Potential Place of SGLT2 Inhibitors in Treatment Paradigms for type 2 Diabetes Mellitus

Objective: Following the first Food and Drug Administration (FDA) approval in 2013, sodium glucose cotransporter 2 (SGLT2) inhibitors have generated much interest among physicians treating patients with type 2 diabetes mellitus (T2DM). Here, the role in treatment with this drug class is considered in the context of T2DM treatment paradigms.Methods: The clinical trials for the SGLT2 inhibitors are examined with a focus on canagliflozin, dapagliflozin, and empagliflozin.Results: Evidence from clinical trials in patients with T2DM supports the use of SGLT2 inhibitors either as monotherapy or in addition to other glucose-lowering treatments as adjuncts to diet and exercise, and we have gained significant clinical experience in a relatively short time.Conclusion: The drugs appear to be useful in a variety of T2DM populations, contingent primarily on renal function. Most obviously, SGLT2 inhibitors appear to be well suited for patients with potential for hypoglycemia or weight gain. In clinical trials, patients treated with SGLT2 inhibitors have experienced moderate weight loss and a low risk of hypoglycemic events except when used in combination with an insulin secretagogue. In addition, SGLT2 inhibitors have been shown to reduce blood pressure, so they may be beneficial in patients with T2DM complicated by hypertension. SGLT2 inhibitors were incorporated into the 2015 American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) position statement on the management of hyperglycemia and received an even more prominent position in the American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE) comprehensive diabetes management guidelines and algorithm.Abbreviations: AE = adverse event A1C = glycated hemoglobin CI = confidence interval CKD = chronic kidney disease DKA = diabetic ketoacidosis DPP-4 = dipeptidyl peptidase 4 eGFR = estimated glomerular filtration rate FDA = Food and Drug Administration FPG = fasting plasma glucose GLP-1 = glucagon-like peptide 1 HDL-C = high-density lipoprotein cholesterol HR = hazard ratio LADA = late-onset autoimmune diabetes of adulthood LDL-C = low-density lipoprotein cholesterol MACE = major adverse cardiovascular events SGLT1 = sodium glucose cotransporter 1 SGLT2 = sodium glucose cotransporter 2 T1DM = type 1 diabetes mellitus T2DM = type 2 diabetes mellitus UACR = urine albumin to creatinine ratio     

Anti-Obesity Pharmacotherapy and the Potential for Preventing Progression from Prediabetes to Type 2 Diabetes

Objective: Type 2 diabetes and its associated complications place heavy burdens on affected individuals, their caregivers, and society. The prevalence of type 2 diabetes is increasing worldwide. Attempts to combat this problem have been extended to the treatment of obesity and prevention of progression from prediabetes to type 2 diabetes. As such, weight loss is an important component of type 2 diabetes prevention. However, successful strategies for achieving sustained weight loss have remained elusive. Although lifestyle modification remains a cornerstone of this approach, it has become clear that changes to lifestyle alone will not suffice for many patients. A pragmatic approach includes consideration of pharmacotherapeutic options.Methods: This review discusses the different pharmacotherapeutic options for the treatment of obesity and prediabetes.Results: Approved anti-obesity therapies and antihyperglycemic agents associated with weight loss may prove effective earlier in the treatment paradigm, and other promising agents that are in clinical development for chronic weight management show promise for both weight reduction and a reduction in the risk of type 2 diabetes in high-risk individuals.Conclusion: Long-term evaluation of safety and efficacy is required for many of these agents before we can begin to optimize their use in clinical practice, but treatment choices for obese or prediabetic patients are increasing.Abbreviations: AACE = American Association of Clinical Endocrinologists ADA = American Diabetes Association AE = adverse event AMA = American Medical Association BMI = body mass index CI = confidence interval CR = controlled release DPP = Diabetes Prevention Program IFG = impaired fasting glucose IGT = impaired glucose tolerance FDA = Food and Drug Administration FPG = fasting plasma glucose GLP-1 = glucagon-like peptide-1 GLP-1 RA = glucagon-like peptide-1 receptor agonist HbA_1c= glycosylated hemoglobin ITT-LOCF = intention-totreat with last observation carried forward LS = least squares NB = naltrexone/bupropion OR = odds ratio PHEN = phentermine PYE = patient years of exposure PYY = peptide YY SGLT-2 = sodium glucose cotransporter 2 TPM = topiramate TZD = thiazolidinedione     

