A 45-year-old woman with long-standing hypertension and premature menopause presented with progressive bilateral pitting leg edema. Initial evaluation showed albuminuria, microscopic hematuria and pyuria, severe mixed dyslipidemia, and prediabetes. Despite optimization of blood pressure and cardiometabolic therapy, edema progressed to the thighs, and urinary protein excretion increased. Renal ultrasonography showed increased parenchymal echogenicity, with scarring of the lower half of the left kidney. Subsequent evaluation revealed hypoalbuminemia and nephrotic-range proteinuria of 8.64 g/day. Autoimmune and viral hepatitis screening was negative, and a right renal biopsy confirmed minimal change disease (MCD)/podocytopathy. Treatment with prednisolone 60 mg/day and diuretic therapy led to rapid clinical remission, with complete resolution of edema and reduction of 24-hour urinary protein to 190 mg/day by May 2025 and 55 mg/day by July 2025. The course was complicated by steroid-induced Cushingoid features and worsening glycemia, requiring temporary addition of glimepiride. By March 2026, the patient remained clinically well with excellent lipid and glycemic control. This case highlights the importance of early nephrology referral and kidney biopsy in adults with progressive albuminuria and edema, even when cardiometabolic comorbidities such as hypertension, prediabetes, and severe dyslipidemia coexist.

Background/Objectives: Diabetes mellitus type 2 (T2DM) is often associated with hypertension, necessitating treatment with combinations of medications that address both glycemic control and blood pressure. Whether commonly co-prescribed antihypertensives modify the glycemic efficacy of a sulfonylurea remains insufficiently characterized in controlled preclinical models. Methods: One hundred adult male Wistar rats were allocated to ten parallel groups (n = 10): healthy and diabetic untreated controls; glimepiride, bisoprolol or amlodipine monotherapy (in healthy and diabetic animals); and the diabetic combinations glimepiride+bisoprolol and glimepiride+amlodipine. T2DM was induced with a high-fat diet plus low-dose streptozotocin (35 mg/kg, i.p.) and confirmed by fasting blood glucose ≥ 200 mg/dL. Glycated hemoglobin (HbA1c) was measured weekly for 11 weeks. Non-parametric inference (Kruskal-Wallis, Dunn's with Bonferroni correction, Mann-Whitney U, Wilcoxon signed-rank) was complemented by Random Forest regression and PCA/K-means clustering. Results: Week-11 HbA1c differed markedly across groups (Kruskal-Wallis H = 94.3, p < 0.001). Glimepiride + bisoprolol achieved near-normal control (4.37% ± 0.15), statistically indistinguishable from healthy groups (p ≥ 0.33), and was the only diabetic regimen with a declining trajectory (-0.66 percentage points; Wilcoxon p = 0.004). Adding either antihypertensive to glimepiride did not worsen glycemic control. Amlodipine monotherapy did not attenuate hyperglycemia (8.47% ± 0.20), approaching that of untreated diabetic controls (9.31% ± 0.18), consistent with the absence of intrinsic glucose-lowering activity. All agents showed pronounced disease-state dependence (healthy-diabetic divergence 2.33-3.13 points). Random Forest prediction was accurate (R[2] = 0.985), and unsupervised clustering separated effective from ineffective regimens, corroborating the statistical findings. Conclusions: In this model, bisoprolol co-administration enhanced and amlodipine co-administration preserved glimepiride-mediated glycemic control. Glimepiride+bisoprolol emerged as the most effective regimen, supporting cardioselective β-blockade as a metabolically favorable antihypertensive partner for sulfonylurea therapy and warranting clinical confirmation. More broadly, these results provide a preclinical, evidence-based rationale for selecting metabolically favorable antihypertensives in patients with coexisting T2DM and hypertension, with the potential to improve glycemic outcomes and reduce the risk of adverse drug-disease interactions during combination therapy.

