Antidiabetic Research Articles

A SYSTEMATIC REVIEW ON ADHERENCE TO ORAL ANTIDIABETIC DRUGS IN PATIENTS WITH TYPE 2 DIABETES MELLITUS

Type 2 diabetes mellitus (DM) is a chronic metabolic disorder in which prevalence has been increasing steadily all over the world and one of the main reason for this is poor adherence to oral anti-diabetic drugs, which can lead to therapy failure and increase risk of complications. So we planned this systematic review with an aim to get an adherence estimation to oral anti-diabetic drugs in type 2 diabetes mellitus patients for which a literature search was performed in pubmed, Google Scholar, scopus, and central databases to find observational studies on therapeutic adherence in users of oral anti-diabetic drugs. Our analyses showed that adherence rate to oral anti-diabetic drugs therapy ranged from 23 to 90%. This review confirms that many patients for whom diabetes medication was prescribed were poor compliers with treatment of oral anti-diabetic drugs.

Analytical Techniques for the Determination of Metformin and its Combinations with Oral Antidiabetic Agents in Pharmaceutical Dosage Forms: Combinations with Sulphonylurea Antidiabetic Drugs

The sulfonylurea class of antidiabetic agents includes a range of closely related compounds, allowing for similar analytical approaches when combined with metformin. This article provides a comprehensive review of published methods for determining sulfonylureas and metformin combinations in bulk and pharmaceutical preparations. Various techniques such as high-performance liquid chromatography (HPLC), thin-layer chromatography (TLC), capillary zone electrophoresis (CZE), and spectrophotometric methods have been widely used for these compounds, yielding reliable results. Additionally, the article discusses the number of citations for each method and its specific purpose, offering critical commentary. Keywords: metformin; sulphonylureas; combination; determination; analytical techniques

Relationship between diabetes-related clinical characteristics and preserved ratio impaired spirometry (PRISm): findings from NHANES 2007–2012

IntroductionTo analyse the relationship between diabetes, its severity (including blood glucose levels, disease duration, antidiabetic drug use and number of comorbidities) and preserved ratio impaired spirometry (PRISm) using data from...

Highly prevalent geriatric medications and their effect on β-amyloid fibril formation.

The unprecedented increase in the older population and ever-increasing incidence of dementia are leading to a "silver tsunami" in upcoming decades. To combat multimorbidity and maintain daily activities, elderly people face a high prevalence of polypharmacy. However, how these medications affect dementia-related pathology, such as Alzheimer's β-amyloid (Aβ) fibrils formation, remains unknown. In the present study, we aimed to analyze the medication profiles of Alzheimer's disease (AD; n = 124), mild cognitive impairment (MCI; n = 114), and non-demented (ND; n = 228) patients to identify highly prevalent drugs and to determine the effects of those drugs on Aβ fibrils formation. Study subjects (≥ 65 years) were recruited from an academic geriatric practice that heavily focuses on memory disorders. The disease state was defined based on the score of multiple cognitive assessments. Individual medications for each subject were listed and categorized into 10 major drug classes. Statistical analysis was performed to determine the frequency of individual and collective drug classes, which are expressed as percentages of the respective cohorts. 10 µM monomeric β-amyloid (Aβ) 42 and fibrillar Aβ (fAβ) were incubated for 6-48h in the presence of 25 µM drugs. fAβ was prepared with a 1:10 ratio of Aβ42 to Aβ40. The amount of Aβ fibrils was monitored using a thioflavin T (Th-T) assay. Neuronal cells (N2A and SHSY-5Y) were treated with 25 µM drugs, and cell death was measured using a lactose dehydrogenase (LDH) assay. We noticed a high prevalence (82-90%) of polypharmacy and diverse medication profiles including anti-inflammatory (65-77%), vitamin and mineral (64-72%), anti-cholesterol (33-41%), anti-hypersensitive (35-39%), proton pump inhibitor (23-34%), anti-thyroid (9-21%), anti-diabetic (5-13%), anti-constipation (9-11%), anti-coagulant (10-13%), and anti-insomnia (9-20%) drugs in the three cohorts. Our LDH assay with 18 highly prevalent drug components showed toxic effects of Norvasc, Tylenol, Colace, and Plavix on N2A cells, and of vitamin D and Novasc on SH-SY5Y cells. All these drugs except Colace significantly reduced the amount of Aβ fibril when incubated with Aβ42 for a short period (6h). However, Lipitor, vitamin D, Levothyroxine, Prilosec, Flomax, and Norvasc prominently reduce the amount of fibrils when incubated with monomeric Aβ42 for a longer period (48h). Furthermore, our disaggregation study with fAβ showed consistent results for cholecalciferol (vitamin D), omeprazole (Prilosec), clopidogrel hydrogensulfate (Flomax), levothyroxine, and amlodipine (Norvasc). The chemical structures of these four efficient molecules contain polyphenol components, a characteristic feature of the structures of polyphenolic inhibitors of Aβ fibrillation. A higher polypharmacy incidence was observed in an elderly population of 228 ND, 114 MCI, and 124 AD patients. We found that several highly recommended drug components, including vitamin D3, Levothyroxine, Prilosec, Flomax, and Norvasc, efficiently reduce the amount of fibrils formed by monomeric Aβ42 and existing preformed Aβ fibrils in vitro. However, only Levothyroxine was able to prevent Aβ-mediated toxicity to SH-SY5Y cells. Our study suggested that these drugs likely function as polyphenolic inhibitors of Aβ.