Self Blood Glucose Monitoring Underestimates Hyperglycemia And Hypoglycemia As Compared To Continuous Glucose Monitoring In Type 1 And Type 2 Diabetes

Objective: When glucose records from self blood glucose monitoring (SBGM) do not reflect estimated average glucose from glycosylated hemoglobin (HgBA1) or when patients' clinical symptoms are not explained by their SBGM records, clinical management of diabetes becomes a challenge. Our objective was to determine the magnitude of differences in glucose values reported by SBGM versus those documented by continuous glucose monitoring (CGM).Methods: The CGM was conducted by a clinical diabetes educator (CDE)/registered nurse by the clinic protocol, using the Medtronic iPRO2™ system. Patients continued SBGM and managed their diabetes without any change. Data from 4 full days were obtained, and relevant clinical information was recorded. De-identified data sets were provided to the investigators.Results: Data from 61 patients, 27 with type 1 diabetes (T1DM) and 34 with T2DM were analyzed. The lowest, highest, and average glucose recorded by SBGM were compared to the corresponding values from CGM. The lowest glucose values reported by SBGM were approximately 25 mg/dL higher in both T1DM (P = .0232) and T2DM (P = .0003). The highest glucose values by SBGM were approximately 30 mg/dL lower in T1DM (P = .0005) and 55 mg/dL lower in T2DM (P<.0001). HgBA1c correlated with the highest and average glucose by SBGM and CGM. The lowest glucose values were seen most frequently during sleep and before breakfast; the highest were seen during the evening and postprandially.Conclusion: SBGM accurately estimates the average glucose but underestimates glucose excursions. CGM uncovers glucose patterns that common SBGM patterns cannot.Abbreviations: CDE = certified diabetes educator; CGM = continuous glucose monitoring; HgBA1c = glycosylated hemoglobin; MAD = mean absolute difference; SBGM = self blood glucose monitoring; T1DM = type 1 diabetes; T2DM = type 2 diabetes     

N-Indolylglycosides bearing modifications at the glucose C6-position as sodium-dependent glucose co-transporter 2 inhibitors

Suppression of glucose reabsorption through the inhibition of sodium-dependent glucose co-transporter 2 (SGLT2) is a promising therapeutic approach for the treatment of type 2 diabetes. To investigate the effect of C6-substitution on inhibition of SGLT2 by N-indolylglucosides, a small library of 6-triazole, 6-amide, 6-urea, and 6-thiourea N-indolylglycosides were synthesized and tested. A detailed structure–activity relationship (SAR) study culminated in the identification of 6-amide derivatives 6a and 6o as potent SGLT2 inhibitors, which were further tested for inhibitory activity against SGLT1. The data obtained indicated that 6a and 6o are mildly to moderately selective for SGLT2 over SGLT1. Both compounds were also evaluated in a urinary glucose excretion test and pharmacokinetic study; 6a was found capable of inducing urinary glucose excretion in normal SD rats.     

Glycemic Effects Of Sglt-2 Inhibitor Canagliflozin In Type 1 Diabetes Patients Using The Dexcom G4 Platinum Cgm

Objective: Limited information is available on chronic use of sodium glucose cotransporter 2 inhibitors in type 1 diabetes (T1D). We conducted a retrospective review of T1D patients on Dexcom G4Platinum continuous glucose monitors (DCGMs) >1 year (mean, 4.6 years) who were prescribed canagliflozin (CANA) 100 mg daily and had a baseline DCGM 30-day download prior to and a second download after at least 1 month (mean, 3.7 months) taking CANA 100 mg daily. The glycemic, weight, and systolic blood pressure (SBP) effects are reported.Methods: We identified 27 patients meeting the selection criteria: 14 men; 25 white; 22 on pump; average T1D duration, 34 years (range, 12 to 48 years); average hemoglobin A1C (A1C), 7.6% (range, 6.1 to 9.8%); 22 with baseline A1C 7.0% or higher. All patients had an estimated glomerular filtration rate (eGFR) at baseline of 60 mL/min/1.73 m² or higher and were normotensive or on stable therapy. On average, 29 days of CGM data was reviewed. Total daily insulin dose (TDD) was available in 21 patients. We identified 27 patients who were judged to be candidates for CANA but did not have any change in glycemic therapy other than insulin adjustment as controls.Results: CANA resulted in significant reductions in mean blood glucose, CGM standard deviation, time in hyperglycemia, A1C, weight, SBP, and TDD, with increased time in target, with minimal increase in hypoglycemia and no significant change in eGFR. Three females developed genital mycotic infections but continued therapy, 2 developed ketoacidosis from insulin interruption.Conclusion: CANA offers promise as adjunct therapy in T1D, though caution is advised.Abbreviations:A1C = hemoglobin A1CCANA = canagliflozinCGM = continuous glucose monitorCSII = continuous subcutaneous insulin infusionDCGM = Dexcom G4Platinum CGMDKA = diabetic ketoacidosisGMI = genital mycotic infectionMG = mean glucosePCGM = personal continuous glucose monitoringSBP = systolic blood pressureSGLT-2i = sodium-glucose cotransporter 2 inhibitorSH = severe hypoglycemiaT2D = type 2 diabetesT1D = type 1 diabetes     