The prevalence of type 2 diabetes mellitus (T2DM) is rising in Nepal, making the glimepiride-metformin fixed-dose combination (FDC) a commonly used treatment due to its complementary mechanisms of action, effectiveness, and cost-efficiency. This expert opinion aims to identify diverse patient populations most likely to benefit from this combination and guide evidence-based, individualized diabetes management in Nepal. An expert advisory panel consisting of nine clinicians from Nepal convened across two meetings (held in February and March 2025) to share their perspectives on the glimepiride and metformin FDC. Their insights were based on real-world practice patterns, treatment challenges, and local prescribing dynamics to develop clinically relevant recommendations. The expert panel discussions, supported by clinical data, demonstrated that the glimepiride-metformin FDC is a widely used, effective, and affordable option for managing T2DM. It is particularly beneficial for patients requiring rapid glycemic control, those recently diagnosed, and individuals in resource-limited settings. The FDC was found to provide significant glycated hemoglobin (HbA1c) reductions, tolerability at low doses, and improved treatment adherence due to its simplified regimen. While challenges such as the risk of hypoglycemia, weight gain, and limited formulation availability persist, the combination remains a preferred choice in settings where cost and availability are critical concerns. The panel emphasized the importance of individualized dose titration and regular follow-up to optimize outcomes. The glimepiride and metformin FDC continue to be a clinically effective, affordable, and widely applicable treatment option for T2DM in Nepal, particularly suited to meet the needs of diverse patient populations, specifically in resource-limited settings.

Sulfonylureas (SUs) have been used in the treatment of type 2 diabetes since the 1950s, yet growing evidence shows that many members of this class also exert biologically relevant off-target effects that may be exploited in oncology and other therapeutic contexts. This review provides a structured overview of the literature from 1956 to 2025, integrating preclinical studies, clinical and epidemiological data, pharmacovigilance signals, and patent activity. To facilitate comparison across compounds, the available evidence is organized into drug-specific mechanistic maps rather than treated as a uniform class effect. Across the literature, SUs have been linked to modulation of KATP channels, ABC transporters involved in multidrug resistance, gap-junction communication, redox balance, mitochondrial function, inflammatory signaling, and DNA damage-related pathways. However, these activities differ markedly between individual agents. Glibenclamide emerges primarily as a chemosensitizing and transporter-modulating compound, gliclazide as a drug with antioxidant, anti-inflammatory, and DNA-protective properties, glimepiride as a promising synergistic agent with additional AKR1C3-inhibitory activity, tolbutamide as a modulator of gap-junction signaling and mitochondrial stability, and chlorpropamide derivatives as ALDH-targeting chemosensitizers. At the same time, the review highlights major translational constraints, including weak baseline cytotoxicity for most SUs, frequent exposure mismatches between experimental and clinical settings, heterogeneous safety profiles, photoreactivity, and limited commercial incentives for development, while also outlining practical strategies to address these limitations. Overall, SUs should not be viewed as a single repurposing candidate, but as a chemically related set of drugs that require indication-specific and compound-specific selection for future oncology applications.

In patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin and sulfonylurea, evidence directly comparing glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors as add-on therapy is limited; therefore, we compared dulaglutide and empagliflozin in this setting. This 12-week, single-center, randomized, open-label, parallel-group pilot study included a 24-week observational extension. Patients with HbA1c≥7.0% receiving stable doses of metformin and glimepiride were randomized to dulaglutide 0.75 mg/week or empagliflozin 10 mg/day. Doses were uptitrated at week 4 if tolerated and maintained for 12 weeks, with follow-up until week 36. The primary endpoint was the change in HbA1c at week 12. Secondary endpoints included changes in glycemic and obesity-related parameters. Exploratory analyses were performed to assess plasma metabolite profiles using liquid chromatography-mass spectrometry, and gut microbiota using 16S rRNA gene sequencing. Twenty-four patients completed the 12-week study (dulaglutide, n=13; empagliflozin, n=11). Both treatments significantly reduced HbA1c at week 12, with no significant between-group difference. Empagliflozin significantly reduced HOMA-IR, whereas dulaglutide significantly increased HOMA-β. At week 12, empagliflozin was associated with greater reductions in body weight and body fat compared with dulaglutide, whereas these differences were attenuated at week 36. Exploratory analyses suggested potential, modest treatment-related differences in plasma metabolite profiles and microbiome-metabolic associations, without marked alterations in overall microbial diversity. As add-on therapy to metformin and sulfonylurea, both dulaglutide and empagliflozin improved glycemic control, with no significant between-group difference observed in this exploratory pilot study. Empagliflozin induced earlier weight loss, whereas dulaglutide showed more gradual weight reduction over time, accompanied by exploratory findings suggesting possible differences in plasma and microbiome-related metabolic signatures.

