Diabetes Drug Research Articles

Metformin-associated lactic acidosis: A mini review of pathophysiology, diagnosis and management in critically ill patients

Metformin is a common diabetes drug that may reduce lactate clearance by inhibiting mitochondrial oxidative phosphorylation, leading to metformin-associated lactic acidosis (MALA). As diabetes mellitus is a common chronic metabolic condition found in critically ill patients, pre-existing metformin use can often be found in critically ill patients admitted to the intensive care unit or the high dependency unit. The aim of this narrative mini review is therefore to update clinicians about MALA, and to provide a practical approach to its diagnosis and treatment. MALA in critically ill patients may be suspected in a patient who has received metformin and who has a high anion gap metabolic acidosis, and confirmed when lactate exceeds 5 mmol/L. Risk factors include those that reduce renal elimination of metformin (renal impairment from any cause, histamine-2 receptor antagonists, ribociclib) and excessive alcohol consumption (as ethanol oxidation consumes nicotinamide adenine dinucleotides that are also required for lactate metabolism). Treatment of MALA involves immediate cessation of metformin, supportive management, treating other concurrent causes of lactic acidosis like sepsis, and treating any coexisting diabetic ketoacidosis. Severe MALA requires extracorporeal removal of metformin with either intermittent hemodialysis or continuous kidney replacement therapy. The optimal time to restart metformin has not been well-studied. It is nonetheless reasonable to first ensure that lactic acidosis has resolved, and then recheck the kidney function post-recovery from critical illness, ensuring that the estimated glomerular filtration rate is 30 mL/min/1.73 m2 or better before restarting metformin.

PT5 Impacts of National Drug Price Negotiation on Type 2 Diabetes Drugs Price, Volume, and Spending in China

PT5 Impacts of National Drug Price Negotiation on Type 2 Diabetes Drugs Price, Volume, and Spending in China

Drugs for diabetes first, then weight loss, now maybe AUD

Drugs for diabetes first, then weight loss, now maybe AUD

848-P: Comparing Generative AI to Human Responses for Personalized Diabetes Drug Selection

848-P: Comparing Generative AI to Human Responses for Personalized Diabetes Drug Selection

Development of Novel Tools for Dissection of Central Versus Peripheral Dopamine D2-Like Receptor Signaling in Dysglycemia.

Dopamine (DA) D2-like receptors in both the central nervous system (CNS) and the periphery are key modulators of metabolism. Moreover, disruption of D2-like receptor signaling is implicated in dysglycemia. Yet, the respective metabolic contributions of CNS versus peripheral D2-like receptors including D2 (D2R) and D3 (D3R) receptors remain poorly understood. To address this, we developed new pharmacological tools, D2-like receptor agonists with diminished and delayed blood-brain barrier capability, to selectively manipulate D2R/D3R signaling in the periphery. We designated bromocriptine methiodide (BrMeI), a quaternary methiodide analogue of D2R/D3R agonist and diabetes drug bromocriptine, as our lead compound based on preservation of D2R/D3R binding and functional efficacy. We then used BrMeI and unmodified bromocriptine to dissect relative contributions of CNS versus peripheral D2R/D3R signaling in treating dysglycemia. Systemic administration of bromocriptine, with unrestricted access to CNS and peripheral targets, significantly improved both insulin sensitivity and glucose tolerance in obese, dysglycemic mice in vivo. In contrast, metabolic improvements were attenuated when access to bromocriptine was restricted either to the CNS through intracerebroventricular administration or delayed access to the CNS via BrMeI. Our findings demonstrate that the coordinated actions of both CNS and peripheral D2-like receptors are required for correcting dysglycemia. Ultimately, the development of a first-generation of drugs designed to selectively target the periphery provides a blueprint for dissecting mechanisms of central versus peripheral DA signaling and paves the way for novel strategies to treat dysglycemia.