Relationship of Adipokines and Proinflammatory Cytokines Among Asian Indians With Obesity and Youth Onset Type 2 Diabetes

Objective: It is well known that inflammation is associated with diabetes, but it is unclear whether obesity mediates this association in individuals with youth-onset type 2 diabetes mellitus (T2DM-Y).Methods: We recruited individuals with T2DM-Y (age at onset <25 years) and age-matched normal glucose tolerance (NGT) subjects. Participants were further classified using Asia-Pacific body mass index cut-points for obesity and categorized as: nonobese NGT (n = 100), Obese NGT (n = 50), nonobese T2DM-Y (n = 50), and obese T2DM-Y (n = 50). We compared adipokines (adiponectin and leptin) and proinflammatory cytokines (tumor necrosis factor alpha &lsqb;TNF-α] and monocyte chemotactic protein-1 &lsqb;MCP-1]) across groups.Results: Compared to nonobese NGT, the other 3 groups (obese NGT, nonobese T2DM-Y, and obese T2DM-Y) were found to have lower adiponectin (7.7 vs. 5.7, 4.2, 3.8 μg/mL, P<.01), and higher leptin (3.6 vs. 5.4, 5.7, 7.9 μg/mL, P<.001) and MCP 1 (186 vs. 272, 340, 473 pg/mL, P<.001) respectively. However, TNF-α levels were higher only among nonobese T2DM-Y (112 pg/mL) and obese T2DM-Y (141 pg/mL, P<.01 for each). After adjusting for age, sex, waist, hypertension, homeostatic model assessment of insulin resistance (HOMA-IR), serum cholesterol, triglycerides, and family history of diabetes, adiponectin was associated with 33% and 41% lower odds of being nonobese T2DM and obese T2DM, respectively. However, adjusted for same factors, leptin, TNF-α, and MCP-1 were associated with markedly higher odds (5- to 14-fold) of nonobese and obese T2DM.Conclusion: In young Asian Indians, leptin and proinflammatory cytokines are positively, and adiponectin negatively, associated with both nonobese and obese T2DM-Y compared to nonobese NGT individuals.Abbreviations: BMI = body mass index CI = confidence interval FPG = fasting plasma glucose HOMA-IR = homeostatic model assessment of insulin resistance IGT = impaired glucose tolerance MCP-1 = monocyte chemotactic protein-1 NGT = normal glucose tolerance OGTT = oral glucose tolerance test OR = odds ratio T2DM-Y = youth-onset type 2 diabetes TNF-α = tumor necrosis factor-α     

C-Glucosides with heteroaryl thiophene as novel sodium-dependent glucose cotransporter 2 inhibitors

Canagliflozin (1), a novel inhibitor for sodium-dependent glucose cotransporter 2 (SGLT2), has been developed for the treatment of type 2 diabetes. To investigate the effect of replacement of the phenyl ring in 1 with heteroaromatics, C-glucosides 2 were designed, synthesized, and evaluated for their inhibitory activities against SGLT2. Of these, 3-pyridyl, 2-pyrimidyl or 5-membered heteroaryl substituted derivatives showed highly potent inhibitory activity against SGLT2, while 5-pyrimidyl substitution was associated with slightly reduced activity. In particular, 2g (TA-3404) had remarkable anti-hyperglycemic effects in high-fat diet fed KK (HF-KK) mice.     

