Reductions in Insulin Resistance are Mediated Primarily via Weight Loss in Subjects With Type 2 Diabetes on Semaglutide.

CONTEXT: Semaglutide, a once-weekly glucagon-like peptide-1 analog approved for use in patients with type 2 diabetes (T2D), demonstrated superior body weight (BW) reductions and decreased insulin resistance (IR) vs comparators across the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) 1-3 clinical trials. OBJECTIVE: To investigate the relationship between IR and BW across the SUSTAIN 1-3 trials. DESIGN: Post hoc analysis of the SUSTAIN 1-3 trials. SETTING: Three hundred and eleven sites in 30 countries. PATIENTS OR OTHER PARTICIPANTS: 2432 subjects with T2D. INTERVENTIONS: Semaglutide 0.5 or 1.0 mg, placebo or active comparator (sitagliptin 100 mg, exenatide extended release 2.0 mg). MAIN OUTCOME MEASURE: To assess the extent of the effect on IR that is mediated (indirect effect) and not mediated (direct effect) by the effect on BW. RESULTS: Across SUSTAIN 1-3, mean BW was significantly reduced with semaglutide 0.5 mg (3.7 kg to 4.3 kg; P < 0.0001) and semaglutide 1.0 mg (4.5 kg to 6.1 kg; P < 0.0001) vs comparators (1.0 kg to 1.9 kg). There were greater reductions in IR with semaglutide 0.5 mg (27% to 36%) and semaglutide 1.0 mg (32% to 46%) vs comparators (17% to 28%). Greater reductions in BW were generally associated with greater decreases in IR. The effect on IR was primarily mediated by weight loss (70% to 80% and 34% to 94%, for semaglutide 0.5 mg and 1.0 mg, respectively, vs comparator). CONCLUSIONS: Semaglutide consistently reduced BW and IR in subjects with T2D in SUSTAIN 1-3. In this analysis, IR improvement was positively associated with, and primarily mediated by, the effect of semaglutide on BW.

Achieving glycaemic control without weight gain, hypoglycaemia, or gastrointestinal adverse events in type 2 diabetes in the SUSTAIN clinical trial programme.

AIM: To evaluate the potential for semaglutide to help people with type 2 diabetes (T2D) achieve glycated haemoglobin (HbA1c) targets while avoiding unwanted outcomes, such as weight gain, hypoglycaemia and gastrointestinal (GI) side effects. MATERIALS AND METHODS: Data from the phase IIIa SUSTAIN 1 to 5 clinical trials were analysed. Participants had inadequately controlled T2D and were drug-naïve (SUSTAIN 1) or on a range of background treatments (SUSTAIN 2 to 5). The main protocol-specified composite endpoint was the proportion of participants achieving HbA1c <53 mmol/mol (7.0%) at end of treatment (30 or 56 weeks) without weight gain and with no severe or blood glucose (BG)-confirmed symptomatic hypoglycaemia. A post hoc composite endpoint was the proportion of participants achieving the primary composite endpoint without moderate or severe GI adverse events (AEs). RESULTS: Across the SUSTAIN trials 1 to 5, 3918 participants with T2D were randomized to once-weekly subcutaneous semaglutide 0.5 mg, 1.0 mg, or comparators (placebo, sitagliptin 100 mg, exenatide extended release 2.0 mg or insulin glargine). The proportion of participants achieving HbA1c <53 mmol/mol (7.0%) with no weight gain and no severe/BG-confirmed symptomatic hypoglycaemia was 47% to 66% (semaglutide 0.5 mg) and 57% to 74% (semaglutide 1.0 mg) vs 7% to 19% (placebo) and 16% to 29% (active comparators; all P < .0001). More participants achieved the primary composite endpoint with no moderate or severe GI AEs with semaglutide vs comparators (all P < .0001). CONCLUSION: Semaglutide helped more people with T2D achieve HbA1c targets than did comparators in the SUSTAIN 1 to 5 trials, while avoiding unwanted outcomes such as weight gain, hypoglycaemia and GI side effects.

Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on Glycemic Control in Patients With Type 2 Diabetes: A Randomized Clinical Trial.

