Nascent shifts in renal cellular metabolism, structure, and function due to chronic empagliflozin in prediabetic mice.

Sodium-glucose cotransporter, type 2 inhibitors (SGLT2i) are emerging as the gold standard for treatment of type 2 diabetes (T2D) with renal protective benefits independent of glucose lowering. We took a high-level approach to evaluate the effects of the SGLT2i, empagliflozin (EMPA) on renal metabolism and function in a prediabetic model of metabolic syndrome. Male and female 12-wk-old TallyHo (TH) mice, and their closest genetic lean strain (Swiss-Webster, SW) were treated with a high-milk-fat diet (HMFD) plus/minus EMPA (@0.01%) for 12-wk. Kidney weights and glomerular filtration rate were slightly increased by EMPA in the TH mice. Glomerular feature analysis by unsupervised clustering revealed sexually dimorphic clustering, and one unique cluster relating to EMPA. Periodic acid Schiff (PAS) positive areas, reflecting basement membranes and mesangium were slightly reduced by EMPA. Phasor-fluorescent life-time imaging (FLIM) of free-to-protein bound NADH in cortex showed a marginally greater reliance on oxidative phosphorylation with EMPA. Overall, net urine sodium, glucose, and albumin were slightly increased by EMPA. In TH, EMPA reduced the sodium phosphate cotransporter, type 2 (NaPi-2), but increased sodium hydrogen exchanger, type 3 (NHE3). These changes were absent or blunted in SW. EMPA led to changes in urine exosomal microRNA profile including, in females, enhanced levels of miRs 27a-3p, 190a-5p, and 196b-5p. Network analysis revealed "cancer pathways" and "FOXO signaling" as the major regulated pathways. Overall, EMPA treatment to prediabetic mice with limited renal disease resulted in modifications in renal metabolism, structure, and transport, which may preclude and underlie protection against kidney disease with developing T2D.NEW & NOTEWORTHY Renal protection afforded by sodium glucose transporter, type 2 inhibitors (SGLT2i), e.g., empagliflozin (EMPA) involves complex intertwined mechanisms. Using a novel mouse model of obesity with insulin resistance, the TallyHo/Jng (TH) mouse on a high-milk-fat diet (HMFD), we found subtle changes in metabolism including altered regulation of sodium transporters that line the renal tubule. New potential epigenetic determinants of metabolic changes relating to FOXO and cancer signaling pathways were elucidated from an altered urine exosomal microRNA signature.

Predictive factors and the management of hyperglycemia in patients with acromegaly and Cushing's disease receiving pasireotide treatment: post hoc analyses from the SOM230B2219 study.

Introduction: Pasireotide, a somatostatin receptor ligand, is approved for treating acromegaly and Cushing's disease (CD). Hyperglycemia during treatment can occur because of the drug's mechanism of action, although treatment discontinuation is rarely required. The prospective, randomized, Phase IV SOM230B2219 (NCT02060383) trial was designed to assess optimal management of pasireotide-associated hyperglycemia. Here, we investigated predictive factors for requiring antihyperglycemic medication during pasireotide treatment. Methods: Participants with acromegaly or CD initiated long-acting pasireotide 40 mg/28 days intramuscularly (acromegaly) or pasireotide 600 µg subcutaneously twice daily during pre-randomization (≤16 weeks). Those who did not need antihyperglycemic medication, were managed with metformin, or received insulin from baseline entered an observational arm ending at 16 weeks. Those who required additional/alternative antihyperglycemic medication to metformin were randomized to incretin-based therapy or insulin for an additional 16 weeks. Logistic-regression analyses evaluated quantitative and qualitative factors for requiring antihyperglycemic medication during pre-randomization. Results: Of 190 participants with acromegaly and 59 with CD, 88 and 15, respectively, did not need antihyperglycemic medication; most were aged <40 years (acromegaly 62.5%, CD 86.7%), with baseline glycated hemoglobin (HbA1c) <6.5% (<48 mmol/mol; acromegaly 98.9%, CD 100%) and fasting plasma glucose (FPG) <100 mg/dL (<5.6 mmol/L; acromegaly 76.1%, CD 100%). By logistic regression, increasing baseline HbA1c (odds ratio [OR] 3.6; P=0.0162) and FPG (OR 1.0; P=0.0472) and history of diabetes/pre-diabetes (OR 3.0; P=0.0221) predicted receipt of antihyperglycemic medication in acromegaly participants; increasing baseline HbA1c (OR 12.6; P=0.0276) was also predictive in CD participants. Investigator-reported hyperglycemia-related adverse events were recorded in 47.9% and 54.2% of acromegaly and CD participants, respectively, mainly those with diabetes/pre-diabetes. Conclusion: Increasing age, HbA1c, and FPG and pre-diabetes/diabetes were associated with increased likelihood of requiring antihyperglycemic medication during pasireotide treatment. These risk factors may be used to identify those who need more vigilant monitoring to optimize outcomes during pasireotide treatment.