Effects of a multicomponent communication training to involve older people in decisions to DEPRESCRIBE cardiometabolic medication in primary care (CO-DEPRESCRIBE): protocol for a cluster randomized controlled trial with embedded process and economic evaluation

BackgroundDeprescribing of medication for cardiovascular risk factors and diabetes has been incorporated in clinical guidelines but proves to be difficult to implement in primary care. Training of healthcare providers is needed to enhance deprescribing in eligible patients. This study will examine the effects of a blended training program aimed at initiating and conducting constructive deprescribing consultations with patients.MethodsA cluster-randomized trial will be conducted in which local pharmacy-general practice teams in the Netherlands will be randomized to conducting clinical medication reviews with patients as usual (control) or after receiving the CO-DEPRESCRIBE training program (intervention). People of 75 years and older using specific cardiometabolic medication (diabetes drugs, antihypertensives, statins) and eligible for a medication review will be included. The CO-DEPRESCRIBE intervention is based on previous work and applies models for patient-centered communication and shared decision making. It consists of 5 training modules with supportive tools. The primary outcome is the percentage of patients with at least 1 cardiometabolic medication deintensified. Secondary outcomes include patient involvement in decision making, healthcare provider communication skills, health/medication-related outcomes, attitudes towards deprescribing, medication regimen complexity and health-related quality of life. Additional safety and cost parameters will be collected. It is estimated that 167 patients per study arm are needed in the final intention-to-treat analysis using a mixed effects model. Taking loss to follow-up into account, 40 teams are asked to recruit 10 patients each. A baseline and 6-months follow-up assessment, a process evaluation, and a cost-effectiveness analysis will be conducted.DiscussionThe hypothesis is that the training program will lead to more proactive and patient-centered deprescribing of cardiometabolic medication. By a comprehensive evaluation, an increase in knowledge needed for sustainable implementation of deprescribing in primary care is expected.Trial registrationThe study is registered at ClinicalTrials.gov (identifier: NCT05507177).

Diabetes and risk of hospitalisation due to infection in northeastern Thailand: Retrospective cohort study using population-based healthcare service data.

Population-based studies describing the association between diabetes and increased risk of infection have largely been based in high-income countries. There is limited information describing the burden of infectious disease attributable to diabetes in low and middle-income countries. This study aimed to describe the burden and risk of infectious disease hospitalisation in people with diabetes compared to those without diabetes in northeastern Thailand. In a retrospective cohort study using electronic health record data for 2012-2018 for 3.8 million people aged ≥20 years in northeastern Thailand, hospitalisation rates for any infectious diseases (ICD-10 codes A00-B99) were estimated and negative binomial regression used to estimate rate ratios (RR) for the association between diabetes and infectious disease hospitalisation adjusted for age, sex and area of residence. In this study, 164,177 people had a diagnosis of diabetes mellitus at any point over the study period. Infectious disease hospitalisation rates per 1000 person-years (95%CI) were 71.8 (70.9, 72.8), 27.7 (27.1, 28.3) and 7.5 (7.5, 7.5) for people with prevalent diabetes, incident diabetes and those without diabetes respectively. Diabetes was associated with a 4.6-fold higher risk of infectious disease hospitalisation (RR (95% CI) 4.59 (4.52, 4.66)). RRs for infectious disease hospitalisation were 3.38 (3.29, 3.47) for people with diabetes managed by lifestyle alone and 5.29 (5.20, 5.39) for people receiving prescriptions for diabetes drugs. In this Thai population, diabetes was associated with substantially increased risk of hospitalisation due to infectious diseases and people with diabetes who were on pharmacological treatment had a higher risk than those receiving lifestyle modification advice alone.

Hepatic function of glucagon-like peptide-1 and its based diabetes drugs.

Incretins are gut-produced peptide-hormones that potentiate insulin secretion, especially after food intake. The concept of incretin was formed more than 100 years ago,even before insulin was isolated and utilized in the treatment of subjects with type 1 diabetes. The first incretin, glucose-dependent insulinotropic polypeptide (GIP), was identified during later 1960's and early 1970's; while the second one, known as glucagon-like peptide-1 (GLP-1), was recognized during 1980's. Today, GLP-1-based therapeutic agents [also known as GLP-1 receptor (GLP-1R) agonists, GLP-1RAs] are among the first line drugs for type 2 diabetes. In addition to serving as incretin, extra-pancreatic functions of GLP-1RAs have been broadly recognized, including those in the liver, despite the absence of GLP-1R in hepatic tissue. The existence of insulin-independent or gut-pancreas-liver axis-independent hepatic function of GLP-1RAs explains whythose therapeutic agents are effective in subjects withinsulin resistance and their profound effect on lipid homeostasis. Following a brief review on the discovery of GLP-1, we reviewed literature on the exploration of hepatic function of GLP-1 and GLP-1RAs and discussed recent studies on the role of hepatic hormone fibroblast growth factor 21 (FGF21) in mediating function of GLP-1RAs in animal models. This was followed by presenting our perspective views.