Diabetes mellitus (DM) is one of the world's most common non-communicable diseases. DM is a group of metabolic disorders in which blood glucose levels increase due to reduced insulin production or action, resulting in hyperglycemia. Various anti-diabetic medications, including insulin, metformin, glimepiride, glipizide, and thiazolidinedione, are used to control hyperglycemia in diabetic patients. These anti-diabetic medications have been shown to affect the gingiva, bone, fibroblast cells, pulpal tissues, dental stem cells, saliva, teeth, and oral microbiome. Metformin (a biguanide), insulin, and oral sulfonylureas (glipizide and glimepiride) have regenerative and host-modulating effects. Metformin and insulin can promote the growth of osteoblasts (bone-forming cells) and periodontal ligament fibroblasts and enhance the differentiation of mesenchymal stem cells to repair the lost periodontal tissues. Metformin is used in both systemic and local forms as a gel or scaffolds along with periodontal therapy (scaling and root planing) and surgical procedures to promote repair of periodontal tissues, alveolar bone defects, furcation defects, and osseointegration of dental implants. Although the effect of metformin on oral tissues is well established, the role of other anti-diabetic drugs on the oral and periodontal tissues is not comprehensively discussed. Thus, this review aims to discuss the positive and negative effects of various anti-diabetic medications on the oral cavity.

Diabetes mellitus (DM) represents a major and growing global health challenge. Among antidiabetic medications, sulfonylureas and meglitinides remain clinically relevant insulin secretagogues for the management of type 2 DM (T2DM). However, many drugs in these classes belong to Biopharmaceutics Classification System (BCS) Class II, which are characterized by low aqueous solubility and high membrane permeability. These physicochemical constraints result in slow dissolution, variable oral absorption, suboptimal bioavailability and inadequate glycemic control. Converting drugs into their amorphous form can enhance solubility and dissolution; however, amorphous drugs are inherently unstable and prone to recrystallization, limiting their practical use. Amorphous solid dispersion (ASD), which incorporates poorly soluble antidiabetic drugs into a polymeric matrix, offers a promising strategy to overcome these limitations. The polymeric carrier stabilizes the drug in its high-energy amorphous state, improving solubility, dissolution, and ultimately, bioavailability. In ASD systems, drug molecules are dispersed within the polymer matrix at the molecular level, forming extremely fine dispersion domains that may be even smaller than conventional nanoparticle systems, thereby enhancing apparent solubility and dissolution. This review provides a comprehensive overview of ASD applications in antidiabetic therapy, discussing the principles of ASD, commonly used polymeric carriers, fabrication methods, and recent in vitro and in vivo findings. Studies consistently show that ASD formulations of antidiabetic drugs such as glimepiride, repaglinide, gliclazide, gliquidone, and glyburide enhance insulin secretion and contribute to more effective glycemic control, showing the potential of ASD in improving the therapeutic performance of poorly soluble antidiabetic agents. By enhancing solubility, stability, and bioavailability, ASD technology holds significant promise for developing more potent and effective antidiabetic therapies, ultimately supporting better patient care and addressing the global burden of diabetes mellitus.