Active vitamin D treatment in the prevention of sarcopenia in adults with prediabetes (DPVD ancillary study): a randomised controlled trial.

BACKGROUND: Observational studies show inverse associations between serum 25-hydroxyvitamin D concentrations and sarcopenia incidence; however, it remains unclear whether treatment with vitamin D prevents its development. We aimed to assess whether treatment with active vitamin D (eldecalcitol [0·75 µg per day]) can reduce the development of sarcopenia among adults with prediabetes. METHODS: This randomised, double-blind, placebo-controlled, multicenter trial as an ancillary study was conducted at 32 clinics and hospital sites in Japan. Participants were assigned (1:1) by using a central randomisation method in which a randomisation list was made for each hospital separately using a stratified permuted block procedure. The primary endpoint was sarcopenia incidence during 3 years in the intention-to-treat population defined as weak handgrip strength (<28 kg for men and <18 kg for women) and low appendicular skeletal muscle index (<7·0 kg/m2 for men and <5·7 kg/m2 for women in bioelectrical impedance analysis). Although the usual criterion of hypercalcaemia was 10·4 mg/dL (2·6 mmol/L) or higher, hypercalcaemia that was enough to discontinue the study was defined as 11·0 mg/dL or higher. This study is registered with the UMIN clinical trials registry, UMIN000005394. FINDINGS: A total of 1094 participants (548 in the eldecalcitol group and 546 in the placebo group; 44·2% [484 of 1094] women; mean age 60·8 [SD 9·2] years) were followed up for a median of 2·9 (IQR 2·8-3·0) years. Eldecalcitol treatment as compared with placebo showed statistically significant preventive effect on sarcopenia incidence (25 [4·6%] of 548 participants in the eldecalcitol group and 48 [8·8%] of 546 participants in the placebo group; hazard ratio 0·51; 95% CI 0·31 to 0·83; p=0·0065). The incidence of adverse events did not differ between the two groups. INTERPRETATION: We found that treatment with eldecalcitol has the potential to prevent the onset of sarcopenia among people with prediabetes via increasing skeletal muscle volume and strength, which might lead to a substantial risk reduction of falls. FUNDING: Kitakyushu Medical Association. TRANSLATION: For the Japanese translation of the abstract see Supplementary Materials section.

Effect of topical testosterone on pre-diabetes and diabetes.

Overview of: Bhasin S, Lincoff AM, Nissen SE, et al. Effect of testosterone on progression from prediabetes to diabetes in men with hypogonadism: a substudy of the TRAVERSE randomized clinical trial. JAMA Intern Med. 2024. doi: 10.1001/jamainternmed.2023.7862. [Epub ahead of print 5 February 2024].

Does metformin reduce the risk of cancer in obesity and diabetes? A systematic review and meta-analysis.

AIM: To evaluate the effect of metformin on cancer incidence in subjects with overweight/obesity and/or prediabetes/diabetes. MATERIALS AND METHODS: We searched MEDLINE, Embase and CENTRAL for randomized controlled trials (RCTs) in adults with overweight/obesity and/or prediabetes/diabetes that compared metformin to other interventions for ≥24 weeks. Independent reviewers selected and extracted data including population and intervention characteristics and new diagnoses of cancer. We used the RoB 2.0 risk-of-bias tool and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework to assess risk of bias and certainty of evidence. RESULTS: From 14 895 records after removal of duplicates, 27 trials were included, providing a total of 10 717 subjects in the metformin group and 10 003 in the control group, with 170 and 208 new cases of cancer, respectively. Using a random-effects model, the relative risk was 1.07 (95% confidence interval 0.87-1.31), with similar results in subgroup analyses by study duration or effect of control intervention on weight. Risk of bias in most studies was low, and no evidence of publication bias was found. Trial sequential analysis provided evidence that the cumulative sample size was large enough to exclude a significant effect of metformin on cancer incidence. CONCLUSIONS: Metformin did not reduce cancer incidence in RCTs involving subjects with overweight/obesity and/or prediabetes/diabetes.

Effect of Testosterone on Progression From Prediabetes to Diabetes in Men With Hypogonadism: A Substudy of the TRAVERSE Randomized Clinical Trial.