Histoplasmosis in Non-HIV Infected Patients: Another Neglected Infection in French Guiana.

(1) Background: Only a few studies on histoplasmosis in immunocompetent patients have been reported in French Guiana. Therefore, we conducted a detailed clinical description of hospitalized patients suffering with histoplasmosis among non-HIV patients. (2) Methods: This is a single-center, retrospective study conducted at Cayenne Hospital Center between 2008 and 2022. (3) Results: Our cohort was composed of 31 (91%) adults (>18 years of age) and 3 (9%) children, with a sex ratio, M:F, of 1:2. The median age was higher among the women than among the men (70 versus 54 years). The collection of respiratory samples constituted the majority of the performed examinations (38%). Fever (>37 °C) was found in 56% of patients. Surprisingly, the histoplasmosis was disseminated in 82% of patients with an overall case fatality rate of 14.7%. However, immunosuppressive conditions were found in 52% (16/31) of the adult patients, including lymphoid hemopathies, diabetes and immunosuppressive drugs. Conclusions: This disease, though rare and usually considered a mostly benign disease in non-HIV patients, presented a relatively high mortality rate in our cohort. Thus, histoplasmosis should be suspected, screened and investigated as a first line of defense in highly endemic areas, even in immunocompetent and non-HIV patients, especially those with fever or chronic respiratory symptoms.

Drug Development Failure: How GLP-1 Development Was Abandoned in 1990.

Many factors determine whether and when a class of therapeutic agents will be successfully developed and brought to market, and historians of science, entrepreneurs, drug developers, and clinicians should be interested in accounts of both successes and failures. Successes induce many participants and observers to document them, whereas failed efforts are often lost to history, in part because involved parties are typically unmotivated to document their failures. The GLP-1 class of drugs for diabetes and obesity have emerged over the past decade as clinical and financial blockbusters, perhaps soon becoming the highest single source of revenue for the pharmaceutical industry (Berk 2023). In that context, it is instructive to tell the story of the first commercial effort to develop this class of drugs for metabolic disease, and how, despite remarkable early success, the work was abandoned in 1990. Told by a key participant in the effort, this story documents history that would otherwise be lost and suggests a number of lessons about drug development that remain relevant today.

Cross Sectional Study of Acute Toxicity with Anti Diabetic Drugs in Patients Presented to Poisoning Center During 2022

Cross Sectional Study of Acute Toxicity with Anti Diabetic Drugs in Patients Presented to Poisoning Center During 2022

Comparing the effectiveness and cost-effectiveness of sulfonylureas and newer diabetes drugs as second-line therapy for patients with type 2 diabetes

IntroductionWe aimed to compare the effectiveness and cost-effectiveness profiles of glucagon-like peptide-1 receptor agonist (GLP-1-RA), sodium-glucose cotransporter 2 inhibitor (SGLT2i), and dipeptidyl peptidase-4 inhibitor (DPP-4i) compared with sulfonylureas and glinides...

Analisis Efisiensi Waktu Siklus Untuk Meningkatkan Produktivitas Dengan Line Balancing Pada Proses Pengemasan Produksi Obat Diabetes di PT.OPQ

Operation Excelence is needed at manufacturing process in order to achive optimum cost. One of method is using line balancing. It work by increasing efficiency and remove bottole neck at workstation.. The purpose of this research is to increase productivity in the work path of diabetes drug production line, it means that all work stations can achieve optimum output, eliminate or reduce material accumulation by identifying line balances at work stations. By using the Line Balancing method. The method used is the Ranked Position Weight (RPW) heuristic method. As result productivity was increasing, with line efficiency from 58.36% to 80.25%, balance delay from 41.64% to 19.75%, a decrease in the amount of material accumulation between work stations on the diabetes drug production trajectory from 25 - 1175 doos / hour to 4 - 174 doos / hour, and eliminating the bottleneck on the trajectory of diabetes drug production.

Association between 23 drugs and inflammatory bowel disease: a two-sample Mendelian randomization study.