The benefits and risks of new antidiabetic drugs for the treatment of geriatric patients with diabetes

The benefits and risks of new antidiabetic drugs for the treatment of geriatric patients with diabetes

Discovery of α-amylase and α-glucosidase dual inhibitors from NPASS database for management of Type 2 Diabetes Mellitus: A chemoinformatic approach.

Postprandial hyperglycemia, typical manifestation of Type 2 Diabetes Mellitus (T2DM), is associated with notable global morbidity and mortality. Preventing the advancement of this condition by delaying the rate of glucose absorption through inhibition of α-amylase and α-glucosidase enzymatic activities is of utmost importance. Finding a safe antidiabetic drug is essential since those that are currently on the market have drawbacks like unpleasant side effects. The current study utilized computer-aided drug design (CADD), as a quick and affordable method to find a substitute drug template that can be used to control postprandial hyperglycemia by modulating the activity of α-amylase and α-glucosidase enzymes. The Natural Products Activity and Species database (NPASS) (30,926 compounds) was screened in silico, with a focus on evaluating drug-likeness, toxicity profiles and ability to bind on a target protein. Two molecules NPC204580 (Chrotacumine C) and NPC137813 (1-O-(2-Methoxy-4-Acetylphenyl)-6-O-(E-Cinnamoyl)-Beta-D-Glucopyranoside) were identified as potential dual inhibitors for α-amylase and α-glucosidase with free binding energies of -14.46 kcal/mol and -12.58 kcal/mol for α-amylase, and -8.42 kcal/mol and -8.76 kcal/mol for α-glucosidase, respectively. The molecules showed ionic, H-bonding and hydrophobic interactions with critical amino acid residues of both enzymes. Moreover, 100 ns molecular dynamic simulations showed that both molecules are stable on the receptors' active sites based on root mean square deviation (RMSD), root mean square fluctuation (RMSF), and the Generalized Born surface area (GBSA) energy calculated. The two compounds are thus promising therapeutic agents for T2DM that merit further investigation due to their excellent binding energies, encouraging pharmacokinetics, toxicity profiles, and stability as demonstrated in simulated studies.

One step closer to solving the mystery of the anti-inflammatory effects of glucagon-like peptide-1 receptor agonists.

Glucagon-like peptide-1 (GLP-1) receptor agonists are antidiabetic drugs that possess a suppressive effect on the progression of atherosclerosis, and it has been thought that their anti-inflammatory effect is involved in their effect, but the detailed mechanism was unknown. Recently, Ben Nasr and colleagues have proposed easily understood mechanism for the anti-inflammatory effect of GLP-1 receptor agonists. They discovered that some normal Tcells express GLP-1 receptors on their cell membranes and showed that GLP-1 has an inhibitory effect on T-cell function.

Targeting Glucose Metabolism: A Novel Therapeutic Approach for Parkinson’s Disease

