Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials.

OBJECTIVE: To evaluate sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists in patients with type 2 diabetes at varying cardiovascular and renal risk. DESIGN: Network meta-analysis. DATA SOURCES: Medline, Embase, and Cochrane CENTRAL up to 11 August 2020. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials comparing SGLT-2 inhibitors or GLP-1 receptor agonists with placebo, standard care, or other glucose lowering treatment in adults with type 2 diabetes with follow up of 24 weeks or longer. Studies were screened independently by two reviewers for eligibility, extracted data, and assessed risk of bias. MAIN OUTCOME MEASURES: Frequentist random effects network meta-analysis was carried out and GRADE (grading of recommendations assessment, development, and evaluation) used to assess evidence certainty. Results included estimated absolute effects of treatment per 1000 patients treated for five years for patients at very low risk (no cardiovascular risk factors), low risk (three or more cardiovascular risk factors), moderate risk (cardiovascular disease), high risk (chronic kidney disease), and very high risk (cardiovascular disease and kidney disease). A guideline panel provided oversight of the systematic review. RESULTS: 764 trials including 421 346 patients proved eligible. All results refer to the addition of SGLT-2 inhibitors and GLP-1 receptor agonists to existing diabetes treatment. Both classes of drugs lowered all cause mortality, cardiovascular mortality, non-fatal myocardial infarction, and kidney failure (high certainty evidence). Notable differences were found between the two agents: SGLT-2 inhibitors reduced admission to hospital for heart failure more than GLP-1 receptor agonists, and GLP-1 receptor agonists reduced non-fatal stroke more than SGLT-2 inhibitors (which appeared to have no effect). SGLT-2 inhibitors caused genital infection (high certainty), whereas GLP-1 receptor agonists might cause severe gastrointestinal events (low certainty). Low certainty evidence suggested that SGLT-2 inhibitors and GLP-1 receptor agonists might lower body weight. Little or no evidence was found for the effect of SGLT-2 inhibitors or GLP-1 receptor agonists on limb amputation, blindness, eye disease, neuropathic pain, or health related quality of life. The absolute benefits of these drugs vary substantially across patients from low to very high risk of cardiovascular and renal outcomes (eg, SGLT-2 inhibitors resulted in 3 to 40 fewer deaths in 1000 patients over five years; see interactive decision support tool (https://magicevidence.org/match-it/200820dist/#!/) for all outcomes. CONCLUSIONS: In patients with type 2 diabetes, SGLT-2 inhibitors and GLP-1 receptor agonists reduced cardiovascular and renal outcomes, with some differences in benefits and harms. Absolute benefits are determined by individual risk profiles of patients, with clear implications for clinical practice, as reflected in the BMJ Rapid Recommendations directly informed by this systematic review. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019153180.

Shortening of telomere length by metabolic factors in diabetes: protective effects of fenofibrate.

People with diabetes mellitus have shorter telomeres compared with non-diabetic subjects. The aim of this study was to investigate an in-vitro model of telomere shortening under diabetes metabolic conditions. The mechanisms of the accelerated telomere length attrition and the potential telomere protective action of fenofibrate with related cellular mechanisms were also examined. Human dermal fibroblasts were passaged and cultured in normal (5.5 mM) or high (25 mM) D-glucose, across 7 days with hydrogen peroxide (H2O2), glucosamine (GA), or glycated albumin (AGEs-BSA). Relative telomere length (RTL) was determined by qPCR. The expression of shelterin complex members which regulate telomere stability were measured by qRT-PCR and Western immunoblot. Culture in high glucose decreased RTL compared with normal glucose: H2O2 and GA lowered the RTL after 7 days (each P < 0.05 vs untreated control), whereas AGEs-BSA had no effect compared with control-BSA. At day 7 the mRNA levels of most shelterin complex members, were induced by H2O2 and to a lesser extent by GA. Trf1 and Trf2 protein were induced by H2O2. Co-treatment with fenofibrate (100 µM) significantly attenuated the reduction in RTL caused by H2O2 and GA and prevented Trf induction by H2O2. However knockdown of Trf1 and Trf2 expression using specific siRNA did not prevent H2O2 effects to lower RTL, thus implicating factors other than these Trfs alone in the fenofibrate protection against the H2O2 induction of RTL lowering. These in vitro findings demonstrate that diabetic conditions can induce telomere shortening and that fenofibrate has protective effects on telomere attrition, through as yet undefined mechanisms.

Monocyte CD163 is altered in association with diabetic complications: possible protective role.