Importance: The effect of testosterone replacement therapy (TRT) in men with hypogonadism on the risk of progression from prediabetes to diabetes or of inducing glycemic remission in those with diabetes is unknown. Objective: To evaluate the efficacy of TRT in preventing progression from prediabetes to diabetes in men with hypogonadism who had prediabetes and in inducing glycemic remission in those with diabetes. Design, Setting, and Participants: This nested substudy, an intention-to-treat analysis, within a placebo-controlled randomized clinical trial (Testosterone Replacement Therapy for Assessment of Long-Term Vascular Events and Efficacy Response in Hypogonadal Men [TRAVERSE]) was conducted at 316 trial sites in the US. Participants included men aged 45 to 80 years with hypogonadism and prediabetes or diabetes who were enrolled in TRAVERSE between May 23, 2018, and February 1, 2022. Intervention: Participants were randomized 1:1 to receive 1.62% testosterone gel or placebo gel until study completion. Main Outcomes and Measures: The primary end point was the risk of progression from prediabetes to diabetes, analyzed using repeated-measures log-binomial regression. The secondary end point was the risk of glycemic remission (hemoglobin A1c level <6.5% [to convert to proportion of total hemoglobin, multiply by 0.01] or 2 fasting glucose measurements <126 mg/dL [to convert to mmol/L, multiply by 0.0555] without diabetes medication) in men who had diabetes. Results: Of 5204 randomized participants, 1175 with prediabetes (mean [SD] age, 63.8 [8.1] years) and 3880 with diabetes (mean [SD] age, 63.2 [7.8] years) were included in this study. Mean (SD) hemoglobin A1c level in men with prediabetes was 5.8% (0.4%). Risk of progression to diabetes did not differ significantly between testosterone and placebo groups: 4 of 598 (0.7%) vs 8 of 562 (1.4%) at 6 months, 45 of 575 (7.8%) vs 57 of 533 (10.7%) at 12 months, 50 of 494 (10.1%) vs 67 of 460 (14.6%) at 24 months, 46 of 359 (12.8%) vs 52 of 330 (15.8%) at 36 months, and 22 of 164 (13.4%) vs 19 of 121 (15.7%) at 48 months (omnibus test P = .49). The proportions of participants with diabetes who experienced glycemic remission and the changes in glucose and hemoglobin A1c levels were similar in testosterone- and placebo-treated men with prediabetes or diabetes. Conclusions and Relevance: In men with hypogonadism and prediabetes, the incidence of progression from prediabetes to diabetes did not differ significantly between testosterone- and placebo-treated men. Testosterone replacement therapy did not improve glycemic control in men with hypogonadism and prediabetes or diabetes. These findings suggest that TRT alone should not be used as a therapeutic intervention to prevent or treat diabetes in men with hypogonadism. Trial Registration: ClinicalTrials.gov Identifier: NCT03518034.

A meta-analysis of diabetes risk prediction models applied to prediabetes screening.

AIM: To provide a systematic overview of diabetes risk prediction models used for prediabetes screening to promote primary prevention of diabetes. METHODS: The Cochrane, PubMed, Embase, Web of Science and China National Knowledge Infrastructure (CNKI) databases were searched for a comprehensive search period of 30 August 30, 2023, and studies involving diabetes prediction models for screening prediabetes risk were included in the search. The Quality Assessment Checklist for Diagnostic Studies (QUADAS-2) tool was used for risk of bias assessment and Stata and R software were used to pool model effect sizes. RESULTS: A total of 29 375 articles were screened, and finally 20 models from 24 studies were included in the systematic review. The most common predictors were age, body mass index, family history of diabetes, history of hypertension, and physical activity. Regarding the indicators of model prediction performance, discrimination and calibration were only reported in 79.2% and 4.2% of studies, respectively, resulting in significant heterogeneity in model prediction results, which may be related to differences between model predictor combinations and lack of important methodological information. CONCLUSIONS: Numerous models are used to predict diabetes, and as there is an association between prediabetes and diabetes, researchers have also used such models for screening the prediabetic population. Although it is a new clinical practice to explore, differences in glycaemic metabolic profiles, potential complications, and methods of intervention between the two populations cannot be ignored, and such differences have led to poor validity and accuracy of the models. Therefore, there is no recommended optimal model, and it is not recommended to use existing models for risk identification in alternative populations; future studies should focus on improving the clinical relevance and predictive performance of existing models.

Effect of cinnamon spice on continuously monitored glycemic response in adults with prediabetes: a 4-week randomized controlled crossover trial.