Glucose metabolism is essential for the maintenance and function of the central nervous system. Although the brain constitutes only 2% of the body weight, it consumes approximately 20% of the body’s total energy, predominantly derived from glucose. This high energy demand of the brain underscores its reliance on glucose to fuel various functions, including neuronal activity, synaptic transmission, and the maintenance of ion gradients necessary for nerve impulse transmission. Increasing evidence shows that many neurodegenerative diseases, including Parkinson’s disease (PD), are associated with abnormalities in glucose metabolism. PD is characterized by the progressive loss of dopaminergic neurons in the substantia nigra, accompanied by the accumulation of α-synuclein protein aggregates. These pathological features are exacerbated by mitochondrial dysfunction, oxidative stress, and neuroinflammation, all of which are influenced by glucose metabolism disruptions. Emerging evidence suggests that targeting glucose metabolism could offer therapeutic benefits for PD. Several antidiabetic drugs have shown promise in animal models and clinical trials for mitigating the symptoms and progression of PD. This review explores the current understanding of the association between PD and glucose metabolism, emphasizing the potential of antidiabetic medications as a novel therapeutic approach. By improving glucose uptake and utilization, enhancing mitochondrial function, and reducing neuroinflammation, these drugs could address key pathophysiological mechanisms in PD, offering hope for more effective management of this debilitating disease.

Enhancing the anticancer effect of metformin through nanoencapsulation: Apoptotic induction, inflammatory reduction, and suppression of cell migration in colorectal cancer cells.

Colorectal cancer (CRC) continues to be a significant health challenge, necessitating the development of efficient therapeutic strategies. Drug repurposing, which involves the use of existing medications for new purposes, presents a promising opportunity. Metformin, a widely used antidiabetic drug, has demonstrated potential anticancer effects. To enhance its efficacy, we formulated nano-metformin, metformin encapsulated within pectin nanoparticles. Our study aimed to evaluate the superiority of nano-metformin over free metformin in treating CRC. The cytotoxicity of both metformin and nano-metformin on Caco-2 CRC cells was assessed using the MTT assay, revealing a significant dose-dependent inhibition of cell growth using nano-metformin. The anti-inflammatory potential was evaluated by measuring the levels of nitric oxide and the pro-inflammatory cytokines IL-2 and IL-6 following lipopolysaccharide (LPS) induction, and the results revealed that treating LPS-induced cells with nano-metformin significantly reduced the production of these inflammatory mediators. To elucidate the mechanism of cell death, we employed an acridine orange/ethidium bromide staining assay, which revealed the enhancement of apoptotic cell death following treatment with nano-metformin. Additionally, we examined the expression of key apoptotic regulators using real-time qPCR. Nano-metformin, in particular, significantly downregulated the expression of the antiapoptotic markers Bcl-2 and Survivin while upregulating the proapoptotic caspases 3, 7, and 9. The comet assay revealed significant DNA damage induced by treatment with the nano-metformin compared with that in the free form. Moreover, nano-metformin significantly reduced the migration ability of cells. In conclusion, our work revealed the superior efficacy of our formulated nanoform over free metformin, highlighting its potential as a promising therapeutic agent for CRC treatment.

A unique compound ameliorating endoplasmic reticulum stress and insulin resistance by binding to β tubulin.

Insulin is secreted by the pancreatic β-cells and regulates glucose uptake. Endoplasmic reticulum (ER) stress is known to induce insulin resistance. Identifying novel compounds, which can ameliorate ER stress and insulin resistance may be beneficial in the treatment of diabetes. Since treatment with compounds sourced from edible plants is relatively safe, this study aimed to identify a plant-derived potential compound attenuating insulin resistance. In the present study, we identified apigenin as an effective compound for ameliorating ER stress and insulin resistance. It attenuated ER stress-induced cell death and hepatic insulin resistance and improved abnormal glucose tolerance in a db/db diabetic model. The molecular mechanism of apigenin involved direct binding to β-tubulin and improving tubulin stability, thereby recovering insulin resistance and developing diabetes. To our knowledge, no known antidiabetic drugs are yet known to target β-tubulin. Edible plants containing apigenins, such as onions, oranges, and parsley, have been consumed since a long time. Therefore, the use of natural edible plants as a source may offer a safe strategy for the prevention of diabetes.

The cellular and molecular mechanisms mediating the protective effects of sodium-glucose linked transporter 2 inhibitors against metabolic dysfunction-associated fatty liver disease.

Metabolic dysfunction-associated fatty liver disease (MAFLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is a common, highly heterogeneous condition that affects about a quarter of the world's population, with no approved drug therapy. Current evidence from preclinical research and a number of small clinical trials indicates that SGLT2 inhibitors could also be effective for MAFLD. MAFLD is associated with a higher risk of chronic liver disease and multiple extrahepatic events, especially cardiovascular disease (CVD) and chronic kidney disease (CKD). MAFLD is considered a more appropriate terminology than NAFLD because it captures the complex bidirectional interplay between fatty liver and metabolic dysfunctions associated with disease progression, such as obesity and type 2 diabetes mellitus (T2DM). SGLT2 inhibitors are antidiabetic drugs that block glucose reabsorption in the kidney proximal tubule. In this article, we reviewed current clinical evidence supporting the potential use of SGLT2 inhibitors as a drug therapy for MAFLD and discussed the possible cellular and molecular mechanisms involved. We also reviewed the clinical benefits of SGLT2 inhibitors against MAFLD-related comorbidities, especially CVD, CKD and cardiovascular-kidney-metabolic syndrome (CKM). The broad beneficial effects of SGLT2 inhibitors support their use, likely in combination with other drugs, as a therapy for MAFLD.