The Association of Decreased Serum Gdnf Level with Hyperglycemia and Depression in Type 2 Diabetes Mellitus

Objective: Comorbidity of diabetes and depression is a critical problem. Decreased glial-derived neurotrophic factor (GDNF) has been demonstrated in depression, but no evidence of a relationship between GDNF and diabetes has been shown. The present studies were designed to investigate the relationship between GDNF and metabolism.Methods: In Study 1, we performed a case-control study in which subjects with type 2 diabetes mellitus (T2DM), prediabetes (p-DM), and normal glucose tolerance (NGT) were included. In Study 2, we performed a cross-sectional study in 296 patients having pre-existing diabetes in whom the levels of serum GDNF, blood glucose, blood lipids, blood pressure, body mass index, scores from the Patient Health Questionnaire (PHQ-9), the EuroQol-5 scale, and the diabetes distress scale were measured, as well as single-nucleotide polymorphisms of GDNF including rs884344, rs3812047, and rs2075680.Results: In Study 1, serum GDNF concentration was significantly lower in the T2DM group than in the NGT group (NGT: 11.706 ± 3.918 pg/mL; p-DM: 10.736 ± 3.722 pg/mL; type 2 diabetes mellitus &lsqb;T2DM group]: 9.884 ± 2.804 pg/mL, P = .008). In Study 2, significantly decreased serum GDNF levels were observed in subjects with poor glycemic control or depression (glycated hemoglobin &lsqb;HbA1c] <7.0% without depression: 11.524 ± 2.903 pg/mL; HbA1c ≥7.0% without depression: 10.625 ± 2.577 pg/mL; HbA1c <7.0% with depression: 10.355 ± 2.432 pg/mL; HbA1c ≥7.0% with depression: 8.824 ± 2.102 pg/mL, P = .008). Double-factor variance analysis showed that glycemic control and depression were independent factors for the GDNF level. Moreover, the serum GDNF level was significantly inversely associated with the fasting plasma glucose, 2 hours postprandial plasma glucose, HbA1c, and PHQ-9 score.Conclusion: Glycemic dysregulation was an independent factor for the GDNF level. These findings suggest that GDNF level might be involved in the pathophysiology of T2DM and depression through various pathways.Abbreviations: BP = blood pressure; CHO = cholesterol; DDS = diabetes distress scale; DM = diabetes mellitus; EQ-5D = the health-related dimensions of the EuroQol-5 scale; FPG = fasting plasma glucose; GDNF = glial-derived neurotrophic factor; HbA1c = glycated hemoglobin; HDL = high-density lipoprotein; LDL = low-density lipoprotein; NGT = normal glucose tolerance; PHQ-9 = Patient Health Questionnaire; p-DM = prediabetes; PPG = postprandial plasma glucose; SNP = single-nucleotide polymorphism; T2DM = type 2 diabetes mellitus; TG = triglyceride     

Efficacy and Safety of Iglarlixi in Hispanics and Non-Hispanic Whites with Type 2 Diabetes

Objective: Type 2 diabetes (T2D) is more common in Hispanic than non-Hispanic white (NHW) populations worldwide, and ethnicity, among other factors, may affect response to therapy. The efficacy and safety of insulin glargine 100 units/mL (iGlar) and the fixed-ratio combination of iGlar and the glucagon-like peptide 1 receptor agonist lixisenatide (iGlarLixi) was assessed in Hispanic and NHW patients with T2D from 25 countries.Methods: In this post hoc analysis, data from two 30-week randomized controlled trials comparing iGlar and iGlarLixi in patients with T2D uncontrolled on basal insulin ± oral antidiabetes drugs (OADs; LixiLan-L: NCT02058160) or uncontrolled on metformin ± OADs (LixiLan-O: NCT02058147) were evaluated.Results: Of the 1,512 patients included across trials, 301 were Hispanic and 1,211 NHW. Compared with iGlar, iGlarLixi resulted in greater reductions in glycated hemoglobin (A1C) and 2-hour postprandial glucose and a higher proportion of patients at target A1C <7.0% (<53 mmol/mol), regardless of ethnicity. Among NHWs from the LixiLan-L trial, documented symptomatic hypoglycemia (plasma glucose ≤70 mg/dL) rates were higher with iGlar compared with iGlarLixi (P = .06), whereas this trend was reversed among Hispanics (P = .07). Nevertheless, in both trials, a greater proportion of patients taking iGlarLixi than iGlar reached the composite efficacy endpoints of target A1C without hypoglycemia and target A1C without weight gain, regardless of ethnicity.Conclusion: These results indicate that iGlarLixi is a viable therapeutic option for both Hispanic and NHW patients with T2D, as it is efficacious without a significant increase in hypoglycemia, irrespective of ethnicity.Abbreviations: A1C = glycated hemoglobin; BMI = body mass index; FPG = fasting plasma glucose; FRC = fixed-ratio combination; GLP-1 RA = glucagon-like peptide 1 receptor agonist; HDL-C = high-density-lipoprotein cholesterol; iGlar = insulin glargine; iGlarLixi = insulin glargine + lixisenatide; LDL-C = low-density-lipoprotein cholesterol; NHW = non-Hispanic white; OAD = oral antidiabetes drug; PPG = postprandial glucose; T2D = type 2 diabetes     