BACKGROUND: Previous clinical studies showing that cinnamon spice lowers blood glucose concentrations had inconsistent results. OBJECTIVES: To determine the effect of daily cinnamon spice supplementation in an amount commonly used for seasoning on glucose concentrations in adults with obesity and prediabetes. METHODS: Following a 2-wk run-in period of maintaining a low polyphenol/fiber diet, 18 participants with obesity and prediabetes underwent a 10-wk randomized, controlled, double-blind, crossover trial (mean age 51.1 y; mean fasting plasma glucose 102.9 mg/dL). The participants were randomly assigned to take cinnamon (4 g/d) or placebo for 4-wk, followed by a 2-wk washout period, and then crossed over to the other intervention for an additional 4-wk. Glucose changes were measured with continuous glucose monitoring. Oral glucose tolerance testing immediately following ingestion of cinnamon or placebo was performed at 4-time points to assess their acute effects both at the baseline and end of each intervention phase. Digestive symptom logs were obtained daily. RESULTS: There were 694 follow-up days with 66,624 glucose observations. When compared with placebo, 24-h glucose concentrations were significantly lower when cinnamon was administered [mixed-models; effect size (ES) = 0.96; 95 % confidence interval (CI): -2.9, -1.5; P < 0.001]. Similarly, the mean net-area-under-the-curve (netAUC) for glucose was significantly lower than for placebo when cinnamon was given (over 24 h; ES = -0.66; 95 % CI: 2501.7, 5412.1, P = 0.01). Cinnamon supplementation resulted in lower glucose peaks compared with placebo (Δpeak 9.56 ± 9.1 mg/dL compared with 11.73 ± 8.0 mg/dL; ES = -0.57; 95 % CI: 0.8, 3.7, P = 0.027). Glucose-dependent-insulinotropic-polypeptide concentrations increased during oral glucose tolerance testing + cinnamon testing (mixed-models; ES = 0.51; 95 % CI: 1.56, 100.1, P = 0.04), whereas triglyceride concentrations decreased (mixed-models; ES = 0.55; 95 % CI: -16.0, -1.6, P = 0.02). Treatment adherence was excellent in both groups (cinnamon: 97.6 ± 3.4 % compared with placebo: 97.9 ± 3.7 %; ES = -0.15; 95 % CI: -1.8, 0.2, P = 0.5). No differences were found in digestive symptoms (abdominal pain, borborygmi, bloating, excess flatus, and stools/day) between cinnamon and placebo groups. CONCLUSIONS: Cinnamon, a widely available and low-cost supplement, may contribute to better glucose control when added to the diet in people who have obesity-related prediabetes. This trial was registered at clinicaltrials.gov as NCT04342624.

Carnosine supplementation improves glucose control in adults with pre-diabetes and type 2 diabetes: A randomised controlled trial.

BACKGROUND AND AIMS: Type 2 diabetes (T2DM) is a major cause of morbidity and mortality globally. Carnosine, a naturally occurring dipeptide, has anti-inflammatory, antioxidant, and anti-glycating effects, with preliminary evidence suggesting it may improve important chronic disease risk factors in adults with cardiometabolic conditions. METHODS AND RESULTS: In this randomised controlled trial, 43 adults (30%F) living with prediabetes or T2DM consumed carnosine (2 g) or a matching placebo daily for 14 weeks to evaluate its effect on glucose metabolism assessed via a 2-h 75 g oral glucose tolerance test. Secondary outcomes included body composition analysis by dual energy x-ray absorptiometry (DEXA), calf muscle density by pQCT, and anthropometry. Carnosine supplementation decreased blood glucose at 90 min (-1.31 mmol/L; p = 0.02) and 120 min (-1.60 mmol/L, p = 0.02) and total glucose area under the curve (-3.30 mmol/L; p = 0.04) following an oral glucose tolerance test. There were no additional changes in secondary outcomes. The carnosine group results remained significant before and after adjustment for age, sex, and change in weight (all>0.05), and in further sensitivity analyses accounting for missing data. There were no significant changes in insulin levels. CONCLUSION: This study provides preliminary support for larger trials evaluating carnosine as a potential treatment for prediabetes and the initial stages of T2DM. Likely mechanisms may include changes to hepatic glucose output explaining the observed reduction in blood glucose without changes in insulin secretion following carnosine supplementation.

Berberine attenuates cognitive dysfunction and hippocampal apoptosis in rats with prediabetes.

The cognitive dysfunction caused by prediabetes causes great difficulties in human life, and the terrible thing is that the means to prevent the occurrence of this disease are very limited at present, Berberine has shown the potential to treat diabetes and cognitive dysfunction, but it still needs to be further explored to clarify the mechanism of its therapeutic effect. Therefore, the aim of this study was to investigate the effects and mechanisms of Berberine on prediabetes-induced cognitive dysfunction. Prediabetes rat model was induced by a high-fat diet and a normal diet was used as a control. They were fed for 20 weeks. At week 13, the model rats were given 100 mg/kg Berberine by gavage for 7 weeks. The cognitive function of rats was observed. At the same time, OGTT, fasting blood glucose, blood lipids, insulin and other metabolic parameters, oxidative stress, and apoptosis levels were measured. The results showed that the model rats showed obvious glucose intolerance, elevated blood lipids, and insulin resistance, and the levels of oxidative stress and apoptosis were significantly increased. However, after the administration of Berberine, the blood glucose and lipid metabolism of prediabetic rats were significantly improved, and the oxidative stress level and apoptosis level of hippocampal tissue were significantly reduced. In conclusion, Berberine can alleviate the further development of diabetes in prediabetic rats, reduce oxidative stress and apoptosis in hippocampal tissue, and improve cognitive impairment in prediabetic rats.

Supplementation of papaya leaf juice has beneficial effects on glucose homeostasis in high fat/high sugar-induced obese and prediabetic adult mice.

