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Effects of exenatide once weekly plus dapagliflozin, exenatide once weekly alone, or dapagliflozin alone added to metformin monotherapy in subgroups of patients with type 2 diabetes in the DURATION-8 randomized controlled trial.
Frías, JP, Hardy, E, Ahmed, A, Öhman, P, Jabbour, S, Wang, H, Guja, C
Diabetes, obesity & metabolism. 2018;(6):1520-1525
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Abstract
This analysis assessed whether responses with exenatide once weekly plus dapagliflozin (n = 231), exenatide once weekly alone (n = 230), or dapagliflozin alone (n = 233) differed in key patient subpopulations of the DURATION-8 trial. Potential treatment-by-subgroup interactions for changes in glycated haemoglobin (HbA1c) and body weight after 28 weeks were evaluated among subgroups determined by baseline HbA1c, age, sex, body mass index, type 2 diabetes duration, race, ethnicity and estimated glomerular filtration rate (eGFR). Exenatide once weekly plus dapagliflozin reduced HbA1c and body weight across all subgroups: least-squares mean reductions ranged from -8.4 to -26.1 mmol/mol (-0.77% to -2.39%) for HbA1c and from -2.07 to -4.55 kg for body weight. Potential treatment-by-subgroup interactions (P < .10) were found for HbA1c change by age (P = .016) and eGFR (P = .097). Age subgroup analysis findings were not consistent with expected mechanistic effects, with the small number of patients aged ≥65 years (n = 74 vs n = 499 for patients aged <65 years) limiting the interpretability of the interaction term. In the exenatide once weekly plus dapagliflozin and dapagliflozin groups, but not the exenatide once weekly group, HbA1c reductions were greater among patients with eGFR ≥90 vs ≥60 to <90 mL/min/1.73 m2 (least-squares mean reductions of -23.6 vs -19.0 mmol/mol [-2.16% vs -1.74%], -17.3 vs -12.0 mmol/mol [-1.58% vs -1.10%], and -17.7 vs -16.9 mmol/mol [-1.62% vs -1.55%] for the respective treatments); this was consistent with the mechanism of action of dapagliflozin. A potential treatment-by-subgroup interaction was observed for change in body weight by sex (P = .099), with greater weight loss for women vs men across all treatments (range -2.56 to -3.98 kg vs -0.56 to -2.99 kg). In conclusion, treatment with exenatide once weekly plus dapagliflozin reduced HbA1c and body weight across all patient subgroups and was more effective than exenatide once weekly or dapagliflozin alone in all adequately sized subgroups.
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Prospective Randomized Biomarker Study of Metformin and Lifestyle Intervention for Prevention in Obese Women at Increased Risk for Endometrial Cancer.
Yates, MS, Coletta, AM, Zhang, Q, Schmandt, RE, Medepalli, M, Nebgen, D, Soletsky, B, Milbourne, A, Levy, E, Fellman, B, et al
Cancer prevention research (Philadelphia, Pa.). 2018;(8):477-490
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Abstract
Obesity increases risk of endometrial cancer through dysregulation of estrogen and insulin signaling. The primary aim of this study was to evaluate the impact of metformin or lifestyle intervention on endometrial proliferation in postmenopausal obese women. Secondary aims included evaluating obesity-related biomarkers and adverse events experienced. Obese, postmenopausal women with prediabetes were randomized into four groups for a 16-week intervention using a 2 (metformin 1700 mg/day vs. placebo) × 2 (lifestyle intervention vs. no lifestyle intervention) factorial design. Pre- and postintervention endometrial proliferation, anthropometrics, body composition, and serum biomarkers (sex hormones, sex hormone binding globulin, IGF-I, adiponectin, omentin, insulin, glucose, and others) were assessed. Data were analyzed with linear regression models and false-discovery rate correction. Of 576 women approached for the study, 52 attended initial screening, 29 were eligible and randomized, and 26 completed the study. Lifestyle intervention resulted in significant loss of weight (-4.23 kg, P = 0.006) and total fat mass (-3.23 kg, P < 0.001). Participants receiving metformin lost 3.43 kg of weight (P = 0.023), but this was not statistically significant after multiple comparisons adjustment controlling false-discovery rate to 10%. Endometrial proliferation was low at baseline (mean 7.1%) and remained unchanged by 16 weeks, but included substantial variability. Metformin and lifestyle intervention produced minor changes to serum biomarkers. Lifestyle intervention produced the most significant changes in weight and body composition. While it is known that obese postmenopausal women are at increased risk for endometrial cancer, improved biomarkers are needed to stratify risk and test prevention strategies, particularly at the endometrial tissue level. Cancer Prev Res; 11(8); 477-90. ©2018 AACR.
