the fate of cancer cells, and tumor-infiltrating immune cells have emerged as key players in shaping this... (Review)
Review
The tumor microenvironment (TME) plays a pivotal role in the fate of cancer cells, and tumor-infiltrating immune cells have emerged as key players in shaping this complex milieu. Cancer is one of the leading causes of death in the world. The most common standard treatments for cancer are surgery, radiation therapy, and chemotherapeutic drugs. In the last decade, immunotherapy has had a potential effect on the treatment of cancer patients with poor prognoses. One of the immune therapeutic targeted approaches that shows anticancer efficacy is a type 2 diabetes medication, metformin. Beyond its glycemic control properties, studies have revealed intriguing immunomodulatory properties of metformin. Meanwhile, several studies focus on the impact of metformin on tumor-infiltrating immune cells in various tumor models. In several tumor models, metformin can modulate tumor-infiltrated effector immune cells, CD8, CD4 T cells, and natural killer (NK) cells, as well as suppressor immune cells, T regulatory cells, tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs). In this review, we discuss the role of metformin in modulating tumor-infiltrating immune cells in different preclinical models and clinical trials. Both preclinical and clinical studies suggest that metformin holds promise as adjunctive therapy in cancer treatment by modulating the immune response within the tumor microenvironment. Nonetheless, both the tumor type and the combined therapy have an impact on the specific targets of metformin in the TME. Further investigations are warranted to elucidate the precise mechanisms underlying the immunomodulatory effects of metformin and to optimize its clinical application in cancer patients.
Topics: Humans; Metformin; Diabetes Mellitus, Type 2; Immunotherapy; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes
PubMed: 37686159
DOI: 10.3390/ijms241713353 -
Otology & Neurotology : Official... Oct 2023Metformin treatment will protect mice from noise-induced hearing loss (NIHL).
HYPOTHESIS
Metformin treatment will protect mice from noise-induced hearing loss (NIHL).
BACKGROUND
We recently identified metformin as the top-ranking, Food and Drug Administration-approved drug to counter inner ear molecular changes induced by permanent threshold shift-inducing noise. This study is designed to functionally test metformin as a potential otoprotective drug against NIHL.
METHODS
Male and female B6CBAF1/J mice were obtained at 7 to 8 weeks of age. A cohort of the females underwent ovariectomy to simulate menopause and eliminate the effect of ovarian-derived estrogens. At 10 weeks of age, mice underwent a permanent threshold shift-inducing noise exposure (102.5 or 105 dB SPL, 8-16 kHz, 2 h). Auditory brainstem response (ABR) thresholds were obtained at baseline, 24 h after noise exposure, and 1 week after noise exposure. Mice were administered metformin (200 mg/kg/d) or a saline control in their drinking water after the baseline ABR and for the remainder of the study. After the 1-week ABR, mice were euthanized and cochlear tissue was analyzed.
RESULTS
Metformin treatment reduced the 1-week ABR threshold shift at 16 kHz ( p < 0.01; d = 1.20) and 24 kHz ( p < 0.01; d = 1.15) as well as outer hair cell loss in the 32-45.5 kHz range ( p < 0.0001; d = 2.37) in male mice. In contrast, metformin treatment did not prevent hearing loss or outer hair cell loss in the intact or ovariectomized female mice.
CONCLUSIONS
Metformin exhibits sex-dependent efficacy as a therapeutic for NIHL. These data compel continued investigation into metformin's protective effects and demonstrate the importance of evaluating the therapeutic efficacy of drugs in subjects of both sexes.
Topics: Female; Male; United States; Animals; Mice; Hearing Loss, Noise-Induced; Deafness; Cochlea; Ear, Inner; Metformin
PubMed: 37641232
DOI: 10.1097/MAO.0000000000004002 -
Biomedicine & Pharmacotherapy =... Dec 2023Metformin (Met) is the recommended first-line therapeutic drug for type 2 diabetes mellitus (T2DM) and exerts protective effects on β-cell damage. Ferroptosis, a new...
Metformin (Met) is the recommended first-line therapeutic drug for type 2 diabetes mellitus (T2DM) and exerts protective effects on β-cell damage. Ferroptosis, a new form of cell death, is associated with pancreatic islet injury in patients with T2DM. However, the protective effects of Met treatment against β-cell damage through ferroptosis modulation remain under-reported. This study investigated the in vivo effects of Met treatment on pancreatic β-cell ferroptosis using two different diabetic mouse models, namely, low-dose streptozotocin (STZ) and high-fat diet (HFD)-induced diabetic mice and db/db mice. Met treatment significantly restored insulin release, reduced cell mortality, and decreased the overproduction of lipid-related reactive oxygen species in the islets of both STZ/HFD-induced diabetic mice and db/db mice. Administration of the Ras-selective lethal 3 injection significantly attenuated the antiferroptosis effects of Met. Mechanistically, Met treatment alleviated β-cell ferroptosis in T2DM, which was associated with the regulation of the GPX4/ACSL4 axis in the islets. In conclusion, our findings highlight the significance of ferroptosis in T2DM β-cell damage and provide novel insights into the protective effects of Met against islet β cells.
Topics: Humans; Mice; Animals; Diabetes Mellitus, Type 2; Metformin; Diabetes Mellitus, Experimental; Ferroptosis; Insulin-Secreting Cells; Insulin
PubMed: 37924788
DOI: 10.1016/j.biopha.2023.115835