Green metrics-based HPLC method for quantification of three antidiabetic drugs in tablet dosage form using Box–Behnken design

Green metrics-based HPLC method for quantification of three antidiabetic drugs in tablet dosage form using Box–Behnken design

Utility of Gold/Multiwalled Carbon Nanocomposite for Electrochemical Determination of Omarigliptin in Tablets and Human Plasma

Abstract An innovative voltammetric sensor was developed to estimate omarigliptin, a novel long-acting anti-diabetic drug. The sensor utilized a carbon paste electrode enhanced with a nanocomposite of carbon nanotubes and electrodeposited gold nanoparticles. The modified electrode was characterized using scanning electron microscopy and electrochemical impedance spectroscopy. The modification significantly improved the electrode's sensitivity and electrochemical efficiency and decreased its electron transfer resistance. The surface area of the modified electrode increased by about 2.8-fold compared to the bare electrode. Omarigliptin's oxidation behavior on the modified electrode was pH-dependent and irreversible, resulting in a peak current 4 times higher than the unmodified electrode. The modified electrode revealed good reproducibility, reusability, and stability. It allows for sensitive voltammetric analysis of omarigliptin over a linear range of 0.4–27 µM (LOD=0.12 µM) and good applicability in tablets and plasma. The recovery percentages are 98.47–101.27% in tablets and 95.86–105.02% in plasma. The modified electrode exhibits good selectivity towards OMR without interference from tablet excipients, endogenous plasma components, and co-administered drugs. The comparison with the reported methods reveals the superiority of the proposed method in terms of sensitivity, selectivity, applicability, and eco-friendliness. Finally, the proposed method demonstrates excellent environmental profiles based on recent assessment metrics.

Insulin Resistance Is a Modifying Factor for Parkinson's Disease.

Parkinson's disease (PD) is the second most common, and the fastest-growing neurodegenerative disorder with unclear etiology in most cases. Therefore, the identification of non-genetic risk factors for PD pathology is crucial to develop effective preventative or therapeutic strategies. An increasing number of evidence suggests that central insulin resistance might have an essential role in PD pathology. Nevertheless, it is not clear whether insulin resistance arises from external factors/lifestyle, comorbidities such as type 2 diabetes or it can occur in a PD patient's brain independently from peripheral insulin resistance. We aimed to investigate insulin resistance and its role in GBA1mutation-associated PD pathogenesis and phenotype severity. Midbrain organoids, generated from induced pluripotent stem cells (iPSCs) of PD patients carrying the GBA1-N370S heterozygous mutation (GBA-PD) and healthy donors, were exposed to different insulin concentrations to modify insulin signaling function. Transcriptomics analysis was performed to explore insulin signaling gene expression patterns in GBA-PD and to find a potential target for GBA-PD-associated phenotype rescue. The insulin signaling pathway genes show dysregulation in GBA-PD. Particularly, we highlight that a knockdown of FOXO1 mitigates the loss of dopaminergic neurons and cellular death in GBA-PD. Additionally, our findings suggest a promising therapeutic potential of the anti-diabetic drug Pioglitazone in decreasing dopaminergic neuron loss associated with GBA-PD. Local insulin signaling dysfunction plays a substantial role in GBA-PD pathogenesis, exacerbating dopaminergic neuron death. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Alkaloids Isolated from Vepris glandulosa with Antidiabetic Properties: An In Vitro and In Silico Analysis.