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An observational study of vitamin b12 levels and peripheral neuropathy profile in patients of diabetes mellitus on metformin therapy.
Gupta, K, Jain, A, Rohatgi, A
Diabetes & metabolic syndrome. 2018;(1):51-58
Abstract
METHODS A descriptive, observational study was completed in a tertiary care hospital between November 2014 and March 2016. Fifty consecutive patients of Type 2-Diabetes Mellitus who had been on metformin therapy for at least three months were included in our study. Several Parameters were compared with vitamin B12 levels and severity of peripheral neuropathy (using Toronto Clinical Scoring System (TCSS) and Nerve Conduction Velocity). These included the duration of diabetes, duration of metformin usage, dietary history, and HbA1c levels. Definite B12 deficiency was defined as B12<150pg/ml and possible B12 deficiency as <220pg/ml. RESULTS In our study, we found a negative correlation between duration of metformin use and Vitamin B12 levels(r=-0.40). The mean Vitamin B12 levels seen in our study was 212.3pg/mL. There is a positive correlation between the duration of metformin therapy and peripheral neuropathy (r=0.40). The mean TCSS score was 6.8. The percentage of patients with mild neuropathy was 28%, with moderate neuropathy was 20% and severe neuropathy in 12% of the patients. The average duration of metformin use in patients without peripheral neuropathy was 5.5yrs whereas the average length of metformin use in patients with peripheral neuropathy was 10.4 yrs. CONCLUSION Patients on long-term metformin therapy are at a high risk for Vitamin B12 deficiency and peripheral neuropathy. Interval Screening for peripheral neuropathy is recommended for patients on metformin even if Vitamin B12 levels appear to be normal.
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Renal function markers and metformin eligibility.
Tavares Bello, C, Castro Fonseca, R, Sousa Santos, F, Sequeira Duarte, J, Azinheira, J, Vasconcelos, C
Minerva endocrinologica. 2018;(3):246-252
Abstract
BACKGROUND Metformin is the cornerstone of the pharmacological therapy for type 2 diabetes mellitus (T2DM). It belongs to the biguanide class of drugs and it improves hepatic insulin resistance and enhances GLP-1 and peptide YY secretion. Despite being considered safe regarding hypoglycemic risk, renal dysfunction remains the main obstacle to its use due to the underlying risk of lactic acidosis. In the recent past many authors used creatinine values as the decisive marker when it came to choose between pharmacological agents in DM. Serum creatinine values equal or above 1.4 and 1.5 mg/dL were considered contraindications for metformin use in women and men respectively. Nowadays, creatinine is not the only surrogate of renal dysfunction and formulas such as the MDRD and CKD-EPI, that besides serum creatinine also include variables such as gender, age and race, have replaced serum creatinine as the standard for renal function assessment. Furthermore, since the associations between metformin and lactic acidosis in renal disease are not straightforward, its use has been considered safe down to creatinine clearances of 30 mL/min/1.73 m2. The authors describe a population with T2DM being treated with metformin and evaluate the impact of the solo evaluation of serum creatinine or CKD-EPI on biguanide prescription. METHODS Retrospective, observational, single-center study. All type 2 diabetic patients with regular follow up in a Central University Hospital Endocrinology-Diabetology Outpatient Clinic who were being treated with metformin and had at least 2 creatinine and estimated glomerular filtration rate (eGFR) measurements in the last decade were included. Patients were stratified according to renal function-based metformin contraindication criteria: creatinine group included patients with serum creatinine levels above 1.4 and 1.5 mg/dL in women and men respectively, and eGFR group included patients with eGFR below 30 mL/min/1.73 m2. The entire population and both groups are described and compared regarding comorbidities, demographic and laboratory data. The authors report the impact of each renal function marker (serum creatinine or eGFR) when used solo regarding metformin prescription eligibility. RESULTS A total of 2218 patients (61.3% females) with a mean age of 70±12 years is studied. Mean diabetes duration was 11.8±8.8 years. No cases with an eGFR below 30 mL/min/1.73 m2 were identified. On the other hand, in patients with GFR greater than 30 mL/min/1.73 m2, creatinine alone would contraindicate therapy in 274 patients (12.4% of the study population). Comparing Stage 3 chronic kidney disease patients without creatinine contraindication criteria with those with creatinine based contraindication, the data reveals that a higher prevalence of males, with longer diabetes duration, higher target organ damage (cerebrovascular disease, peripheral artery disease, heart failure, neuropathy and retinopathy) and with worse glycemic control were prevalent more in the elevated creatinine group. The use of serum creatinine as the single marker for renal function would significantly reduce metformin eligibility (OR=0.88, 95% CI: 0.8-0.95, P=0.002). CONCLUSIONS Metformin is the first line pharmacological agent in type 2 diabetes mellitus patients, being associated with significant HbA1c reductions and improvements in both micro and macrovascular outcomes. Avoiding its use due to imprecise renal function markers would potentially render the patient deprived of optimal pharmacological therapy for T2DM. Creatinine contraindication criteria alone are associated with unnecessary under prescription of metformin.