The scavenger receptor CD163 is exclusively expressed by monocyte/macrophages and is shed by matrix metalloproteinases (MMPs) and neutrophil elastase (ELA2) as soluble CD163 (sCD163). Monocyte phenotype is altered in diabetes, but the relationship among monocyte CD163, sCD163, and diabetic complications is not known and was investigated in this study. Blood was obtained from patients with diabetes for >10 yr and mice with diabetes for ≤20 wk. Blood from people and mice without diabetes acted as controls. The percentage of CD163+ monocytes and monocyte CD163 mRNA was determined by flow cytometry and qRT-PCR, respectively. Plasma sCD163, MMPs, and ELA2 were measured by ELISA. The ability of glucocorticoids to stimulate isolated monocyte CD163 expression was also investigated. The percentage of CD163+ monocytes was significantly decreased and sCD163 significantly increased (both P < 0.05) in patients with diabetes with complications compared to those without complications. Plasma ELA2 and MMP-3 were also increased (P < 0.05), but CD163 mRNA was unaltered. sCD163 correlated with worsening renal function, as determined by eGFR (r = -0.48, P < 0.05). In diabetic mice, increased sCD163 at wk 5 and decreased percentage of CD163+ monocytes at wk 10 preceded alteration in kidney collagen IV mRNA at wk 20 (all P < 0.05). In vitro incubation of monocytes in anti-inflammatory glucocorticoid increased the percentage of CD163+ monocytes (P < 0.05). In people, higher sCD163 and decreased percentage of CD163+ monocytes were consistent with increased monocyte activation and shedding. The murine data indicated that these changes preceded the development of diabetic complications. Taken together, these results suggest that higher circulating percentage of CD163+ monocytes may have anti-inflammatory effects and may protect from development of diabetic complications.

Shorter telomeres in adults with Type 1 diabetes correlate with diabetes duration, but only weakly with vascular function and risk factors.

OBJECTIVE: To determine if white blood cell (WBC) telomeres are shorter in Type 1 diabetes (T1D) than in subjects without diabetes (non-DB), and shorter in T1D subjects with vs. without vascular complications; and to determine associations with vascular biomarkers. RESEARCH DESIGN AND METHODS: WBC relative telomere length (RTL) was determined by quantitative PCR in a cross-sectional study of 140 non-DB and 199 T1D adults, including 128 subjects without vascular complications (T1DNoCx) and 71 subjects with vascular complications (T1DCx). Relationships of RTL with age, T1D duration, arterial elasticity, pulse pressure and vascular risk factors were determined. RESULTS: RTL did not differ by gender within T1D and non-DB groups. Age-adjusted RTL was shorter in T1D vs. non-DB subjects (1.48±0.03 AU vs. 1.64±0.04 AU, p=0.002), but did not differ by T1D complication status (T1DNoCX 1.50±0.04 vs. T1DCX 1.46±0.05, p=0.50), nor correlate with arterial elasticity. Univariate analysis in T1D showed RTL correlated (inversely) with age r=-0.27, p=0.0001, T1D duration r=-0.16, p=0.03, and pulse pressure (r=-0.15, p=0.04), but not with HbA1c, BP, renal function (serum creatinine, ACR, eGFR), lipids, insulin sensitivity, inflammation (CRP, CAMs) or oxidative stress (OxLDL, OxLDL/LDL-C, MPO, PON-1). Multiple regression analysis showed independent determinants of RTL were age and T1D presence (r=0.29, p<0.0001). CONCLUSIONS: In this cross-sectional study telomeres were shorter in T1D. RTL correlated inversely with T1D duration, but did not differ by complication status and weakly correlated with pulse pressure and vascular risk factors. Only age and T1D were independent determinants of RTL. Longitudinal studies are merited.

Gender difference in the neuroendocrine regulation of growth hormone axis by selective estrogen receptor modulators.

CONTEXT: In men, GH secretion is stimulated by estradiol derived locally from aromatization of testosterone. Recently, we showed that local estrogen also plays a major role in the central regulation of GH secretion in women. Tamoxifen and raloxifene are selective estrogen receptor modulators (SERMs), drugs that block central estrogen action but exert estrogen-like effects in the liver, inhibiting hepatic IGF-I production. The relative impact of SERMs on the GH-IGF-I axis in men and women has not been investigated. OBJECTIVE: The aim of the study was to determine whether there is a gender difference in the impact of SERMs on the GH-IGF-I axis. DESIGN: We conducted a comparative, randomized, open-label, crossover study of tamoxifen and raloxifene. PATIENTS AND INTERVENTION: Ten healthy postmenopausal women and ten healthy men were randomized to 2-wk sequential treatment with tamoxifen (10 and 20 mg/d) and raloxifene (60 and 120 mg/d) with a washout of 2 wk between treatments. MAIN OUTCOME MEASURES: The GH response to arginine, IGF-I, testosterone, and SHBG was measured. RESULTS: In women, but not in men, tamoxifen significantly attenuated the GH response to arginine. The GH response was not significantly blunted by raloxifene in both sexes. Both SERMs significantly reduced mean IGF-I levels to a similar degree in men and women. In men, both SERMs significantly increased LH and testosterone levels. CONCLUSIONS: In summary, GH secretion was blunted by tamoxifen in women in the face of reduced IGF-I feedback inhibition but not in men in whom the gonadal axis was stimulated. We conclude that potential blunting of GH secretion in men by SERMs was counteracted by concomitant central stimulation of GH secretion by testosterone. In therapeutic doses, tamoxifen may induce detrimental metabolic effects in women, but not men.