Prediabetes is characterized by a cluster of glycemic parameters higher than normal but below the threshold of type 2 diabetes mellitus (T2DM). In recent years, phytochemical-rich plant extracts have gained popularity as therapeutic agents for metabolic disorders. This study investigated the effects of papaya leaf (PL) juice supplementation on blood glucose levels in diet-induced obese and prediabetic adult mice. B65JL F1 mice (n = 20) at 12-14 months old were fed a high fat/sugar diet (HFHS) for 120 days. Mice were switched to restricted rodent chow of 3 g feed/30 g body weight/day, supplemented with 3 g/100 mL PL juice for 30 days. HFHS diet remarkably increased fasting plasma glucose levels from 114 ± 6.54 mg/dL to 192.7 ± 10.1 mg/dL and body weight from 32.5 ± 1.6 to 50.3 ± 4.1 g. HFHS diet results in hyperglycemia, insulin resistance, hyperlipidemia, and liver steatosis. The combination of PL juice and restricted diet significantly reduced body weight and fasting blood glucose levels to 43.75 ± 1.4 g and 126.25 ± 3.2 mg/dl, respectively. Moreover, PL juice with a restricted diet significantly improved lipid profile: cholesterol from 204 to 150 mg/dL, LDL-c from 110.4 to 50 mg/dL, and triglyceride from 93.7 to 60 mg/dL. Additionally, PL juice combined with a restricted diet significantly reduced adiposity, reversed fatty liver, and restored skeletal muscle Glut4 and phosphorylated (p-AKT (ser473). This study demonstrated that supplementation of PL juice with a restricted diet was more effective than a restricted diet alone in reversing major symptoms related to prediabetic and obesity conditions.

Baicalin ameliorates insulin resistance and regulates hepatic glucose metabolism via activating insulin signaling pathway in obese pre-diabetic mice.

BACKGROUND: Diabetes belongs to the most prevalent metabolic diseases worldwide, which is featured with insulin resistance, closely associated with obesity and urgently needs to be treated. Baicalin, belonging to natural flavonoids, has been reported to inhibit oxidative stress or inflammatoin. PURPOSE: This study investigated the properties of baicalin on modulating abnormal glucolipid metabolism, as well as the underlying in-vitro and in-vivo mechanisms. METHODS: Insulin-resistant (IR)-HepG2 cells were stimulated by dexamethasone (20 µM) and high glucose (50 mM) for 48 h and incubated with or without baicalin or metformin for another 16 h. Male C57BL/6 J mice were fed with a high-fat diet (HFD, 60 % kcal% fat) during the total 14 weeks. Obese mice were then administered with baicalin (50 and 100 mg/kg) or vehicle solution everyday through oral gavage during the last 4-week period. Moreover, baicalin metabolisms in vitro and in vivo were determined using UPLC/MS/MS to study its metabolism situation. RESULTS: Exposure to dexamethasone and high glucose damaged the abilities of glycogen synthesis and glucose uptake with elevated oxidative stress and increased generation levels of advanced glycation end-products (AGEs) in HepG2 cells. These impairments were basically reversed by baicalin treatment. Four-week oral administration with baicalin ameliorated hyperglycemia and dyslipidemia in HFD-induced obese and pre-diabetic mice. Downregulation of IRS/PI3K/Akt signaling pathway accomplished with reduced GLUT4 expression and enhanced GSK-3ß activity was observed in insulin resistant HepG2 cells as well as liver tissues from pre-diabetic mice; and such effect was prevented by baicalin. Moreover, baicalin and its matabolites were detected in IR-HepG2 cells and mouse plasma. CONCLUSION: The study illustrated that baicalin alleviated insulin resistance by activating insulin signaling pathways and inhibiting oxidative stress and AGEs production, revealing the potential of baicalin to be a therapeutic natural flavonoid against hepatic insulin and glucose-lipid metabolic disturbance in pre-diabetes accompanied with obesity.

Akt Signaling and Nitric Oxide Synthase as Possible Mediators of the Protective Effect of N-acetyl-L-cysteine in Prediabetes Induced by Sucrose.

The aim of this work was to evaluate possible mechanisms involved in the protective effect of N-acetyl-L-cysteine (NAC) on hepatic endocrine-metabolic, oxidative stress, and inflammatory changes in prediabetic rats. For that, normal male Wistar rats (60 days old) were fed for 21 days with 10% sucrose in their drinking water and 5 days of NAC administration (50 mg/kg, i.p.) and thereafter, we determined: serum glucose, insulin, transaminases, uric acid, and triglyceride levels; hepatic fructokinase and glucokinase activities, glycogen content, lipogenic gene expression; enzymatic and non-enzymatic oxidative stress, insulin signaling pathway, and inflammatory markers. Results showed that alterations evinced in sucrose-fed rats (hypertriglyceridemia, hyperinsulinemia, and high liver fructokinase activity together with increased liver lipogenic gene expression and oxidative stress and inflammatory markers) were prevented by NAC administration. P-endothelial nitric oxide synthase (P-eNOS)/eNOS and pAKT/AKT ratios, decreased by sucrose ingestion, were restored after NAC treatment. In conclusion, the results suggest that NAC administration improves glucose homeostasis, oxidative stress, and inflammation in prediabetic rats probably mediated by modulation of the AKT/NOS pathway. Administration of NAC may be an effective complementary strategy to alleviate or prevent oxidative stress and inflammatory responses observed in type 2 diabetes at early stages of its development (prediabetes).