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Efficacy and safety of sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors as monotherapy or add-on to metformin in patients with type 2 diabetes mellitus: A systematic review and meta-analysis.
Wang, Z, Sun, J, Han, R, Fan, D, Dong, X, Luan, Z, Xiang, R, Zhao, M, Yang, J
Diabetes, obesity & metabolism. 2018;(1):113-120
Abstract
AIMS: To compare the efficacy and safety of dipeptidyl peptidase-4 inhibitors (DPP-4is) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is) as monotherapy or add-on to metformin (Met) in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS PubMed, Embase and ClinicalTrials.gov sites were systematically searched for randomized controlled trials to assess the efficacy and safety of DPP-4is and SGLT-2is in patients with T2DM. Risk ratio (RR) and weighted mean difference (WMD) were used to evaluate outcomes. RESULTS In the analysis of 25 randomized trials, which involved 14 619 patients, SGLT-2is were associated with a significantly stronger reduction in haemoglobin A1c (HbA1c) (WMD 0.13%, 95% credible interval [CI], 0.04%-0.22%, P = .005) and fasting plasma glucose (FPG) (WMD 0.80 mmol/L, 95% CI, 0.58-1.01 mmol/L, P < .00001) than were DPP-4is. However, no significant difference between the 2 drug categories was found in the risk of hypoglycaemic events (RR, 0.99; 95% CI, 0.78-1.26, P = .92). SGLT-2is plus Met was associated with a more significant decrease in FPG (WMD 0.71 mmol/L, 95% CI, 0.43-1.00 mmol/L, P < .00001) than was DPP-4is plus Met. However, no differences were found in the reduction of HbA1c (WMD 0.11%, 95% CI, -0.03%-0.25%, P = .12) or the risk of hypoglycaemic events (RR, 1.02; 95% CI, 0.80-1.31, P = .86). CONCLUSIONS This review revealed that, compared to DPP-4is, SGLT-2is significantly reduced HbA1c, FPG and body weight without increasing the risk of hypoglycaemia in diabetes treatment.
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Proton Pump Inhibitors, H2-Receptor Antagonists, Metformin, and Vitamin B-12 Deficiency: Clinical Implications.
Miller, JW
Advances in nutrition (Bethesda, Md.). 2018;(4):511S-518S
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Abstract
There is clear evidence that proton-pump inhibitors (PPIs), H2-receptor antagonists (H2RAs), and metformin can reduce serum vitamin B-12 concentrations by inhibiting the absorption of the vitamin. However, it is unclear if the effects of these drugs on serum vitamin B-12 are associated with increased risk of biochemical or functional deficiency (as is indicated by elevated blood concentrations of homocysteine and methylmalonic acid) or clinical deficiency (including megaloblastic anemia and neurologic disorders such as peripheral neuropathy and cognitive dysfunction). This review provides an overview of vitamin B-12 absorption and biochemistry and the mechanisms by which PPIs, H2RAs, and metformin affect these functions. It also summarizes the literature relating the use of these drugs to the risk of vitamin B-12 deficiency. Also discussed is that strategies for assessing vitamin B-12 status and diagnosing vitamin B-12 deficiency have evolved in recent years beyond solely measuring serum total vitamin B-12. Multiple analyte testing, a strategy in which ≥2 of 4 biomarkers of vitamin B-12 status-serum total vitamin B-12, holotranscobalamin, homocysteine, and methylmalonic acid-are measured, increases sensitivity and specificity for diagnosing vitamin B-12 deficiency. It is concluded that randomized controlled trials are now needed that use the strategy of multiple analyte testing to determine if PPIs, H2RAs, and metformin do indeed increase the risk of vitamin B-12 deficiency. Until these studies are conducted, a reasonable recommendation for physicians and their patients who are taking these drugs is to monitor vitamin B-12 status and to provide vitamin B-12 supplements if altered blood biomarkers or clinical signs consistent with low or deficient vitamin B-12 status develop.
