Tolerability of nausea and vomiting and associations with weight loss in a randomized trial of liraglutide in obese, non-diabetic adults.

BACKGROUND: Liraglutide 3.0 mg, with diet and exercise, produced substantial weight loss over 1 year that was sustained over 2 years in obese non-diabetic adults. Nausea was the most frequent side effect. OBJECTIVE: To evaluate routinely collected data on nausea and vomiting among individuals on liraglutide and their influence on tolerability and body weight. DESIGN: A randomized, placebo-controlled, double-blind 20-week study with an 84-week extension (sponsor unblinded at 20 weeks, open-label after 1 year) in eight European countries (Clinicaltrials.gov: NCT00422058). SUBJECTS: After commencing a 500-kcal/day deficit diet plus exercise, 564 participants (18-65 years, body mass index (BMI) 30-40 kg m(-2)) were randomly assigned (after a 2-week run-in period) to once-daily subcutaneous liraglutide (1.2, 1.8, 2.4 or 3.0 mg), placebo or open-label orlistat (120 mg × 3 per day). After 1 year, participants on liraglutide/placebo switched to liraglutide 2.4 mg, and subsequently, to liraglutide 3.0 mg (based on 20-week and 1-year results, respectively). RESULTS: The intention-to-treat population comprised 561 participants (n=90-98 per arm, age 45.9±10.3 years, BMI 34.8±2.7 kg m(-2) (mean±s.d.)). In year 1, more participants reported ⩾1 episode of nausea/vomiting on treatment with liraglutide 1.2-3.0 mg (17-38%) than with placebo or orlistat (both 4%, P⩽0.001). Most episodes occurred during dose escalation (weeks 1-6), with 'mild' or 'moderate' symptoms. Among participants on liraglutide 3.0 mg, 48% reported some nausea and 13% some vomiting, with considerable variation between countries, but only 4 out of 93 (4%) reported withdrawals. The mean 1-year weight loss on treatment with liraglutide 3.0 mg from randomization was 9.2 kg for participants reporting nausea/vomiting episodes, versus 6.3 kg for those with none (a treatment difference of 2.9 kg (95% confidence interval 0.5-5.3); P=0.02). Both weight losses were significantly greater than the respective weight losses for participants on placebo (P<0.001) or orlistat (P<0.05). Quality-of-life scores at 20 weeks improved similarly with or without nausea/vomiting on treatment with liraglutide 3.0 mg. CONCLUSION: Transient nausea and vomiting on treatment with liraglutide 3.0 mg was associated with greater weight loss, although symptoms appeared tolerable and did not attenuate quality-of-life improvements. Improved data collection methods on nausea are warranted.

One year of liraglutide treatment offers sustained and more effective glycaemic control and weight reduction compared with sitagliptin, both in combination with metformin, in patients with type 2 diabetes: a randomised, parallel-group, open-label trial.

AIM: The aim of this study was to compare the efficacy and safety of once-daily human glucagon-like peptide-1 analogue liraglutide with dipeptidyl peptidase-4 inhibitor sitagliptin, each added to metformin, over 52 weeks in individuals with type 2 diabetes. METHODS: In an open-label, parallel-group trial, metformin-treated participants were randomised to liraglutide 1.2 mg/day (n=225), liraglutide 1.8 mg/day (n=221) or sitagliptin 100 mg/day (n=219) for 26 weeks (main phase). Participants continued the same treatment in a 26-week extension. RESULTS: Liraglutide (1.2 or 1.8 mg) was superior to sitagliptin for reducing HbA(1c) from baseline (8.4-8.5%) to 52 weeks: -1.29% and -1.51% vs. -0.88% respectively. Estimated mean treatment differences between liraglutide and sitagliptin were as follows: -0.40% (95% confidence interval -0.59 to -0.22) for 1.2 mg and -0.63% (-0.81 to -0.44) for 1.8 mg (both p<0.0001). Weight loss was greater with liraglutide 1.2 mg (-2.78 kg) and 1.8 mg (-3.68 kg) than sitagliptin (-1.16 kg) (both p<0.0001). Diabetes Treatment Satisfaction Questionnaire scores increased significantly more with liraglutide 1.8 mg than with sitagliptin (p=0.03). Proportions of participants reporting adverse events were generally comparable; minor hypoglycaemia was 8.1%, 8.3% and 6.4% for liraglutide 1.2 mg, 1.8 mg and sitagliptin respectively. Gastrointestinal side effects, mainly nausea, initially occurred more frequently with liraglutide, but declined after several weeks. CONCLUSION: Liraglutide provides greater sustained glycaemic control and body weight reduction over 52 weeks. Treatment satisfaction was significantly greater with 1.8 mg liraglutide, similar to 26-week results. The safety profiles of liraglutide and sitagliptin are consistent with previous reports.

Insulin and glucose profiles during continuous subcutaneous insulin infusion compared with injection of a long-acting insulin in Type 2 diabetes.