Efficacy and safety of bempedoic acid among patients with and without diabetes: prespecified analysis of the CLEAR Outcomes randomised trial.

BACKGROUND: Statins reduce LDL cholesterol and cardiovascular events among those with or without diabetes but have been reported to increase new-onset diabetes. The CLEAR Outcomes trial demonstrated that bempedoic acid reduced the risk of major adverse cardiovascular events among statin-intolerant patients at high cardiovascular risk. In this prespecified analysis, our dual aims were to evaluate the cardiovascular benefits of bempedoic acid, an ATP-citrate lyase inhibitor, in individuals with diabetes, and to evaluate the risk of new-onset diabetes and HbA1c among those without diabetes in the CLEAR Outcomes trial. METHODS: CLEAR Outcomes was a randomised, double-blind, placebo-controlled trial conducted across 1250 primary care and outpatient sites in 32 countries. Patients with or without cardiovascular disease who were unwilling or unable to take guideline-recommended doses of statins and an LDL cholesterol of 2·59 mmol/L or more were randomly assigned (1:1) in a double-blinded manner to either bempedoic acid 180 mg once per day or placebo. In this prespecified analysis, the efficacy endpoint was a time-to-event analysis of four-component major adverse cardiovascular event (MACE-4), which is the composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularisation, using the intention-to-treat population stratified by baseline glycaemia status. The prespecified analysis of risk of new-onset diabetes and HbA1c increase was evaluated in patients without diabetes at baseline. The CLEAR Outcomes trial was completed on Nov 7, 2022, and is registered with ClinicalTrials.gov (NCT02993406). FINDINGS: Between Dec 22, 2016, and Nov 7, 2022, 13 970 patients were screened and randomly assigned; 6373 (45·6%) with diabetes, 5796 (41·5%) with prediabetes, and 1801 (12·9%) with normoglycaemia. Over a median of 3·4 years follow up, patients with diabetes had significant relative and absolute cardiovascular risk reductions in MACE-4 endpoints with bempedoic acid (HR 0·83; 95% CI 0·72-0·95; absolute risk reduction of 2·4%) compared to placebo, with no statistical evidence of effect modification across glycaemic strata (interaction p=0·42). The proportion of patients who developed new-onset diabetes were similar between the bempedoic acid and placebo groups, with 429 of 3848 (11·1%) with bempedoic acid versus 433 of 3749 (11·5%) with placebo (HR 0·95; 95% CI 0·83-1·09). HbA1c concentrations at month 12 and the end of the study were similar between randomised groups in patients who had prediabetes and normoglycaemia. Placebo-corrected LDL cholesterol concentrations and high-sensitivity C-reactive protein at 6 months were reduced in each glycaemic stratum (diabetes, prediabtes, and normoglycaemia) for patients randomly assigned to bempedoic acid (all p<0·001). INTERPRETATION: Among patients with diabetes, bempedoic acid reduces LDL cholesterol and high-sensitivity C-reactive protein and risk of cardiovascular events. Patients without diabetes had no increase in new-onset diabetes or worsening HbA1c with bempedoic acid. The efficacy and cardiometabolic safety profile of bempedoic acid makes it a clinical option for those with and without diabetes. FUNDING: Esperion Therapeutics.

Liraglutide 3.0 mg (Saxenda©) for Weight Loss and Remission of Pre-Diabetes. Real-World Clinical Evaluation of Effectiveness among Patients Awaiting Bariatric Surgery.

OBJECTIVE: The effectiveness of liraglutide 3.0 mg (Saxenda) therapy to induce weight loss among obese patients prior to bariatric surgery remains uncertain. METHODS: Clinical data was retrospectively obtained from patients with prediabetes (HbA1c 42-47 mmol/mol) and selected patients on the waiting list for bariatric surgery at the Royal Derby Hospital. Clinical data was collected retrospectively at 6, 12, 26 and 52 week intervals. The outcomes included mean weight change, proportion of patients achieving ≥ 5% and ≥ 10% weight loss and achieving HbA1c reduction to normal range values. RESULTS: Fifty patients (mean age of 46.2 ± 10.5 years; 76% female and 94% had Class III obesity) who completed 52 and/or 26 weeks of treatment were included. Liraglutide 3.0 mg produced a consistent and statistically significant reduction in weight (kg), BMI (kg/m2) and HbA1c (mmol/mol) across all four time intervals. Average ± SD reduction for weight, BMI and HbA1c respectively at 26 weeks were: -10.9 ± 9.1 (P < 0.01), -3.67 ± 3.5 (P < 0.01), -4.7 IQR 4.95 (P < 0.001), and at 52 weeks were: -14 ± 9.2 kg (P < 0.001), -4.64 ± 4.0 (P < 0.001 and -5.5 IQR 4 (P = 0.009). 85.7% and 33.3% of patients achieved ≥ 5% and 10% weight loss target respectively at 52 weeks. 92.3% and 72.2% achieved remission of pre-diabetes by 6 and 12 months respectively. Liraglutide 3.0 mg was well-tolerated with only 10% discontinuing medication due to tolerability issues. CONCLUSION: Liraglutide 3.0 mg, with lifestyle management, reduced weight and improved glycaemic control. These results support liraglutide's application in certain high-risk populations, including patients waiting for bariatric surgical intervention.