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Comparative efficacy of once-weekly semaglutide and SGLT-2 inhibitors in type 2 diabetic patients inadequately controlled with metformin monotherapy: a systematic literature review and network meta-analysis.
Sharma, R, Wilkinson, L, Vrazic, H, Popoff, E, Lopes, S, Kanters, S, Druyts, E
Current medical research and opinion. 2018;(9):1595-1603
Abstract
OBJECTIVE Treatment intensification with additional anti-diabetic agents is recommended in type 2 diabetes (T2D) for patients inadequately controlled on metformin monotherapy. The present network meta-analysis (NMA) evaluated comparative efficacy and safety of once-weekly semaglutide and sodium-glucose co-transporter 2 inhibitors (SGLT-2is) in T2D patients inadequately controlled with metformin. METHODS Randomized controlled trials with ≥20 weeks duration were searched in EMBASE, MEDLINE, and CENTRAL. Primary efficacy outcomes were: change from baseline in HbA1c, weight, systolic blood pressure (SBP), post-prandial blood glucose (PPG), and fasting blood glucose (FPG). Treatment effects at 26 (±4) weeks were compared using Bayesian NMAs. Meta-regression and sensitivity analysis were used to address the trial heterogeneity. RESULTS Eight trials were found eligible for this NMA. Statistically significant reductions in HbA1c were observed with both 1.0 mg and 0.5 mg doses of once-weekly semaglutide when compared to SGLT-2is. The mean differences in change from baseline in HbA1c for once-weekly semaglutide 1.0 mg vs SGLT-2is ranged from -0.66% for canagliflozin 300 mg (95% Credible Intervals [CrI]: -0.82, -0.50%) to -1.11% for dapagliflozin 5 mg (95% CrI: -1.37, -0.85%). Once-weekly semaglutide 1.0 mg performed significantly better than all SGLT-2is of interest in reducing weight and improving FPG levels: however, SBP reduction was not statistically differentiable. Results of sensitivity analysis and meta-regressions aligned with base-case results. NMAs were not possible for PPG and safety outcomes, due to lack of data. CONCLUSION Once-weekly semaglutide treatment is significantly better compared to SGLT-2is in achieving adequate glycemic control in T2D patients inadequately controlled with metformin monotherapy.
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The benefits of adding metformin to tamoxifen to protect the endometrium-A randomized placebo-controlled trial.
Davis, SR, Robinson, PJ, Jane, F, White, S, Brown, KA, Piessens, S, Edwards, A, McNeilage, J, Woinarski, J, Chipman, M, et al
Clinical endocrinology. 2018;(5):605-612
Abstract
BACKGROUND We investigated whether metformin prevents tamoxifen-induced endometrial changes and insulin resistance (IR) after a diagnosis of breast cancer. METHODS This was a single-centre, randomized, double-blind, placebo-controlled, parallel group trial. Postmenopausal women with hormone receptor-positive breast cancer taking tamoxifen were randomly allocated to metformin 850 mg or identical placebo, twice daily, for 52 weeks. Outcome measures included double endometrial thickness (ET) measured by transvaginal ultrasound, fasting insulin, glucose and IR estimated by the homeostasis model of assessment (HOMA-IR). RESULTS A total of 112 women were screened and 102 randomized. Results are presented as median (range). The 101 women who took at least one dose of medication were aged 56 (43-72) years, with 5(0.5-28) years postmenopause, and had taken tamoxifen for 28.9 (0-367.4) weeks. The baseline ET was 2.9 mm (1.4-21.9) for the placebo group (n = 52) and 2.5 mm (1.3-14.8) for the metformin group (n = 50). At 52 weeks, the median ET was statistically significantly lower for the metformin (n = 36) than for the placebo group (n = 45) (2.3 mm (1.4-7.8) vs 3.0 (1.2-11.3); P = 0.05). 13.3% allocated to placebo had an ET greater than 4 mm vs 5.7% for metformin (P = 0.26). There was no endometrial atypia or cancer. Compared with placebo, metformin resulted in significantly greater baseline-adjusted reductions in weight (P < 0.001), waist circumference (0.03) and HOMA-IR (P < 0.001). CONCLUSIONS Metformin appears to inhibit tamoxifen-induced endometrial changes and has favourable metabolic effects. Further research into the adjuvant use of metformin after breast cancer and to prevent EH and cancer is warranted.