Diabetes is a major global health issue and as current treatments fail, the search for new antidiabetic drugs is crucial. This investigation, focusing on identifying potential antidiabetic compounds from the endangered plant species Vepris glandulosa, led to the isolation of two known alkaloids, choisyine acetate (1) and choisyine (2). The study established the in vitro inhibitory activities and in silico molecular interaction of the two alkaloids with α-amylase based on IC50 values, Linewaever-Burk/Dixon plot kinetic analyses and Molecular docking, respectively. The α-amylase inhibition assay revealed noncompetitive inhibition for both compounds with IC50 and Ki values of 4.74±0.17 and 4.75 mM for compound 1, and 11.29±0.44 and 12.37 mM for compound 2, respectively. In comparison, the standard drug acarbose displayed a competitive mode of inhibition, with IC50 and Ki values of 11.99±0.02 and 12.68 mM, respectively. The binding affinities with α-amylase were -6.42 and -6.07 kcal/mol for compounds 1 and 2, respectively relative to acarbose -8.03 Kcal/mol. Moreover, the predicted physicochemical and ADMET properties of these two compounds justified their potential as lead compounds for drug discovery. These compounds demonstrated remarkable inhibition potential comparable to the standard drug, highlighting their potential as viable alternatives in the management of diabetes.

Effect of GLP-1 receptor agonists on prostate cancer risk reduction: a systematic review and meta-analysis.

Prostate cancer is one of the most prevalent malignancies among men globally. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs), primarily used for type 2 diabetes mellitus (T2DM) management, have been investigated for their potential effects on cancer risks. This systematic review and meta-analysis aimed to assess the association between GLP-1 RA use and risk reduction of prostate cancer. A comprehensive literature search was conducted across PubMed, Embase, and Web of Science up to July 30, 2024. Studies that met the inclusion criteria randomized controlled trials, cohort studies, case-control studies, and observational studies assessing the incidence of prostate cancer in GLP-1 RA-treated patients were included. The quality of studies was evaluated using the Newcastle-Ottawa Scale and the Cochrane Risk of Bias tool. Meta-analysis was performed using a random effects model. A total of five studies were included, analyzing data from diverse international contexts. The included studies showed a reduced risk of prostate cancer with both adjusted and unadjusted effect estimates with GLP-1 RAs. The meta-analysis revealed an RR of 0.72 (95% CI: 0.610 to 0.832), indicating a statistically significant 28% reduction in prostate cancer risk associated with GLP-1 RA use compared to placebo or other antidiabetic drugs. Moderate heterogeneity was observed (I2 = 51%). Sensitivity analysis confirmed the results. The findings suggest a significant protective association between GLP-1 RA use and reduced prostate cancer risk in men, particularly those with T2DM. This supports the potential of GLP-1 RAs not only in diabetes management but also as a strategy to mitigate cancer risk. Further research is required to confirm these findings and explore the underlying mechanisms, considering different dosages, durations of therapy, and patient subgroups based on demographic and metabolic characteristics.

Role of Peripheral and Central Insulin Resistance in Neuropsychiatric Disorders.

Insulin acts on different organs, including the brain, which helps it regulate energy metabolism. Insulin signaling plays an important role in the function of different cell types. In this review, we have summarized the key roles of insulin and insulin receptors in healthy brains and in different brain disorders. Insulin signaling, as well as insulin resistance (IR), is a major contributor in the regulation of mood, behavior, and cognition. Recent evidence showed that both peripheral and central insulin resistance play a role in the pathophysiology, clinical presentation, and management of neuropsychiatric disorders like Cognitive Impairment/Dementia, Depression, and Schizophrenia. Many human studies point out Insulin Resistance/Metabolic Syndrome can increase the risk of dementia especially Alzheimer's dementia (AD). IR has been shown to play a role in AD development but also in its progression. This review article discusses the pathophysiological pathways and mechanisms of insulin resistance in major neuropsychiatric disorders. The extent of insulin resistance can be quantified using IR biomarkers like insulin levels, HOMA-IR index, and Triglyceride glucose-body mass index (TyG-BMI) levels. IR has been shown to precede neurodegeneration. Human trials showed current treatment with certain antidiabetic drugs, as well as life style management, like weight loss and exercise for IR, have shown promise in the management of cognitive/neuropsychiatric disorders. This may pave the pathway to the development of new therapeutic approaches to these challenging disorders of dementia and psychiatric diseases. Recent clinical trials are showing some encouraging evidence for these pharmacological and nonpharmacological approaches for IR in psychiatric and cognitive disorders, even though more research is needed to apply this evidence into clinical practice. Early identification and management of IR may help as a strategy to potentially alter neuropsychiatric disorders onset as well as its progression.