Inflammatory bowel disease (IBD) is a group of diseases characterized by chronic and recurrent inflammation of the gastrointestinal tract. The etiology of IBD remains multifaceted and poorly understood, resulting in limited treatment options that primarily target disease induction and remission maintenance. Thus, the exploration of novel therapeutic options for IBD among existing medications is advantageous. Mendelian randomization analysis (MR) serves as a valuable tool in investigating the relationship between drugs and diseases. In this study, MR analysis was employed to investigate the potential causal relationship between 23 approved drugs for the treatment of various diseases and IBD. We performed a two-sample MR analysis using publicly available genome-wide association study (GWAS) statistics. The inverse variance weighting (IVW) method was used as the main analysis method, supplemented by the remaining four methods (weighted median, MR Egger regression, simple and weighted models), and Meta-analysis was performed to expand the sample size to obtain a more reliable composite causal effect. Finally, Cochran's Q statistic and the MR-Egger test for directed pleiotropy were applied to determine whether significant heterogeneity or directed pleiotropy existed. In the main MR analysis (IVW), drugs with a negative causal association with the risk of IBD were immunosuppressant {OR (95% CI) = 0.7389 [0.6311-0.8651], p = 0.0046} and diabetes drugs {OR (95% CI) = 0.9266 [0.8876-0.9674], p = 0.0058}. A positive causal association with the risk of IBD was found for salicylic acid and derivatives {OR (95% CI) = 1.2737 [1.0778-1.5053], p = 0.0345}. Negative causal associations with UC risk were identified for immunosuppressants {OR (95% CI) = 0.6660 [0.5133-0.8640], p = 0.0169} and diabetes medications {OR (95% CI) = 0.9020 [0.8508-0.9551], p = 0.0046}; positive causal associations with UC risk were found for β-receptor blockers {OR (95% CI) = 1.1893 [1.0823-1.3070], p = 0.0046}. A negative causal association with the risk of CD was found for immunosuppressants {OR (95% CI) = 0.6957 [0.5803-0.8341], p = 0.0023}. There was no statistically significant association between the remaining 19 drugs and IBD and subtypes. This MR study provides evidence suggesting that immunosuppressants have a mitigating effect on the risk of IBD and demonstrate consistent efficacy in subtypes of ulcerative colitis (UC) and Crohn's disease (CD). Additionally, diabetes medications show potential in reducing the risk of IBD, particularly in cases of UC, while β-blockers may elevate the risk of UC. Conversely, salicylic acid and its derivatives may increase the risk of IBD, although this effect is not consistently observed in the subtypes of the disease. These findings offer new insights into the prevention and management of IBD.

Electroporation enhances cell death in 3D scaffold-based MDA-MB-231 cells treated with metformin

Triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer lacks estrogen, progesterone, and HER2 receptors and hence, is therapeutically challenging. Towards this, we studied an alternate therapy by repurposing metformin (FDA-approved type-2 diabetic drug with anticancer properties) in a 3D-scaffold culture, with electrical pulses. 3D cell culture was used to simulate the tumor microenvironment more closely and MDA-MB-231, human TNBC cells, treated with both 5 mM metformin (Met) and 8 electrical pulses at 2500 V/cm, 10 µs (EP1) and 800 V/cm, 100 µs (EP2) at 1 Hz were studied in 3D and 2D. They were characterized using cell viability, reactive oxygen species (ROS), glucose uptake, and lactate production assays at 24 h. Cell viability, as low as 20 % was obtained with EP1 + 5 mM Met. They exhibited 1.65-fold lower cell viability than 2D with EP1 + 5 mM Met. ROS levels indicated a 2-fold increase in oxidative stress for EP1 + 5 mM Met, while the glucose uptake was limited to only 9 %. No significant change in the lactate production indicated glycolytic arrest and a non-conducive environment for MDA-MB-231 growth. Our results indicate that 3D cell culture, with a more realistic tumor environment that enhances cell death using metformin and electrical pulses could be a promising approach for TNBC therapeutic intervention studies.