Discovery and preclinical profile of teneligliptin (3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl]thiazolidine): A highly potent,selective, long-lasting and orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes

Dipeptidyl peptidase IV (DPP-4) inhibition is suitable mechanism for once daily oral dosing regimen because of its low risk of hypoglycemia. We explored linked bicyclic heteroarylpiperazines substituted at the γ-position of the proline structure in the course of the investigation of l-prolylthiazolidines. The efforts led to the discovery of a highly potent, selective, long-lasting and orally active DPP-4 inhibitor, 3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl]thiazolidine (8g), which has a unique structure characterized by five consecutive rings. An X-ray co-crystal structure of 8g in DPP-4 demonstrated that the key interaction between the phenyl ring on the pyrazole and the S₂ extensive subsite of DPP-4 not only boosted potency, but also increased selectivity. Compound 8g, at 0.03 mg/kg or higher doses, significantly inhibited the increase of plasma glucose levels after an oral glucose load in Zucker fatty rats. Compound 8g (teneligliptin) has been approved for the treatment of type 2 diabetes in Japan.     

2-Substituted fortimicins by ring opening of 2-deoxy-1,2-epimino-2-epi-fortimicin B and by nucleophilic displacements of 2-O-(methylsulfonyl)fortimicin derivatives

Opening of the aziridine ring of 2-deoxy-1,2-epimino-2-epi-fortimicin B (10) has been effected with both chloride and azide. The reactions are both stereo- and regiospecific and give 2-chloro-2-deoxyfortimicin B (2c) and 2-azido-2-deoxy-fortimicin B (2d). The nucleophilic displacements of the methanesulfonate groups of some 1-N-benzyloxycarbonyl-2-O-(methylsulfonyl)fortimicin derivatives with chloride, azide, and cyanide in N,N-dimethylformamide are dependent both on the nature of the nucleophile and the specific 1-N-benzyloxycarbonyl-2-methanesulfonate employed as the substrate. Striking differences in the stereochemistry of the azide displacements with different 2-methanesulfonates are believed to have a conformational basis. 2-Amino-2-deoxyfortimicin A (1c) and both of the 2-epimeric 2-chloro-2-deoxyfortimicins A (1b) and (5) were prepared for antibacterial assay and the in vitro results are reported.     

A Cross-Sectional Study of the Association between the 1-Hour Oral Glucose Tolerance Test and the Metabolic Syndrome in a High-Risk Sample with Impaired Fasting Glucose

Objective: The aim of this study was to evaluate the association between the 1-hour oral glucose tolerance test (OGTT) (≥155 mg/dL) and metabolic syndrome (MS) in a sample with previous impaired fasting glucose (IFG).Methods: Three hundred and twenty four Peruvian subjects with a history of IFG ≥100 mg/dL were selected for a cross-sectional study. They underwent a 75 g OGTT and were assigned to different groups according to the result. We evaluated the association between 1-hour OGTT and MS.Results: The mean age was 56.5 ± 12.6 years and 191 (61.5%) were female. During the OGTT, we found 28 (8.6%) subjects with diabetes, 74 (22.8%) with IGT, and 222 (68.5%) with a normal glucose tolerance test with a 2-hour glucose <140 mg/dL (NGT). In the NGT group, 124 (38.3%) had 1-hour glucose levels <155 mg/dL, while 98 (30.2%) had 1-hour glucose levels ≥155 mg/dL. Evaluating the association between the 1-hour value in the OGTT and MS, we found that subjects with a 1-hour glucose ≥155 mg/dL were more than twice as likely to have MS as those with a 1-hour glucose <155 mg/dL (odds ratio = 2.64, 95% confidence interval: 1.52 to 4.57). In addition, body mass index, fasting glycemia, triglycerides, and waist circumferences were significantly higher in subjects with 1-hour glucose levels ≥155 mg/dL compared to those with 1-hour glucose levels <155 mg/dL (P<.05).Conclusion: Among subjects with IFG, performing an OGTT was helpful to identify subjects with 1-hour glucose levels ≥155 mg/dL and NGT who were significantly more likely to have MS and a worse cardiometabolic risk profile.Abbreviations: AST = aspartate aminotransferase; BMI = body mass index; CI = confidence interval; IFG = impaired fasting glucose; IGT = impaired glucose tolerance; LDL = low-density lipoprotein; MS = metabolic syndrome; NGT = normal glucose tolerance; OGTT = oral glucose tolerance test; OR = odds ratio; T2DM = type 2 diabetes; TG = triglycerides     

