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Policaptil Gel Retard in adult subjects with the metabolic syndrome: Efficacy, safety, and tolerability compared to metformin.
Guarino, G, Della Corte, T, Strollo, F, Gentile, S, ,
Diabetes & metabolic syndrome. 2021;(3):901-907
Abstract
BACKGROUND Policaptil Gel Retard® (PGR), is a new macromolecule complex based on polysaccharides slowing the rate of carbohydrate and fat absorption. It proved to significantly reduce body weight, acanthosis nigricans expression, HbA1c levels, and glucose metabolism abnormalities in obese, hyper-insulinemic adolescents. No such data are available for adults. AIM: to compare the effects of PGR vs. metformin in adult subjects with the Metabolic Syndrome (MS) and T2DM on a Low Glycemic Index diet. SUBJECTS AND METHODS This spontaneous clinical, longitudinal, single-blind, randomized study based on a per-protocol analysis enrolled 100 outpatients with MS and T2DM consecutively referring to our clinic for three months, and randomly assigned to either the active treatment (Group A:, 6 tablets/day) or the comparator (Group B: Metformin tablets, 1500-2000 mg/day in two divided doses during the two main meals, to minimize side effects) to be taken 30 min before each main meal in equally divided doses. Serum lipid profile, anthropometry, HOMA-IR index, and tolerability parameters were evaluated before and after a 6-month follow-up period. RESULTS all parameters improved at a similar rate in both groups but for the lipid profile, which got even better in Group A. Group A also experienced less prominent gastrointestinal side effects than its counterpart. CONCLUSION For the first time, we showed the non-inferiority of PGR compared to metformin in obese adult subjects with the MS and T2DM as for glycemic control and a clear-cut superiority of PGR in terms of both serum lipid-lowering capacity and tolerability.
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Effects of ipragliflozin versus metformin in combination with sitagliptin on bone and muscle in Japanese patients with type 2 diabetes mellitus: Subanalysis of a prospective, randomized, controlled study (PRIME-V study).
Koshizaka, M, Ishikawa, K, Ishibashi, R, Maezawa, Y, Sakamoto, K, Uchida, D, Nakamura, S, Yamaga, M, Yokoh, H, Kobayashi, A, et al
Journal of diabetes investigation. 2021;(2):200-206
Abstract
AIMS/INTRODUCTION Recent randomized clinical trials have suggested that sodium-glucose cotransporter 2 inhibitors might reduce cardiovascular events and heart failure, and have renal protective effects. Despite these remarkable benefits, the effects of sodium-glucose cotransporter 2 inhibitors on bone and muscle are unclear. MATERIALS AND METHODS A subanalysis of a randomized controlled study was carried out to evaluate the effects of the sodium-glucose cotransporter 2 inhibitor, ipragliflozin, versus metformin on bone and muscle in Japanese patients with type 2 diabetes mellitus (baseline body mass index ≥22 kg/m2 and hemoglobin A1c 7-10%) who were already receiving sitagliptin. These patients were randomly administered ipragliflozin 50 mg or metformin 1,000-1,500 mg daily. The effects of these medications on the bone formation marker, bone alkali phosphatase; the bone resorption marker, tartrate-resistant acid phosphatase 5b (TRACP-5b); handgrip strength; abdominal cross-sectional muscle area; and bone density of the fourth lumbar vertebra were evaluated. RESULTS After 24 weeks of treatment, the changes in bone density of the fourth lumbar vertebra, handgrip strength and abdominal cross-sectional muscle area were not significantly different between the two groups. However, TRACP-5b levels increased in patients treated with ipragliflozin compared with patients treated with metformin (median 11.94 vs -10.30%, P < 0.0001), showing that ipragliflozin can promote bone resorption. CONCLUSIONS There were no adverse effects on bone or muscle when sitagliptin was used in combination with either ipragliflozin or metformin. However, ipragliflozin combination increased the levels of TRACP-5b. A long-term study is required to further understand the effects of this TRACP-5b increase caused by ipragliflozin.
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Efficacy and safety of teneligliptin added to metformin in Chinese patients with type 2 diabetes mellitus inadequately controlled with metformin: A phase 3, randomized, double-blind, placebo-controlled study.