Importance: Glucagon-like peptide-1 (GLP-1) receptor agonists are effective therapies for the treatment of type 2 diabetes and are all currently available as an injection. Objectives: To compare the effects of oral semaglutide with placebo (primary) and open-label subcutaneous semaglutide (secondary) on glycemic control in patients with type 2 diabetes. Design, Setting, and Patients: Phase 2, randomized, parallel-group, dosage-finding, 26-week trial with 5-week follow-up at 100 sites (hospital clinics, general practices, and clinical research centers) in 14 countries conducted between December 2013 and December 2014. Of 1106 participants assessed, 632 with type 2 diabetes and insufficient glycemic control using diet and exercise alone or a stable dose of metformin were randomized. Randomization was stratified by metformin use. Interventions: Once-daily oral semaglutide of 2.5 mg (n = 70), 5 mg (n = 70), 10 mg (n = 70), 20 mg (n = 70), 40-mg 4-week dose escalation (standard escalation; n = 71), 40-mg 8-week dose escalation (slow escalation; n = 70), 40-mg 2-week dose escalation (fast escalation, n = 70), oral placebo (n = 71; double-blind) or once-weekly subcutaneous semaglutide of 1.0 mg (n = 70) for 26 weeks. Main Outcomes and Measures: The primary end point was change in hemoglobin A1c (HbA1c) from baseline to week 26. Secondary end points included change from baseline in body weight and adverse events. Results: Baseline characteristics were comparable across treatment groups. Of the 632 randomized patients (mean age, 57.1 years [SD, 10.6]; men, 395 (62.7%); diabetes duration, 6.3 years [SD, 5.2]; body weight, 92.3 kg [SD, 16.8]; BMI, 31.7 [SD, 4.3]), 583 (92%) completed the trial. Mean change in HbA1c level from baseline to week 26 decreased with oral semaglutide (dosage-dependent range, -0.7% to -1.9%) and subcutaneous semaglutide (-1.9%) and placebo (-0.3%); oral semaglutide reductions were significant vs placebo (dosage-dependent estimated treatment difference [ETD] range for oral semaglutide vs placebo, -0.4% to -1.6%; P = .01 for 2.5 mg, <.001 for all other dosages). Reductions in body weight were greater with oral semaglutide (dosage-dependent range, -2.1 kg to -6.9 kg) and subcutaneous semaglutide (-6.4 kg) vs placebo (-1.2 kg), and significant for oral semaglutide dosages of 10 mg or more vs placebo (dosage-dependent ETD range, -0.9 to -5.7 kg; P < .001). Adverse events were reported by 63% to 86% (371 of 490 patients) in the oral semaglutide groups, 81% (56 of 69 patients) in the subcutaneous semaglutide group, and 68% (48 of 71 patients) in the placebo group; mild to moderate gastrointestinal events were most common. Conclusions and Relevance: Among patients with type 2 diabetes, oral semaglutide resulted in better glycemic control than placebo over 26 weeks. These findings support phase 3 studies to assess longer-term and clinical outcomes, as well as safety. Trial Registration: clinicaltrials.gov Identifier: NCT01923181.

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes.

BACKGROUND: Regulatory guidance specifies the need to establish cardiovascular safety of new diabetes therapies in patients with type 2 diabetes in order to rule out excess cardiovascular risk. The cardiovascular effects of semaglutide, a glucagon-like peptide 1 analogue with an extended half-life of approximately 1 week, in type 2 diabetes are unknown. METHODS: We randomly assigned 3297 patients with type 2 diabetes who were on a standard-care regimen to receive once-weekly semaglutide (0.5 mg or 1.0 mg) or placebo for 104 weeks. The primary composite outcome was the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. We hypothesized that semaglutide would be noninferior to placebo for the primary outcome. The noninferiority margin was 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio. RESULTS: At baseline, 2735 of the patients (83.0%) had established cardiovascular disease, chronic kidney disease, or both. The primary outcome occurred in 108 of 1648 patients (6.6%) in the semaglutide group and in 146 of 1649 patients (8.9%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.58 to 0.95; P<0.001 for noninferiority). Nonfatal myocardial infarction occurred in 2.9% of the patients receiving semaglutide and in 3.9% of those receiving placebo (hazard ratio, 0.74; 95% CI, 0.51 to 1.08; P=0.12); nonfatal stroke occurred in 1.6% and 2.7%, respectively (hazard ratio, 0.61; 95% CI, 0.38 to 0.99; P=0.04). Rates of death from cardiovascular causes were similar in the two groups. Rates of new or worsening nephropathy were lower in the semaglutide group, but rates of retinopathy complications (vitreous hemorrhage, blindness, or conditions requiring treatment with an intravitreal agent or photocoagulation) were significantly higher (hazard ratio, 1.76; 95% CI, 1.11 to 2.78; P=0.02). Fewer serious adverse events occurred in the semaglutide group, although more patients discontinued treatment because of adverse events, mainly gastrointestinal. CONCLUSIONS: In patients with type 2 diabetes who were at high cardiovascular risk, the rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo, an outcome that confirmed the noninferiority of semaglutide. (Funded by Novo Nordisk; SUSTAIN-6 ClinicalTrials.gov number, NCT01720446 .).

Remigration of migrants with severe disease: myth or reality?--a register-based cohort study.