Gender differences in adiponectin and low-grade inflammation among individuals with normal glucose tolerance,prediabetes, and type 2 diabetes

Background: Women with prediabetes and type 2 diabetes mellitus have a higher relative risk of cardiovascular disease than do men. The reason for this is unknown.Objective: We studied the gender differences in adiponectin and in low-grade inflammation, measured by high-sensitivity C-reactive protein (hs-CRP) and interleukin-1 receptor antagonist (IL-1RA), in individuals with normal glucose tolerance, prediabetes, and type 2 diabetes.Methods: In this population-based, cross-sectional study, all individuals born in 1942, 1947, 1952, 1957, and 1962 in Pieksämäki, East Finland, were recruited for participation. A 75-g oral glucose tolerance test and lipid panel were performed, and concentrations of adiponectin, hs-CRP, and IL-1RA were measured. The World Health Organization diagnostic criteria for diabetes and prediabetes (impaired fasting glucose and/or impaired glucose tolerance) were used. Statistical comparisons between men and women were performed by a bootstrap-type ANCOVA.Results: The eligible population included 1294 middle-aged individuals, and of these, 904 (406 men and 498 women) had complete data and were included in the analyses. Absolute adiponectin concentrations were significantly higher in women at all levels of glucose tolerance (normal, prediabetes, and type 2 diabetes), but the gender ratio (women to men) for adiponectin concentrations decreased linearly (P = 0.011) from normal glucose tolerance (1.61; 95% CI, 1.48–1.75) to prediabetes (1.57; 95% CI, 1.36–1.83) and diabetes (1.16; 95% CI, 0.87–1.53). Among participants with normal glucose tolerance, no significant difference was found between the sexes in hs-CRP or IL-1RA. Among patients with prediabetes or diabetes, women had significantly higher concentrations than did men for hs-CRP (for prediabetes, 2.0 vs 1.5 mg/L; ratio, 1.39; 95% CI, 1.04–1.85) and IL-1RA (for prediabetes, 255 vs 178 pg/mL; ratio, 1.43; 95% CI, 1.121.83). The gender ratios (women to men) increased linearly from normal glucose tolerance to prediabetes and type 2 diabetes for both hs-CRP (P = 0.019) and IL-1RA (P = 0.013).Conclusions: Adiponectin concentrations in women decreased relatively more compared with men across individuals with normal glucose tolerance, prediabetes, and type 2 diabetes, whereas inflammatory markers increased relatively more in women. Higher inflammatory stress in women than in men with prediabetes and type 2 diabetes may explain their relatively higher cardiovascular disease risk.     

The inhibitory activity of 2-acetamido-2-deoxy-D-gluconolactones and their isopropylidene derivatives on 2-acetamido-2-deoxy-beta-D-glucosidase

2-Acetamido-2-deoxy-D-glucono-1,4-lactone (1) and 2-acetamido-2-deoxy-D-gluconic acid (3) have been examined for inhibitory activity against 2-acetamido-2-deoxy-β-D-glucosidase from bull epididymis. Crystalline 1 and 3 were compared with the known, crystalline 2-acetamido-2-deoxy-D-glucono-1,5-lactone (2), and a correlation of the activities of these compounds with various factors is presented. The inhibition constant of the 1,5-lactone 2 is lower (0.45μM) than that (4.43μM) of the 1,4-lactone 1. The effect of time is the opposite; whereas the activity of solutions of 2 decreases with time, solutions of 1 show an increase in inhibitory power, but both reach an equilibrium after 5 h. The free acid 3 exhibits no inhibitory activity. 2-Acetamido-2-deoxy-5,6-O-isopropylidene-D-glucono- 1,4-lactone (4) and 2-acetamido-2-deoxy-4,6-O-isopropylidene-D-glucono-1,5-lactone (5), which are appropriately protected to prevent conversion into the other lactone isomer, were also tested; 4 has 1/1000th the activity of 5.     