Ji, L, Li, L, Ma, J, Li, X, Li, D, Meng, B, Lu, W, Sun, J, Liu, Y, Takayanagi, G, et al
Endocrinology, diabetes & metabolism. 2021;(2):e00222
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Abstract
INTRODUCTION We evaluated the efficacy and safety of teneligliptin compared with placebo when added to metformin therapy in Chinese patients with type 2 diabetes inadequately controlled with metformin monotherapy. METHODS This multicentre, randomized, double-blind, placebo-controlled, parallel-group study enrolled type 2 diabetes patients with glycosylated haemoglobin (HbA1c) 7.0%-<10.0% and fasting plasma glucose (FPG) <270 mg/dl, receiving a stable metformin dose ≥1000 mg/day. Teneligliptin 20 mg or placebo was administered orally once daily (qd) before breakfast for 24 weeks. The primary efficacy end-point was change in HbA1c from baseline to Week 24. Safety end-points included the incidence of adverse events (AEs). RESULTS The least square mean (LSM) change from baseline (standard error [SE]) was -0.72 (0.07) (95% confidence intervals [CI], -0.87, -0.58) for teneligliptin and -0.01 (0.07) (95% CI, -0.16, 0.13) for placebo. The differences (LSM ± SE) between the placebo and teneligliptin groups in HbA1c and FPG were -0.71% ± 0.11% (p < .0001) and -16.5 ± 4.7 mg/dl (p = .0005), respectively. Teneligliptin yielded significant changes in HbA1c (-0.81%; p < .0001) and FPG (-22.2 mg/dl; p < .0001) at Week 12. At Week 24, more patients achieved HbA1c <7.0% with teneligliptin (41.7%) compared with placebo (16.1%; p < .0001). Treatment-emergent AE incidence was similar with teneligliptin (58.9%) and placebo (68.3%); upper respiratory tract infection, hyperuricaemia and hyperlipidaemia were the most common AEs. CONCLUSIONS Teneligliptin 20 mg qd for 24 weeks added to ongoing metformin treatment significantly decreased HbA1c and FPG levels compared with placebo in Chinese type 2 diabetes patients. The combination was safe and tolerable.
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Meta-analysis on the efficacy and safety of SGLT2 inhibitors and incretin based agents combination therapy vs. SGLT2i alone or add-on to metformin in type 2 diabetes.
Zhou, Y, Geng, Z, Wang, X, Huang, Y, Shen, L, Wang, Y
Diabetes/metabolism research and reviews. 2020;(2):e3223
Abstract
We aimed to determine whether sodium-glucose cotransporter type 2 inhibitors (SGLT2is) and incretin-based agents combination therapy produces more benefits than SGLT2is alone in patients with type 2 diabetes mellitus (T2DM). PubMed, Embase, and the Cochrane Library were searched for randomized controlled trials (RCTs) comparing SGLT2is plus Dipeptidyl-Peptidase 4 inhibitors (SGLT2is/DPP4is) or glucagon like peptide-1 receptor agonists (SGLT2is/GLP-1RAs) against SGLT2is as monotherapy or add-on to metformin in T2DMs. A total of 13 studies with 7350 participants were included. Combination with GLP-1RAs exhibited more HbA1c reduction (WMD: -0.8; 95% CI, -1.14 to -0.45%), weight loss (-1.46; 95% CI, -2.38 to -0.54 kg), and systolic blood pressure (SBP) reduction (-2.88; 95% CI, -4.52 to -1.25 mmHg) versus SGLT2is alone but increased the gastrointestinal disorder risk (RR: 1.68; 95% CI, 1.14-2.47). Combination with DPP4is exhibited an extra effect on HbA1c reduction (-0.47; 95% CI, -0.58 to -0.37%), a neutral effect on weight (0.19; 95% CI, -0.11 to 0.48 kg) and SBP (-0.01; 95% CI, -0.85 to 0.63 mmHg), and ameliorated the genital infections risk (0.73; 95% CI, 0.54-0.97) versus SGLT2is. Meta-regression indicated the hypoglycemic efficacy of SGLT2is/DPP4is is higher in Asians than in other ethnics, and the differences in BMI across ethnic groups may mediate this effect. SGLT2is and incretin-based agents combination therapy is efficacious and safe versus SGLT2is alone in T2DMs. Particularly, combination with GLP-1RAs shows additional benefits to glycemic, weight, and SBP control to a larger extent than DPP4is, while combination with DPP4is ameliorates the risk for genital infection seen with SGLT2is. We highlight the need for individualized treatment related to the selection of this novel combination therapy.