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Polycystic ovary syndrome (PCOS) and the accompanying disorders of glucose homeostasis among girls at the time of puberty.
Otto-Buczkowska, E, Grzyb, K, Jainta, N
Pediatric endocrinology, diabetes, and metabolism. 2018;(1):40-44
Abstract
Polycystic ovary syndrome (PCOS) usually arises during puberty and is marked by insulin resistance, hyperinsulinemia, and hyperandrogenism. The principle is that the diagnosis of PCOS must be based on the presence of at least two of the following three criteria: chronic anovulation, hyperandrogenism (clinical or biological), and polycystic ovaries. The diagnosis of PCOS in adolescents is particularly difficult due to developmental problems in this group. Many symptoms of PCOS, including acne, menstrual irregularities, and hyperinsulinemia, are common in normal puberty. Adolescents with PCOS are at an increased risk of developing health problems later on in life, such as diabetes, cardiovascular disease, and infertility. One should reckon with the frequent occurrence of the PCOS in type 1 diabetes, when the ovaries and the adrenals are exposed to excessive insulin concentrations. Ovarian hyperandrogenism is common in adolescent girls with type 1 diabetes. Methods of treatment for an adolescent with PCOS include diet and exercise. Metformin is commonly used in young girls and adolescents with PCOS as first-line monotherapy or in combination with anti-androgen medications.
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Impact of Gastric Banding Versus Metformin on β-Cell Function in Adults With Impaired Glucose Tolerance or Mild Type 2 Diabetes.
Xiang, AH, Trigo, E, Martinez, M, Katkhouda, N, Beale, E, Wang, X, Wu, J, Chow, T, Montgomery, C, Nayak, KS, et al
Diabetes care. 2018;(12):2544-2551
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OBJECTIVE Type 2 diabetes (T2D) results from progressive loss of β-cell function. The BetaFat study compared gastric banding and metformin for their impact on β-cell function in adults with moderate obesity and impaired glucose tolerance (IGT) or recently diagnosed, mild T2D. RESEARCH DESIGN AND METHODS Eighty-eight people aged 21-65 years, BMI 30-40 kg/m2, with IGT or diabetes known for <1 year, were randomized to gastric banding or metformin for 2 years. Hyperglycemic clamps (11.1 mmol/L) followed by arginine injection at maximally potentiating glycemia (>25 mmol/L) were performed at baseline, 12 months, and 24 months to measure steady-state C-peptide (SSCP) and acute C-peptide response to arginine at maximum glycemic potentiation (ACPRmax) and insulin sensitivity (M/I). RESULTS At 24 months, the band group lost 10.7 kg; the metformin group lost 1.7 kg (P < 0.01). Insulin sensitivity increased 45% in the band group and 25% in the metformin group (P = 0.30 between groups). SSCP adjusted for insulin sensitivity fell slightly but not significantly in each group (P = 0.34 between groups). ACPRmax adjusted for insulin sensitivity fell significantly in the metformin group (P = 0.002) but not in the band group (P = 0.25 between groups). HbA1c fell at 12 and 24 months in the band group (P < 0.004) but only at 12 months (P < 0.01) in the metformin group (P > 0.14 between groups). Normoglycemia was present in 22% and 15% of band and metformin groups, respectively, at 24 months (P = 0.66 between groups). CONCLUSIONS Gastric banding and metformin had similar effects to preserve β-cell function and stabilize or improve glycemia over a 2-year period in moderately obese adults with IGT or recently diagnosed, mild T2D.