Discovery of 3-(4-methanesulfonylphenoxy)-N-[1-(2-methoxy-ethoxymethyl)-1H-pyrazol-3-yl]-5-(3-methylpyridin-2-yl)-benzamide as a novel glucokinase activator (GKA) for the treatment of type 2 diabetes mellitus

Novel heteroaryl-containing benzamide derivatives were synthesized and screened using an in vitro assay measuring increases in glucose uptake and glucokinase activity stimulated by 10 mM glucose in rat hepatocytes. From a library of synthesized compounds, 3-(4-methanesulfonylphenoxy)-N-[1-(2-methoxy-ethoxymethyl)-1H-pyrazol-3-yl]-5-(3-methyl pyridin-2-yl)-benzamide (19e) was identified as a potent glucokinase activator with assays demonstrating an EC₅₀ of 315 nM and the induction of a 2.23 fold increase in glucose uptake. Compound 19e exhibited a glucose AUC reduction of 32% (50 mg/kg) in an OGTT study with C57BL/6J mice compared to 28% for metformin (300 mg/kg). Single treatment of the compound in C57BL/J6 and ob/ob mice elicited basal glucose lowering activity, while in a two-week repeated dose study with ob/ob mice, the compound significantly decreased blood glucose levels with no evidence of hypoglycemia risk. In addition, 19e exhibited favorable pharmacokinetic parameters in mice and rats and excellent safety margins in liver and testicular toxicity studies. Compound 19e was therefore selected as a development candidate for the potential treatment of type 2 diabetes.     

SGLT-2 Inhibitor Therapy Added to GLP-1 Agonist Therapy in the Management of T2DM

Objective: To assess the real-world efficacy and safety of canagliflozin therapy added to type 2 diabetes mellitus (T2DM) patients who have received a minimum 1 year of glucagon-like peptide-1 (GLP-1) agonist therapy.Methods: This pre-post observational study assessed the efficacy and safety of canagliflozin in a group of T2DM patients from a community endocrinology practice who received GLP-1 agonist therapy for a minimum of 12 months. The primary study outcome was change in mean glycated hemoglobin (HbA1c) level from baseline. Secondary endpoints included changes in average weight, and comparison of the percentage of patients obtaining an HbA1c <7%.Results: A total of 75 patients met all the study criteria. Baseline patient characteristics were as follows: average age, 58 ± 9 years; mean duration of T2DM, 14 ± 6 years; 56% male; 92% Caucasian; baseline body mass index (BMI), 39.4 ± 9.4 kg/m²; and mean baseline HbA1c, 7.94 ± 0.69%. HbA1c and weight were significantly reduced by 0.39% and 4.6 kg, respectively. Adverse effects were reported by 13 (17.3%) patients, including 4 (5.3%) who discontinued canagliflozin because of adverse reactions.Conclusion: Canagliflozin was generally well tolerated and significantly further reduced mean HbA1c levels and body weight in patients with T2DM when added to GLP-1 regimen.Abbreviations:BP = blood pressureBUN = blood urea nitrogenCANTATA = Canagliflozin Treatment and Trial AnalysisDBP = diastolic blood pressureDKA = diabetic ketoacidosisDPP-4 = dipeptidyl peptidase-4EMR = electronic medical recordFDA = Food and Drug AdministrationGFR = glomerular filtration rateGLP-1 = glucagon-like peptide-1HbA1c = glycated hemoglobinHDL-C = high-density lipoprotein cholesterolLDL-C = low-density lipoprotein cholesterolSCr = serum creatinineSGLT-2 = sodium glucose cotransporter 2T2DM = type 2 diabetes mellitusTZD = thiazolidinedioneUTI = urinary tract infection     

Impact of Glucose Management Team on Outcomes of Hospitalization in Patients With Type 2 Diabetes Admitted to the Medical Service