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Sex Differences in Cardiovascular Effectiveness of Newer Glucose-Lowering Drugs Added to Metformin in Type 2 Diabetes Mellitus.
Raparelli, V, Elharram, M, Moura, CS, Abrahamowicz, M, Bernatsky, S, Behlouli, H, Pilote, L
Journal of the American Heart Association. 2020;(1):e012940
Abstract
Background Randomized controlled trials showed that newer glucose-lowering agents are cardioprotective, but most participants were men. It is unknown whether benefits are similar in women. Methods and Results Among adults with type 2 diabetes mellitus not controlled with metformin with no prior use of insulin, we assessed for sex differences in the cardiovascular effectiveness and safety of sodium-glucose-like transport-2 inhibitors (SGLT-2i), glucagon-like peptide-1 receptor agonists (GLP-1RA), dipeptidyl peptidase-4 inhibitors, initiated as second-line agents relative to sulfonylureas (reference-group). We studied type 2 diabetes mellitus American adults with newly dispensed sulfonylureas, SGLT-2i, GLP-1RA, or dipeptidyl peptidase-4 inhibitors (Marketscan-Database: 2011-2017). We used multivariable Cox proportional hazards models with time-varying exposure to compare time to first nonfatal cardiovascular event (myocardial infarction/unstable angina, stroke, and heart failure), and safety outcomes between drugs users, and tested for sex-drug interactions. Among 167 254 type 2 diabetes mellitus metformin users (46% women, median age 59 years, at low cardiovascular risk), during a median 4.5-year follow-up, cardiovascular events incidence was lower in women than men (14.7 versus 16.7 per 1000-person-year). Compared with sulfonylureas, hazard ratios (HRs) for cardiovascular events were lower with GLP-1RA (adjusted HR-women: 0.57, 95% CI: 0.48-0.68; aHR-men: 0.82, 0.71-0.95), dipeptidyl peptidase-4 inhibitors (aHR-women: 0.83, 0.77-0.89; aHR-men: 0.85, 0.79-0.91) and SGLT-2i (aHR-women: 0.58, 0.46-0.74; aHR-men: 0.69, 0.57-0.83). A sex-by-drug interaction was statistically significant only for GLP-1RA (P=0.002), suggesting greater cardiovascular effectiveness in women. Compared with sulfonylureas, risks of adverse events were similarly lower in both sexes for GLP-1RA (aHR-women: 0.81, 0.73-0.89; aHR-men: 0.80, 0.71-0.89), dipeptidyl peptidase-4 inhibitors (aHR-women: 0.82, 0.78-0.87; aHR-men: 0.83, 0.78-0.87) and SGLT-2i (aHR-women: 0.68, 0.59-0.78; aHR-men: 0.67, 0.59-0.78) (all sex-drug interactions for adverse events P>0.05). Conclusions Newer glucose-lowering drugs were associated with lower risk of cardiovascular events than sulfonylureas, with greater effectiveness of GLP-1RA in women than men. Overall, they appeared safe, with a better safety profile for SGLT-2i than for GLP-1RA regardless of sex.
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Comparison of the efficacy between NAC and metformin in treating PCOS patients: a meta-analysis.
Song, Y, Wang, H, Huang, H, Zhu, Z
Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. 2020;(3):204-210
Abstract
Our aim is to evaluate the clinical effectiveness and safety by comparing N-acetyl-cysteine (NAC) with metformin administrated by polycystic ovary syndrome (PCOS) patients. Systematic review and meta-analysis of randomized clinical trials (RCTs). MEDLINE, EMBASE, Web of Science and China National Knowledge Infrastructure were searched for studies. 10 studies were considered eligible for inclusion. NAC significantly reduced BMI and total testosterone, there was no significant difference in pregnancy rate, serum LH level, fasting insulin, and LH/FSH ratio. In conclusions, NAC may be considered as an alternative supplement to metformin, but large-scale randomized controlled trials are needed to assess the efficacy and safety of NAC in PCOS patients.