Weight Loss-Independent Effect of Liraglutide on Insulin Sensitivity in Individuals With Obesity and Prediabetes.

Metabolic effects of glucagon-like peptide 1 (GLP-1) receptor agonists are confounded by weight loss and not fully recapitulated by increasing endogenous GLP-1. We tested the hypothesis that GLP-1 receptor (GLP-1R) agonists exert weight loss-independent, GLP-1R-dependent effects that differ from effects of increasing endogenous GLP-1. Individuals with obesity and prediabetes were randomized to receive for 14 weeks the GLP-1R agonist liraglutide, a hypocaloric diet, or the dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin. The GLP-1R antagonist exendin(9-39) and placebo were administered in a two-by-two crossover study during mixed-meal tests. Liraglutide and diet, but not sitagliptin, caused weight loss. Liraglutide improved insulin sensitivity measured by HOMA for insulin resistance (HOMA-IR), the updated HOMA model (HOMA2), and the Matsuda index after 2 weeks, prior to weight loss. Liraglutide decreased fasting and postprandial glucose levels, and decreased insulin, C-peptide, and fasting glucagon levels. In contrast, diet-induced weight loss improved insulin sensitivity by HOMA-IR and HOMA2, but not the Matsuda index, and did not decrease glucose levels. Sitagliptin increased endogenous GLP-1 and GIP values without altering insulin sensitivity or fasting glucose levels, but decreased postprandial glucose and glucagon levels. Notably, sitagliptin increased GIP without altering weight. Acute GLP-1R antagonism increased glucose levels in all groups, increased the Matsuda index and fasting glucagon level during liraglutide treatment, and increased endogenous GLP-1 values during liraglutide and sitagliptin treatments. Thus, liraglutide exerts rapid, weight loss-independent, GLP-1R-dependent effects on insulin sensitivity that are not achieved by increasing endogenous GLP-1. ARTICLE HIGHLIGHTS: Metabolic benefits of glucagon-like peptide 1 (GLP-1) receptor agonists are confounded by weight loss and are not fully achieved by increasing endogenous GLP-1 through dipeptidyl peptidase 4 (DPP-4) inhibition. We investigated weight loss-independent, GLP-1 receptor (GLP-1R)-dependent metabolic effects of liraglutide versus a hypocaloric diet or the DPP-4 inhibitor sitagliptin. GLP-1R antagonism with exendin(9-39) was used to assess GLP-1R-dependent effects during mixed meals. Liraglutide improved insulin sensitivity and decreased fasting and postprandial glucose prior to weight loss, and these benefits were reversed by exendin(9-39). GLP-1R agonists exert rapid, weight loss-independent, GLP-1R-dependent effects on insulin sensitivity not achieved by increasing endogenous GLP-1.

Liraglutide treatment for the prevention of glucose tolerance deterioration in women with prior gestational diabetes mellitus: A 52-week randomized controlled clinical trial.

AIM: We investigated the effect of 52-week treatment with liraglutide, a glucagon-like peptide 1 receptor agonist, on glucose tolerance and incretin effect in women with previous gestational diabetes mellitus (pGDM). MATERIALS AND METHODS: Women with overweight/obesity and pGDM were randomized to once daily subcutaneous liraglutide 1.8 mg or placebo for 52 weeks. Participants underwent oral glucose tolerance test (OGTT) and isoglycaemic intravenous glucose infusion at baseline and at 52 weeks, and an additional OGTT after the drug wash-out. RESULTS: In total, 104 women [age: mean ± SD, 38 ± 5 years; fasting plasma glucose (FPG): 5.5 ± 0.4 mmol/L; glycated haemoglobin (HbA1c): 33 ± 4 mmol/mol, bodyweight: 88.2 ± 14.8 kg, body mass index: 31.1 ± 4.3 kg/m2 ] were assigned to liraglutide (n = 49) or placebo (n = 55). Estimated treatment difference (ETD) for area under curve during OGTT was -173 (95% confidence interval -250 to -97) mmol/L × min, p < .0001, but after wash-out the difference disappeared [ETD 58 (-30 to 146) mmol/L × min, p = .536]. Liraglutide reduced FPG [ETD -0.2 (-0.4 to -0.1) mmol/L, p = .018], HbA1c [-2.2 (-3.5 to -0.8) mmol/mol, p = .018] and bodyweight [-3.9 (-6.2 to -1.6) kg, p = .012]. No change in the incretin effect was observed. The number of women with prediabetes was reduced from 64% to 10% with liraglutide vs. 50% with placebo [adjusted odds ratio 0.10 (0.03-0.32), p = .002]. CONCLUSIONS: Treatment with liraglutide for 52 weeks improved glucose tolerance, FPG, HbA1c and bodyweight in women with overweight/obesity and pGDM. Progression to prediabetes while on drug was markedly reduced, but after a 1-week drug wash-out, the effect was lost.