Which antidiabetic drugs do patients of T2DM prefer in India and why? A discrete choice experiment

ABSTRACT Background: Uncontrolled diabetes persists despite guideline-based treatment, partly attributed to inadequate patient involvement. This research addresses shared decision-making by eliciting patient preferences in Type 2 Diabetes Mellitus (T2DM) treatment based on certain key attributes and explores their correlation with socio-demographic-clinical profiles. Methods: A discrete choice experiment (DCE) was conducted among T2DM outpatients in an Indian tertiary care center. A choice card was developed using the contextual choice framework, having six second-line antidiabetic drugs (ADs) from different classes incorporating seven attributes. Face-to-face interviews were conducted with patients, and elicited preferences were analyzed using descriptive statistics, Chi-square analysis, and multinomial logistic regression. Results: Out of the 87 evaluated participant choices, the most preferred drug was Glimepiride (51.7%), followed by Dapagliflozin (22.9%) and Teneligliptin (17.2%). Overall, the most important attributes were the effect on weight (29%), followed by route of administration (24%), and additional benefits offered by the drug (18%). Significant associations were found between participants’ drug preferences and their age (P = 0.002), socioeconomic status (P = 0.04), occupation (P = 0.004), and monthly income (P = 0.03). Age was not a significant predictor of drug choice for any of the drugs. Multinomial logistic regression showed that the overall model was statistically significant (P = 0.025), and it correctly predicted drug choice for 58.6% of the participants. Conclusion: Glimepiride was the most preferred option overall while the effect on weight was the most important attribute for patients in determining their preference. The study highlighted the importance of shared decisions and can guide practitioners in considering patient preferences when prescribing antidiabetic drugs.

Curalin supplement as add-on therapy for type 2 diabetes Mellitus

AimsTo examine the efficacy and safety of Curalin, as a supplement to anti-diabetic drugs (ADD). Methods135 patients were enrolled in the study. Among them, 109, ages 18–85 years, with HA1c 7.5–10 % under treatment with ADD were randomized 1:1 to receive Curalin supplement or placebo. The primary efficacy endpoint was the change in HbA1c after 3 months. The secondary endpoint was a decrease in HbA1c by more than 0.5 % and by more than 1 %. The exploratory endpoints included the Diabetes Treatment Satisfaction Questionnaire (DTSQ), clinical and laboratory results. ResultsAfter 3 months, the mean reduction in HbA1c was 1.30 % (SD = 0.79) in the Curalin group compared to 0.10 % (SD = 0.70) in the placebo group (P < 0.0001). A decrease in HbA1c of ≥ 0.5 % was observed in 90.0 % of Curalin patients versus 19.0 % of placebo patients (P < 0.0001). HbA1c reduction of ≥ 1 % occurred in 64.0 % of Curalin patients and 11.9 % of placebo patients (P < 0.0001). Curalin patients reported higher satisfaction (DTSQ) with no severe adverse events. ConclusionsCuralin treatment significantly reduced HbA1c over a period of 3 months and was well-tolerated.

Elucidating the role of weight loss and glycaemic control in patients with type 2 diabetes.

To investigate the independent contributions of glycated haemoglobin (HbA1c) reduction and weight loss to clinical outcomes in patients with type 2 diabetes (T2D) treated with antidiabetic drugs, including glucagon-like peptide-1 receptor agonists (GLP-1RAs). This observational, retrospective cohort study used deidentified electronic health record-derived data from patients evaluated at the Cleveland Clinic (1 January 2000-31 December 2020). Cohort A included 8876 patients with newly diagnosed T2D treated with any of six antidiabetic drug classes. Cohort B included 4161 patients with T2D initiating GLP-1RA treatment. The effects of body mass index (BMI) and HbA1c reduction, variability, and durability on clinical outcomes were investigated. In Cohort A, each 1% BMI reduction was associated with 3%, 1%, and 4% reduced risk of heart failure (p = 0.017), hypertension (p = 0.006), and insulin initiation (p = 0.001), respectively. Each 1% (~11 mmol/mol) HbA1creduction was associated with 4% and 29% reduced risk of hypertension (p = 0.041) and insulin initiation (p = 0.001), respectively. In Cohort B, each 1% BMI reduction was associated with 4% and 3% reduced risk of cardiovascular disease (p = 0.008) and insulin initiation (p = 0.002), respectively. Each 1% (~11 mmol/mol) HbA1c reduction was associated with 4% and 16% reduced risk of chronic kidney disease (p = 0.014) and insulin initiation (p = 1 × 10-4), respectively. Lower BMI variability and greater BMI durability were associated with decreased risk of clinical outcomes in both cohorts. Antidiabetic medication-associated, and specifically GLP-1RA-associated, weight loss and HbA1c reductions independently reduce real-world clinical outcome risk.