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Efficacy of the treatment with dapagliflozin and metformin compared to metformin monotherapy for weight loss in patients with class III obesity: a randomized controlled trial.
Ferreira-Hermosillo, A, Molina-Ayala, MA, Molina-Guerrero, D, Garrido-Mendoza, AP, Ramírez-Rentería, C, Mendoza-Zubieta, V, Espinosa, E, Mercado, M
Trials. 2020;(1):186
Abstract
BACKGROUND Mexico has one of the highest prevalence rates of obesity worldwide. New pharmacological strategies that focus on people with class III obesity are required. Metformin and dapagliflozin are two drugs approved for the treatment of diabetes. Beyond its effects on glucose, metformin has been suggested by some studies to result in weight loss. Therapy with dapagliflozin is associated with a mild but sustained weight loss in patients with diabetes. The primary outcome of the study is to determine if the combined treatment with dapagliflozin and metformin is more effective than monotherapy with metformin for weight loss in patients with class III obesity and prediabetes or diabetes who are awaiting bariatric surgery (including those patients who do have surgery). We also aimed to assess the effect of this combined treatment on waist circumference, triglycerides, blood pressure, and inflammatory cytokines. METHODS This randomized phase IV clinical trial will include patients with diabetes or prediabetes who are between the ages of 18 and 60 years and exhibit grade III obesity (defined as body mass index ≥ 40 kg/m2). Patients using insulin will be excluded. Subjects will be randomized to one of two groups as follows: 1) metformin tablets 850 mg PO bid or 2) metformin tablets 850 mg PO bid plus dapagliflozin tablets 10 mg PO qd. The sample size required is 108 patients, which allows for a 20% dropout rate: 54 patients in the metformin group and 54 in the metformin/dapagliflozin group. All participants will receive personalized nutritional advice during the study. A run-in period of one month will be used to assess tolerance and adherence to treatment regimens. Anthropometric and biochemical variables will be recorded at baseline and at 1, 3, 6, and 12 months. A serum sample to determine glucagon, ghrelin, adiponectin, resistin, interleukin 6, and interleukin 10 will be collected at baseline and before surgery, or at 12 months (whatever happens first). Adherence to treatment and adverse and secondary events will be recorded throughout the study. An intention-to-treat analysis will be used. DISCUSSION Forty-six percent of the patients in our Obesity Clinic have been diagnosed with prediabetes (32%) or diabetes (14%). The use of dapagliflozin in this population could improve weight loss and other cardiovascular factors. This effect could be translated into less time before undergoing bariatric surgery and better control of associated comorbidities. TRIAL REGISTRATION Clinicaltrials.gov, ID: NCT03968224. Retrospectively registered on May 29, 2019.
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Efficacy and Safety of Pioglitazone versus Glimepiride after Metformin and Alogliptin Combination Therapy: A Randomized, Open-Label, Multicenter, Parallel-Controlled Study.
Kim, JM, Kim, SS, Kim, JH, Kim, MK, Kim, TN, Lee, SH, Lee, CW, Park, JY, Kim, ES, Lee, KJ, et al
Diabetes & metabolism journal. 2020;(1):67-77
Abstract
BACKGROUND There is limited information regarding the optimal third-line therapy for managing type 2 diabetes mellitus (T2DM) that is inadequately controlled using dual combination therapy. This study assessed the efficacy and safety of pioglitazone or glimepiride when added to metformin plus alogliptin treatment for T2DM. METHODS This multicenter, randomized, active-controlled trial (ClinicalTrials.gov: NCT02426294) recruited 135 Korean patients with T2DM that was inadequately controlled using metformin plus alogliptin. The patients were then randomized to also receive pioglitazone (15 mg/day) or glimepiride (2 mg/day) for a 26-week period, with dose titration was permitted based on the investigator's judgement. RESULTS Glycosylated hemoglobin levels exhibited similar significant decreases in both groups during the treatment period (pioglitazone: -0.81%, P<0.001; glimepiride: -1.05%, P<0.001). However, the pioglitazone-treated group exhibited significantly higher high density lipoprotein cholesterol levels (P<0.001) and significantly lower homeostatic model assessment of insulin resistance values (P<0.001). Relative to pioglitazone, adding glimepiride to metformin plus alogliptin markedly increased the risk of hypoglycemia (pioglitazone: 1/69 cases [1.45%], glimepiride: 14/66 cases [21.21%]; P<0.001). CONCLUSION Among patients with T2DM inadequately controlled using metformin plus alogliptin, the addition of pioglitazone provided comparable glycemic control and various benefits (improvements in lipid profiles, insulin resistance, and hypoglycemia risk) relative to the addition of glimepiride.