For prehospital providers, there are several causes for the patient with altered mental status or being unconscious to include the mnemonic AEIOU TIPS for Alcohol and acidosis, Endocrine, Epilepsy, Electrolytes, Encephalopathy, Infection, Opiates, Overdose, Uremia, Underdose, Trauma (head injury and blood loss), Insulin, Poisoning, Psychosis, Stroke, Seizure, and Syncope. Hypoglycemia, or low blood glucose level, is one of the most common causes of altered mental status for patients with and without diabetes. Estimates are that 1 to 2 percent of prehospital encounters and 7% of refusals are for hypoglycemia.[1][2] Diabetes mellitus often referred to as "diabetes" or "sugar" by laypeople is the most common endocrine disorder where the body does not either produce enough insulin or has a resistance to the circulating insulin, and is characterized by high blood sugar levels over prolonged periods. The three main types of diabetes are type I (previously referred to as insulin-dependent diabetes mellitus (IDDM) or juvenile-onset), type II (formerly referred to as non-insulin-dependent diabetes mellitus (NIDDM) or adult-onset) and gestational.[3] Insulin is an anabolic hormone produced in the beta cells of the pancreatic islets. The primary function of insulin is to regulate the metabolism of carbohydrates, protein, and fat through the absorption of glucose sugar from the blood into the liver, fat, and skeletal muscle cells. These small glucose molecules are then converted into larger molecules and stored for later usage.  Type 1 Diabetes Mellitus (T1DM) [4] This condition is commonly referred to as insulin-dependent diabetes or previously as childhood/adolescent-onset diabetes. It accounts for approximately 5% to 10% of all cases of diabetes. It can be related to the autoimmune destruction of insulin-producing beta cells in the islets of the pancreas from different causes, including genetic susceptivity, viral illness, toxins or alcohol-induced pancreatitis, or some dietary factors.  The age group affected is usually children and adolescents, but adults can develop T1DM.  As the name "insulin-dependent" implies, it requires the administration of subcutaneous insulin via intermittent injections or pump infusion. Type 2 Diabetes Mellitus (T2DM) [4] [5] This variant is commonly referred to as non-insulin diabetes or previously as adult-onset diabetes.  It accounts for approximately 90% of all cases of diabetes.  It is related to the desensitization of insulin/insulin resistance (response to insulin becomes diminished) in various tissues. Initially, there is an increase in insulin production, but this decreases over time. T2DM most commonly presents in persons older than 45 years, but it increasingly occurs in children, adolescents, and younger adults due to rising levels of obesity, physical inactivity, and energy-dense diets. Gestational Diabetes Mellitus (GDM) Hyperglycemia first detected during pregnancy is classified as gestational diabetes mellitus (GDM). Although it can occur anytime during pregnancy, GDM generally affects pregnant women during the second and third trimesters. According to the American Diabetes Association (ADA), GDM complicates 7% of all pregnancies. Women with GDM and their offspring have an increased risk of developing type 2 diabetes mellitus in the future.  Types of Therapies [6] Therapy for hyperglycemia is dependant upon how much insulin the body is producing, or how well that insulin that is produced is working.  The majority of patients with T2DM will be on an oral type of medication.  Patients with T1DM will be on a combination of either long-acting insulin with short-acting as a sliding scale, intermediate-acting insulin with short-acting insulin as a sliding scale, combination premixed insulin, or be on an insulin pump. Hypoglycemia  One of the public health concerns for diabetes mellitus and unintended complications for the reduction in blood glucose levels is hypoglycemia.[1][7][8] Hypoglycemia, by definition, is a plasma glucose concentration below 70 mg/dL, with most patients not having signs or symptoms until the plasma glucose concentrations drop below 55 mg/dL.[9]  Low plasma glucose concentration that requires assistance from another individual qualifies as severe hypoglycemia, and by context, all EMS encounters fall into this category.[1][10]  There has been an increase in morbidity (poor quality of life, series falls or car accidents, dementia, and hospitalization) and mortality related to severe hypoglycemia.[1]  Based upon 2015 data from NEMSIS, prehospital activation for diabetes-related cases accounts for about 2.3% of all activations, with the primary EMS encounter being hypoglycemia.[11] Patients experiencing severe hypoglycemia or other diabetes-related concerns typically reach out for help by calling 911 who may dispatch a fire department or EMS agency depending on the jurisdiction. Care is then provided by the first on scene provider who may be an emergency medical technician (EMT) intermediate or advanced emergency medical technician (IEMT or AEMT) or paramedic. Treat and release versus transport of patients with hypoglycemia by EMS providers depends on the clinical guidelines or protocols from either the state or regional level by medical directors. It is important to understand that patients with severe hypoglycemia are at a higher risk of having complications related to the hypoglycemic state.  Villani et al. indicated that approximately 50% of patients with severe hypoglycemia required transport to the hospital, and of that group, 41.3% were admitted to the hospital.[12][13][14]  One of the first studies on the topic of treating and releasing hypoglycemic patients in the field was "Development and Evaluation of Criteria Allowing Paramedics to Treat and Release Patients Presenting with Hypoglycemia: A Retrospective Study" published in Prehospital and Disaster Medicine in 1991.   Their study design proposed five criteria that would allow for appropriate release that would not require additional treatment from prehospital providers to include: 1. The patient has a history of type 1 or type 2 diabetes. 2. Blood sugar prior to treatment is below 4.4 mmol/L or 80 mg/dL. 3. Blood sugar after treatment is equal to or greater than 4.4 mmol/L or 80 mg/dL. 4. The patient has a normal mental status within 10 minutes of treatment.  5. The patient does not have any other complicating factors that required ED evaluation to such alcohol, chest pain, dyspnea, injuries related to falls, and/or renal dialysis. A 2016 study by Rostykus et al. reviewed prehospital clinical guidelines for hypoglycemia in 185 EMS agencies in the United States.  It revealed that less than half allowed for non-transport of patients with hypoglycemia after the low plasma glucose level was corrected.[15] A study by Moffet et al. looked at hypoglycemic patients treated by EMS in Alameda County from 2013 to 2015 and found that the transport rate was 13.5%. The demographic trends for those non-transported patients were adult patients < 60 years of age, males, finger stick blood glucose levels > 60 mg/dl, and EMS arrival times between 1800 and 0600.[1]