Structural characterization of squash polysaccharide and its effect on STZ-induced diabetes mellitus model in MIN6 cells

A novel natural water-soluble acidic polysaccharide (PWESP-3) was isolated from squash with a molecular mass of 140.519 kDa, which was composed of arabinose (Ara, 35.30 mol%), galactose (Gal, 61.20 mol%), glucose (Glc, 1.80 mol%), and Mannuronic acid (ManA, 1.70 mol%) and contained Araf-(1→, →3)-Araf-(1→, →5)-Araf-(1→, Glcp-(1→, Galp-(1→, →3,5)-Araf-(1→, →2)-Glcp-(1→, →2)-Manp-(1→, →3)-Glcp-(1→, →4)-Galp-(1→, →3)-Galp-(1→, →6)-Galp-(1→, →3,4)-Galp-(1→, →4,6)-Galp-(1→ residues in the backbone. Moreover, the structure of PWESP-3 was identified by NMR spectra. The branch chain was connected to the main chain by the O-3 and O-4 atom of Gal. In addition, the effect of PWESP-3 on STZ-induced type I diabetes mellitus model in MIN6 cells was investigated. The results showed that PWESP-3 can increase the viability and insulin secretion of MIN6 cells and reduce the oxidative stress caused by ROS and NO. Meanwhile, PWESP-3 can also reduce the content of ATP, Ca2+, mitochondrial membrane potential and Caspase-3 activity in MIN6 cells. Furthermore, treatment with PWESP-3 can prevent single or double stranded DNA breaking to form DNA fragments and improve DNA damage in MIN6 cells, thereby avoiding apoptosis. Therefore, the above data highlight that PWESP-3 can improve the function of insulin secretion in STZ-induced MIN6 cells in vitro and can be used as an alternative food supplement to diabetes drugs.

Endpoints for clinical trials in type 1 diabetes drug development

Endpoints for clinical trials in type 1 diabetes drug development

The cost of influence: How gifts to physicians shape prescriptions and drug costs

This paper investigates the influence of gifts – monetary and in-kind payments – from drug firms to US physicians on prescription behavior and drug costs. Using causal models and machine learning, we estimate physicians’ heterogeneous responses to payments on antidiabetic prescriptions. We find that payments lead to increased prescription of brand drugs, resulting in a cost rise of $23 per dollar value of transfer received. Paid physicians show higher responses when they treat higher proportions of patients receiving a government-funded low-income subsidy that lowers out-of-pocket drug costs. We estimate that introducing a national gift ban would reduce diabetes drug costs by 2%.

A Review: A Comparative Study of Branded and Generic Anti- Diabetic Drugs

This comprehensive review investigates the market landscape of antihypertensive medications, undertaking a detailed comparative analysis of branded and generic options. In the face of rising global prevalence of hypertension, the study aims to provide a holistic perspective on the efficacy, safety, and market dynamics shaping the use of branded and generic drugs in the management of these chronic conditions. Utilizing data derived from market trends, sales analytics, and consumer preferences, the review scrutinizes the market behaviors and forces influencing the adoption of branded and generic antihypertensive drugs. Factors such as cost-effectiveness, patient adherence, and healthcare provider preferences are explored to shed light on the complexities associated with medication selection in the context of chronic disease management. Through an in-depth examination of industry strategies, regulatory frameworks, and the role of healthcare policies, the review aims to uncover the interplay between market dynamics and clinical considerations. It seeks to inform healthcare professionals, policymakers, and industry stakeholders about the evolving landscape of choices in antihypertensive therapies, fostering a nuanced understanding that can guide optimal decision-making in patient care and resource allocation.

Diabetic Drug ontology mapping for individual Diabetic Person and predict Insulin Dosage on Daily Basis

Managing diabetes requires a personalized treatment plan based on the patient's health records and drug usage effectively. In this paper, we have proposed accurate prediction of insulin dosage for diabetic patients daily by using ontology mapping with deep learning recurrent neural network models such as long short-term memory (LSTM), Gated recurrent unit( GRU), and Bidirectional long short-term memory(BiLSTM). The patient's information is arranged in a structured format. The structured ontology data provides a meaningful connection between patients' personal information, physical activity, insulin intake, carbohydrate intake and glucose level. The structured data is beneficial to take decisions effectively to recommend the insulin dosage level daily to avoid a sudden decrease in sugar level. The proposed LSTM model outperforms well on insulin prediction compared to GRU and BiLSTM models. The proposed model is very effective for diabetic personal care and improves patient outcomes and quality of life.