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Comparing the individual effects of metformin and rosiglitazone and their combination in obese women with polycystic ovary syndrome: a randomized controlled trial.
Li, Y, Tan, J, Wang, Q, Duan, C, Hu, Y, Huang, W
Fertility and sterility. 2020;(1):197-204
Abstract
OBJECTIVE To compare the effects of metformin, rosiglitazone, and their combination in obese polycystic ovary syndrome (PCOS) patients with insulin resistance. DESIGN Prospective randomized controlled trail. SETTING Tertiary teaching hospital. PATIENT(S): Obese Chinese women (body mass index [BMI] ≥25 kg/m2) with insulin resistance who fulfilled the Rotterdam criteria of PCOS. INTERVENTION(S): In group 1, 68 patients administered metformin (1,500 mg/day); in group 2, 67 patients administered rosiglitazone (4 mg/day); in group 3, 69 patients administered metformin (1,000 mg/day) and rosiglitazone (4 mg/day) for 6 months, all with the same diet and regular exercise lifestyle recommendation. MAIN OUTCOME MEASURE(S): Average menstrual interval, anthropometric measurements, androgen-related parameters, and metabolic features of insulin, carbohydrates, and lipids, with intention-to-treat analysis. RESULT(S): The baseline parameters showed no statistically significant differences. After the 6-month treatment, most participants showed an improved menstrual pattern. There were statistically significant decreases in acne scores, weight, BMI, waist circumference, waist-to-hip ratio, and serum testosterone. The metabolic indexes of insulin, carbohydrates, and lipids were improved obviously compared with the baseline in each group. Among the three groups, the patients administered 1,500 mg/day metformin experienced greater reductions in weight. However, the rosiglitazone users (alone or combined with metformin) showed a more notable decline in total cholesterol and triglyceride levels. CONCLUSION(S): Considering the benefits of metformin on weight loss, high-dose metformin (1,500 mg/day) along with lifestyle modification should be recommended for obese, insulin-resistant women with PCOS. Rosiglitazone alone or combined with low-dosage metformin plus lifestyle modification should be considered for the women with abnormal lipid profiles. CLINICAL TRIAL REGISTRATION NUMBER ChiCTR-TRC-13003642 (Chinese Clinical Trial Registry).
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Comparison of metformin plus myoinositol vs metformin alone in PCOS women undergoing ovulation induction cycles: randomized controlled trial.
Agrawal, A, Mahey, R, Kachhawa, G, Khadgawat, R, Vanamail, P, Kriplani, A
Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. 2019;(6):511-514
Abstract
The present study was planned to evaluate the benefit of synergetic effect of Metformin plus Myo-inositol versus Metformin alone in infertile polycystic ovarian syndrome (PCOS) women undergoing ovulation induction. One hundred and twenty infertile PCOS women were randomized: Group I (n = 60) received Metformin (500 mg) plus Myoinositol(600 mg) three times a day; Group II received Metformin 500 mg three times a day. Subjects were advised to try for spontaneous conception. Those who did not conceive after 3 months, were given three cycles of ovulation induction + intrauterine insemination. Hormonal and biochemical profile parameters were done at baseline and after 3 months of therapy. Primary outcome measure was live birth rate. Secondary outcomes were improvement in menstrual cycle, hormonal and biochemical parameters, spontaneous conception, abortions, multiple pregnancy, and ovarian hyperstimulation syndrome. Baseline demographic, hormonal and biochemical parameters were comparable in two groups. There was a significant improvement in menstrual cycles (cycle length and bleeding days) in Group I as compared to Group II. The improvement in biochemical and hormonal parameters were comparable in the two groups after 3 months. Live birth rate was significantly higher in the Group I as compared to Group II [55% (33/60); 26.67% (16/60); p = .002]. The study concluded significantly higher live birth rate in women receiving the combination as compared to metformin alone.