Type 2 diabetes mellitus (T2DM) is a progressive metabolic disorder that often requires treatment intensification over time. In complex patients with multiple comorbidities and cognitive impairment, therapeutic decisions must balance glycemic control with safety and feasibility. We present a 59-year-old male with long-standing T2DM, marked body weight fluctuations, and emerging neurocognitive decline. Baseline glycated hemoglobin (HbA1c) was 9.4%, with progressive improvement to 7.1% under quadruple non-insulin therapy consisting of metformin, sitagliptin, glimepiride, and semaglutide. Insulin therapy was avoided due to cognitive impairment and a high risk of dosing errors. Sustained glycemic control was achieved without severe hypoglycemia. This case highlights the importance of individualized, multidisciplinary management in advanced T2DM and demonstrates that non-insulin strategies may be a viable and safe alternative in selected high-risk patients.

This study investigated the rheological behavior of nanosuspensions prepared by a wet media milling technique using various model drugs and hydroxypropyl methylcellulose (HPMC) as a dispersing agent. These nanosuspensions were classified into two groups based on their apparent fluidity: the first included fenofibrate, glimepiride, and phenytoin nanosuspensions, which maintained high fluidity and exhibited Newtonian-like behavior (yield stress <0.09 Pa in the Herschel-Bulkley model); and the second comprised griseofulvin, ketoconazole, and nevirapine nanosuspensions, which showed markedly reduced fluidity and non-Newtonian characteristics (yield stress >1.7 Pa in the Herschel-Bulkley model). Quantitative analysis of HPMC adsorption showed a tendency for drugs with high HPMC adsorption (11.2-12.4 wt%) to demonstrate high fluidity, while drugs with low HPMC adsorption (8.14-8.86 wt%) generally showed reduced fluidity. Notably, fenofibrate remained flowable despite relatively low HPMC adsorption, underscoring that the adsorption amount alone is not sufficient to explain fluidity and that adsorption mode and coverage may also contribute. Rheological analysis under heating conditions revealed that all nanosuspensions exhibited a temperature-dependent rheological transition at temperatures lower than those typically reported for pure HPMC solutions. A reduction in fluidity was observed when this transition occurred below room temperature. Together, these results indicate that drug-dependent fluidity loss in wet-milled nanosuspensions is associated with differences in interfacial HPMC association and temperature-dependent structuring, involving both hydrophobic nanoparticle network formation and HPMC molecular assembly.