BACKGROUND: 'Remigration bias' is often referred to when explaining low mortality outcomes among migrants compared with local-born. The hypothesis suggests that severely ill migrants tend to return to their country of origin, but it has hitherto not been tested in a large-scale epidemiological study. Consequently, we studied whether migrants with severe disease were more likely to emigrate compared with migrants without severe disease. METHODS: A historic prospective cohort study was conducted based on all adult refugees and family reunification immigrants (n = 114,331) who obtained residence permission in Denmark between 1 January 1993 and 31 December 2010. Migrants with severe disease were identified through the Danish National Patient Register. Emigrations during follow-up (1 January 1993 to 31 December 2011) were identified using the Danish Civil Registration System. Hazard ratios were calculated for emigration among migrants with different levels of disease severity, adjusting for sex, age and income. RESULTS: Results showed progressively fewer emigrations with increasing disease severity. Migrants with low (HR = 0.92; 95% CI: 0.80-1.06), moderate (HR = 0.84; 95% CI: 0.67-1.06) and high (HR = 0.70; 95% CI: 0.55-0.90) disease severity had fewer emigrations to 'country of origin' compared with migrants without disease. For emigration to 'any country', results likewise showed fewer emigrations among migrants with low (HR = 0.86; 95% CI: 0.78-0.95), moderate (HR = 0.73; 95% CI: 0.62-0.87) and high (HR = 0.64; 95% CI: 0.53-0.76) disease severity. This tendency was also observed by nationality and migrant status. On the disease-specific level, no uniform tendencies in emigration patterns were identified. CONCLUSION: The results do not generally support the hypothesis of 'remigration bias' but rather suggest the opposite. Accordingly, remigration bias does not appear to explain lower mortality of migrants.

Polychlorinated biphenyl exposure and glucose metabolism in 9-year-old Danish children.

CONTEXT: Human exposure to polychlorinated biphenyls (PCBs) has been associated to type 2 diabetes in adults. OBJECTIVE: We aimed to determine whether concurrent plasma PCB concentration was associated with markers of glucose metabolism in healthy children. SETTING AND DESIGN: Cross-sectional study of 771 healthy Danish third grade school children ages 8-10 years in the municipality of Odense were recruited in 1997 through a two-stage cluster sampling from 25 schools stratified according to location and socioeconomic character; 509 (9.7 ± 0.8 y, 53% girls) had adequate amounts available for PCB analyses. OUTCOME MEASURES: Fasting serum glucose and insulin were measured and a homeostasis assessment model of insulin resistance (HOMA-IR) and ß-cell function (HOMA-B) calculated. Plasma PCB congeners and other persistent compounds were measured and ΣPCB calculated. RESULTS: PCBs were present in plasma at low concentrations, median, 0.19 µg/g lipid (interquartile range, 0.12-0.31). After adjustment for putative confounding factors, the second, third, fourth, and fifth quintiles of total PCB were significantly inversely associated with serum insulin (-14.6%, -21.7%, -18.9%, -23.1%, P trend < .01), compared with the first quintile, but not with serum glucose (P = .45). HOMA-IR and HOMA-B were affected in the same direction due to the declining insulin levels with increasing PCB exposure. Similar results were found for individual PCB congeners, for ßHCB (hexachlorobenzen) and pp-DDE (dichlorodiphenyldichloroethylene). CONCLUSIONS: A strong inverse association between serum insulin and PCB exposure was found while fasting glucose remained within the expected narrow range. Our findings suggest that PCB may not exert effect through decreased peripheral insulin sensitivity, as seen in obese and low-fit children, but rather through a toxicity to ß-cells. It remains to be demonstrated whether lower HOMA-B is caused by destruction of ß-cell-reducing peripheral insulin resistance and thereby increase fasting glucose as previously found.

Duration of residence and disease occurrence among refugees and family reunited immigrants: test of the 'healthy migrant effect' hypothesis.

OBJECTIVES: The 'healthy migrant effect' (HME) hypothesis postulates that health selection has a positive effect on migrants' health outcomes, especially in the first years after migration. We examined the potential role of the HME by assessing the association between residence duration and disease occurrence. METHODS: We performed a historical prospective cohort study. We included migrants who obtained residence permits in Denmark between 1 January 1993 and 31 December 2010 (n = 114,331). Occurrence of severe conditions was identified through linkage to the Danish National Patient Register. Hazard Ratios (HRs) were modelled for disease incidence by residence duration since arrival (0-5 years; 0-10 years; 0-18 years) adjusting for age and sex. RESULTS: Compared with Danish-born individuals, refugees and family reunited immigrants had lower HRs of stroke and breast cancer within 5 years after arrival; however, HRs increased at longer follow-up. For example, HRs of stroke among refugees increased from 0.77 (95% CI: 0.66; 0.91) to 0.96 (95% CI: 0.88; 1.05). For ischaemic heart disease (IHD) and diabetes, refugees and family reunited migrants had higher HRs within 5 years after arrival, and most HRs had increased by end of follow-up. For example, HRs of IHD among family reunited migrants increased from 1.29 (95% CI: 1.17; 1.42) to 1.43 (95% CI: 1.39; 1.52). In contrast, HRs for TB and HIV/AIDS showed a consistent decrease over time. CONCLUSION: Our analyses of the effect of duration of residence on disease occurrence among migrants imply that, when explaining migrants' advantageous health outcomes, the ruling theory of the HME should be used with caution, and other explanatory models should be included.