Neuroendocrine regulation of growth hormone and androgen axes by selective estrogen receptor modulators in healthy men.

CONTEXT: In men, the stimulation of GH and inhibition of LH secretion by testosterone requires aromatization to estradiol. Tamoxifen, a selective estrogen receptor modulator (SERM), possesses central estrogen antagonistic effect but peripheral hepatic agonist effect, lowering IGF-I. Thus, tamoxifen is likely to perturb the neuroendocrine regulation of GH and gonadal axes. Raloxifene, a SERM, is used for therapy of osteoporosis in both sexes. Its neuroendocrine effects in men are poorly understood. OBJECTIVE: The aim was to compare the impact of raloxifene and tamoxifen on GH-IGF-I and gonadal axes in healthy men. DESIGN: We conducted a randomized, open-label crossover study. PATIENTS AND INTERVENTION: Ten healthy men were randomized to 2-wk sequential treatment with tamoxifen (10 and 20 mg/d) and raloxifene (60 and 120 mg/d), with a 2-wk intervening washout period. MAIN OUTCOME MEASURES: We measured the GH response to arginine and circulating levels of IGF-I, LH, FSH, testosterone, and SHBG. RESULTS: Tamoxifen, but not raloxifene, significantly reduced IGF-I levels by 25±6% (P<0.01) and increased SHBG levels by 20±7% (P<0.05) at the higher therapeutic dose. There was a nonstatistically significant trend toward a reduction in the GH response to arginine with both SERMs. Both drugs significantly increased LH, FSH, and testosterone concentrations. The mean increase in testosterone (40 vs. 25%; P<0.05) and LH (70 vs. 30%; P<0.01) was significantly greater with tamoxifen than with raloxifene treatment. CONCLUSIONS: Tamoxifen, but not raloxifene, reduces IGF-I levels. Both SERMs stimulate the gonadal axis, with tamoxifen imparting a greater effect. We conclude that in therapeutic doses, raloxifene perturbs the GH and gonadal axes to a lesser degree than tamoxifen.

Paracrine regulation of growth hormone secretion by estrogen in women.

CONTEXT: Paracrine regulation is emerging as a discrete control mechanism in the endocrine system. In hypogonadal men, stimulation of GH secretion by testosterone requires prior aromatization to estradiol, a paracrine effect unmasked by central estrogen receptor blockade with tamoxifen. In hypogonadal women, estrogen replacement via a physiological non-oral route fails to enhance GH secretion, indicating an absence of an endocrine effect. The aim was to investigate whether local estrogens produced from aromatization regulate GH secretion. DESIGN: We conducted an open-label, two-phase, crossover study. PATIENTS AND INTERVENTION: We compared the effects on GH secretion of tamoxifen with estradiol valerate in postmenopausal women. Ten women were treated with tamoxifen (10 and 20 mg/d) and estradiol valerate (2 mg/d) via oral route for 2 wk each, with a washout period of at least 6 wk. MAIN OUTCOME MEASURES: We measured the GH response to arginine and circulating levels of IGF-I and SHBG, markers of hepatic estrogen effect. RESULTS: The GH response to arginine was reduced by 10- and 20-mg tamoxifen in a dose-dependent manner and potentiated significantly (P<0.05) by estradiol valerate. Mean IGF-I concentration was reduced significantly with high-dose tamoxifen (P<0.01) and estradiol valerate treatment (P<0.05), whereas mean SHBG levels rose with both (P<0.01). CONCLUSIONS: Blunted GH response to stimulation occurring in the face of reduced IGF-I feedback inhibition with tamoxifen indicates that GH secretion was suppressed by estrogen receptor antagonism. Because circulating estradiol was unaffected, these data indicate a significant role of local estrogen in the central control of GH secretion. We conclude that aromatase mediates the paracrine control of GH secretion in women.