Objective: To improve glycemic control of hospitalized patients with diabetes and hyperglycemia, many medical centers have established dedicated glucose management teams (GMTs). However, the impact of these specialized teams on clinical outcomes has not been evaluated.Methods: We conducted a retrospective study of 440 patients with type 2 diabetes admitted to the medical service for cardiac or infection-related diagnosis. The primary endpoint was a composite outcome of several well-recognized markers of morbidity, consisting of: death during hospitalization, transfer to intensive care unit, initiation of enteral or parenteral nutrition, line infection, new in-hospital infection or infection lasting more than 20 days of hospitalization, deep venous thrombosis or pulmonary embolism, rise in plasma creatinine, and hospital re-admissions.Results: Medical housestaff managed the glycemia in 79% of patients (usual care group), while the GMT managed the glycemia in 21% of patients (GMT group). The primary outcome was similar between cohorts (0.95 events per patient versus 0.99 events per patient in the GMT and usual care cohorts, respectively). For subanalysis, the subjects in both groups were stratified into those with average glycemia of <180 mg/dL versus those with glycemia >180 mg/dL. We found a significant beneficial impact of glycemic management by the GMT on the composite outcome in patients with average glycemia >180 mg/dL during their hospital stay. The number of patients who met primary outcome was significantly higher in the usual care group (40 of 83 patients, 48%) than in the GMT-treated cohort (8 of 33 patients, 25.7%) (P<.02).Conclusion: Our data suggest that GMTs may have an important role in managing difficult-to-control hyperglycemia in the inpatient setting.Abbreviations:BG = blood glucoseGMT = glucose management teamHbA1c = hemoglobin A1cICU = intensive care unitPOC = point of careT2D = type 2 diabetes     

Design,synthesis and biological evaluation of (2S,3R,4R,5S,6R)-5-fluoro-6-(hydroxymethyl)-2-aryltetrahydro-2H-pyran-3,4-diols as potent and orally active SGLT dual inhibitors

A new series of (2S,3R,4R,5S,6R)-5-fluoro-6-(hydroxymethyl)-2-aryltetrahydro-2H-pyran-3,4-diols as dual inhibitors of sodium glucose co-transporter proteins (SGLTs) were disclosed. Two methods were developed to efficiently synthesize C₅-fluoro-lactones 3 and 4, which are key intermediates to the C₅-fluoro-hexose based C-aryl glucosides. Compound 2b demonstrated potent hSGLT1 and hSGLT2 inhibition (IC₅₀?=?43?nM for SGLT1 and IC₅₀?=?9?nM for SGLT2). It showed robust inhibition of blood glucose excursion in oral glucose tolerance test (OGTT) in Sprague Dawley (SD) rats and exerted pronounced antihyperglycemic effects in db/db mice and high-fat diet-fed ZDF rats when dosed orally at 10?mg/kg.     

Evaluation of Insulin Glargine and Exenatide Alone and in Combination: a Randomized Clinical Trial with Continuous Glucose Monitoring and Ambulatory Glucose Profile Analysis

Objective: Characterize the effectiveness of insulin glargine alone, exenatide alone, or combined in subjects taking stable doses of metformin and evaluate their impact on hemoglobin A1C, hypoglycemia, weight, and glucose variability.Methods: Open-label, randomized, parallel-arm study of adults with type 2 diabetes naïve to both insulin and glucagon-like peptide 1 (GLP-1) agonist who were not at A1C goal despite treatment with metformin. This prospective interventional study employed blinded continuous glucose monitoring ambulatory glucose profile (AGP) reports over 32 weeks. Subjects were randomized to treatment with glargine (Iglar), exenatide (GLP-1), or combination of glargine and exenatide (Iglar + GLP-1). At midpoint, those not at A1C target had the second medication added; those on Iglar + GLP-1 continued therapy optimization.Results: Decreases in A1C were: 7.6 to 6.2% for Iglar + GLP-1, 7.5 to 6.6% for Iglar, and 7.5 to 6.4% for GLP-1. Iglar + GLP-1 achieved A1C targets faster (14 to 16 weeks) but had more hypoglycemia. Hypoglycemia rates increased slightly for all arms. Weight loss was achieved in all regimens including GLP-1. Glucose variability was not reduced to the same extent in the Iglar arm as the GLP-1 arm.Conclusion: Addition of Iglar and/or GLP-1 to metformin for patients not at treatment goal was safe and effective. The order of medication addition needs to consider individualized AGP patterns and goals. Iglar + GLP-1 resulted in rapid A1C lowering, whereas GLP-1 was noted to have less hypoglycemia. Weight loss was most pronounced in GLP-1 monotherapy, suggesting that GLP-1 may mitigate the weight gain of Iglar. Any treatment with GLP-1 showed significant decreases in glucose variability.Abbreviations: A1C = hemoglobin A1c; AGP = ambulatory glucose profile; CGM = continuous glucose monitoring; GLM = general linear model; GLP-1 = glucagon-like peptide 1 (exenatide); Iglar = insulin glargine; SGLT2 = sodium-glucose cotransporter 2; SMBG = self-monitoring blood glucose; SU = sulfonylurea; T2D = type 2 diabetes mellitus