Metformin prescription for U.S. veterans with prediabetes, 2010-2019.

Affecting an estimated 88 million Americans, prediabetes increases the risk for developing type 2 diabetes mellitus (T2DM), and independently, cardiovascular disease, retinopathy, nephropathy, and neuropathy. Nevertheless, little is known about the use of metformin for diabetes prevention among patients in the Veterans Health Administration, the largest integrated healthcare system in the U.S. This is a retrospective observational cohort study of the proportion of Veterans with incident prediabetes who were prescribed metformin at the Veterans Health Administration from October 2010 to September 2019. Among 1,059,605 Veterans with incident prediabetes, 12,009 (1.1%) were prescribed metformin during an average 3.4 years of observation after diagnosis. Metformin prescribing was marginally higher (1.6%) among those with body mass index (BMI) ≥35 kg/m2, age <60 years, HbA1c≥6.0%, or those with a history of gestational diabetes, all subgroups at a higher risk for progression to T2DM. In a multivariable model, metformin was more likely to be prescribed for those with BMI ≥35 kg/m2 incidence rate ratio [IRR] 2.6 [95% confidence intervals (CI): 2.1-3.3], female sex IRR, 2.4 [95% CI: 1.8-3.3], HbA1c≥6% IRR, 1.93 [95% CI: 1.5-2.4], age <60 years IRR, 1.7 [95% CI: 1.3-2.3], hypertriglyceridemia IRR, 1.5 [95% CI: 1.2-1.9], hypertension IRR, 1.5 [95% CI: 1.1-2.1], Major Depressive Disorder IRR, 1.5 [95% CI: 1.1-2.0], or schizophrenia IRR, 2.1 [95% CI: 1.2-3.8]. Over 20% of Veterans with prediabetes attended a comprehensive structured lifestyle modification clinic or program. Among Veterans with prediabetes, metformin was prescribed to 1.1% overall, a proportion that marginally increased to 1.6% in the subset of individuals at highest risk for progression to T2DM.

The Emerging Role of Prediabetes and Its Management: Focus on L-Arginine and a Survey in Clinical Practice.

The worldwide impressive growth of metabolic disorders observed in the last decades, especially type 2 diabetes mellitus and obesity, has generated great interest in the potential benefits of early identification and management of patients at risk. In this view, prediabetes represents a high-risk condition for the development of type 2 diabetes mellitus and cardiovascular diseases, and an ideal target to intercept patients before they develop type 2 diabetes gaining a prominent role even in international guidelines. For prediabetic individuals, lifestyle modification is the cornerstone of diabetes prevention, with evidence of about 50% relative risk reduction. Accumulating data also show potential benefits from pharmacotherapy. In this context, the only available data pertain to metformin as a pharmaceutical drug and vitamin D and L-arginine as nutraceuticals. L-arginine appears to be a very interesting tool in the clinical management of patients with pre-diabetes. In this review we summarize the current knowledge on the role of L-arginine in prediabetes as a potentially useful preventive strategy against the progression to type 2 diabetes, with a particular focus on the underlying molecular mechanisms and the past and ongoing trials. In this article we also report the interesting data about the perception of the prediabetic condition and its therapeutic management in the clinical practice in Italy. An early identification and a prompt management of people with prediabetes appears to be of paramount importance to prevent the progression to diabetes and avoid its cardiovascular consequences.

The effect of metformin treatment on volumes of free-living physical activity and sedentary behaviour: A post-hoc analysis of the PRE-D trial.

Perceived physical exertion is increased when exercise is performed on metformin treatment, but the clinical relevance of this is unknown. In this post hoc analysis of a randomized, controlled trial, we investigated whether metformin treatment was associated with lower levels of free-living physical activity. Ninety individuals with overweight/obesity (BMI>25 m2/kg) and HbA1c-defined prediabetes (39-47 mmol/mol) were randomized to treatment with dapagliflozin (SGLT2-inhibitor; 10 mg once daily, n=30), metformin (850 mg twice daily, n=30) or no treatment (control, n=30) for 13 weeks in a parallel-group, open-label trial. Before (baseline), during (6 weeks) and immediately after (13 weeks) cessation of treatment, a 6-day assessment of physical activity and sedentary behaviour was performed using accelerometer-based physical activity monitors. Intention-to-treat analyses revealed no within-group changes or differences in change between the groups for any measures of physical activity or sedentary behaviour at neither 6 nor 13 weeks. Short-term metformin treatment does not reduce free-living physical activity level in individuals with overweight/obesity and HbA1c-defined prediabetes.