AIMS: To compare insulin and glucose profiles during basal continuous subcutaneous infusion of a rapid-acting insulin analogue and once daily subcutaneous injection of a long-acting insulin analogue in Type 2 diabetes. METHODS: Twenty-one patients with Type 2 diabetes treated with oral glucose-lowering agents were randomized in this two-period crossover study to an equivalent 24-h dose of continuous subcutaneous infusion of insulin aspart and subsequently once-daily bedtime subcutaneous injection of insulin glargine, or vice versa, for eight consecutive days. Plasma profiles of insulin and glucose were recorded. RESULTS: On the last day of each treatment period, the area under the curve (AUC) for glucose was 10% lower on the continuous subcutaneous infusion regimen compared with the insulin injection regimen (P = 0.002). This was accomplished by a flat exogenous insulin infusion profile compared with a peaking profile with injected insulin (AUC was 74% higher after injection compared with pre-injection levels (P = 0.001)). During the last 6 days in each treatment period, the intra-subject variability of exogenous fasting insulin levels in the mornings was 41% lower during insulin infusion compared with insulin injection (P = 0.012). The corresponding intra-subject variability for fasting glucose only showed a tendency to be lower during infusion as compared to the injection regimen (28%; P = 0.104). Thirteen symptomatic-only or minor hypoglycaemic episodes were recorded during the entire infusion period compared with three episodes during the injection period. CONCLUSIONS: Basal continuous subcutaneous infusion of a rapid-acting insulin analogue improved plasma insulin (more flat insulin profile with a lower variability) and glucose (lower AUC) profiles compared with once-daily subcutaneous injection of a long-acting insulin analogue in Type 2 diabetes.

The Danish PET/depression project: clinical symptoms and cerebral blood flow. A regions-of-interest analysis.

OBJECTIVE: We wanted to explore associations between clinical symptoms of depression and the blood flow to specific regions of the brain. Furthermore, we wanted to compare the regions-of-interest (ROI) method with the functions-of-interest (FOI) approach. METHOD: The resting blood flow to 42 ROI in the brain was obtained with positron emission tomography (PET) imaging in 42 representative in-patients with major depression and 47 matched healthy controls. RESULTS: The patients had increased blood flow to hippocampus, cerebellum, anterior cingulate gyrus, and the basal ganglia. A strong negative correlation was found between the degree of psychomotor retardation of the patients and the blood flow to the dorsolateral and supraorbital prefrontal cortices. The total Hamilton score was correlated with the blood flow to the hippocampus. CONCLUSION: Our findings support the notion that depressed patients have disturbances in the loops connecting the frontal lobes, limbic system, basal ganglia, and cerebellum.

[Organochlorine compounds and breast cancer--is there a connection between environmental pollution and breast cancer?]. / Organiske klorerede forbindelser og brystkraeft--er der en sammenhaeng mellem forurening of miljøet og brystkraeft?

Some organochlorine compounds may have weak oestrogenic effects and are therefore suspected of increasing the risk of breast cancer. The risk of breast cancer was assessed prospectively in relation to the serum concentration of several organochlorines. In all 240 women, who developed breast cancer between 1976 and 1993 were together with 477 breast cancer-free controls enrolled in a cohort-nested case-control study. The serum dieldrin concentration was associated with a significantly increased dose-related risk of breast cancer (Odds Ratio 2.05; 95% confidence interval 1.17-3.57; p for trend 0.01). There was no overall association between risk of breast cancer and DDT or polychlorinated biphenyls. The results support the hypothesis that exposure to oestrogenic organochlorines may increase the risk of breast cancer.

Repeated measurements of organochlorine exposure and breast cancer risk (Denmark).

OBJECTIVE: To prospectively evaluate if repeated measurements of organochlorine exposure provide a more precise measure of breast cancer risk. METHODS: In the Copenhagen City Heart Study (CCHS) participants donated blood twice, in 1976-1978 and 1981 1983. Information on breast cancer risk factors was obtained through standardized questionnaires. A cohort nested case-control study of 155 cases and 274 matched breast cancer-free controls who had participated in both CCHS examinations was conducted. The average serum organochlorine concentration over the course of the two examinations was used, testing a possible association between organochlorine exposure and breast cancer risk. RESULTS: A high serum concentration of p,p'-DDT over the course of the two examinations was associated with a more than three-fold significantly increased risk of breast cancer, and a dose-response relationship was apparent. Furthermore, the risk of breast cancer increased with increasing serum concentrations of PCB congener 118 and 138 and the total amount of DDT isomers (sigmaDDT), but the trends were not significant. CONCLUSION: This study provides new evidence of the adverse effect of some organochlorines on breast cancer risk. Furthermore, repeated assessment of exposure during a relevant time period may provide a more precise risk estimate than a single measurement.

Organochlorine exposure and risk of breast cancer.

BACKGROUND: Some organochlorine compounds may have weak oestrogenic effects and are, therefore, suspected of increasing the risk of breast cancer. We assessed prospectively the risk of breast cancer in relation to serum concentrations of several organochlorine compounds. METHODS: In 1976, serum samples from 7712 women were obtained from participants in the Copenhagen City Heart Study as part of physical examinations and interviews about lifestyle factors. During 17 years of follow-up, 268 women developed invasive breast cancer. Each woman with breast cancer was matched with two breast-cancer-free women from the remaining cohort. We analysed in 1996-97 the serum samples from 240 women with breast cancer and 477 controls. FINDINGS: Dieldrin was associated with a significantly increased dose-related risk of breast cancer (adjusted odds ratio 2.05 [95% CI 1.17-3.57], p for trend 0.01). Beta-hexachlorocyclohexane increased risk slightly but not significantly (p for trend 0.24). There was no overall association between risk of breast cancer and p,p'-dichlorodiphenyltrichloroethane or metabolites or for polychlorinated biphenyls. Exclusion of women with breast cancer diagnosed within 5 years of blood sampling strengthened the result for dieldrin, but did not affect the other results. INTERPRETATION: These findings support the hypothesis that exposure to xeno-oestrogens may increase the risk of breast cancer.