Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study.

OBJECTIVE: The efficacy and safety of adding liraglutide (a glucagon-like peptide-1 receptor agonist) to metformin were compared with addition of placebo or glimepiride to metformin in subjects previously treated with oral antidiabetes (OAD) therapy. RESEARCH DESIGN AND METHODS: In this 26-week, double-blind, double-dummy, placebo- and active-controlled, parallel-group trial, 1,091 subjects were randomly assigned (2:2:2:1:2) to once-daily liraglutide (either 0.6, 1.2, or 1.8 mg/day injected subcutaneously), to placebo, or to glimepiride (4 mg once daily). All treatments were in combination therapy with metformin (1g twice daily). Enrolled subjects (aged 25-79 years) had type 2 diabetes, A1C of 7-11% (previous OAD monotherapy for > or =3 months) or 7-10% (previous OAD combination therapy for > or =3 months), and BMI < or =40 kg/m(2). RESULTS: A1C values were significantly reduced in all liraglutide groups versus the placebo group (P < 0.0001) with mean decreases of 1.0% for 1.8 mg liraglutide, 1.2 mg liraglutide, and glimepiride and 0.7% for 0.6 mg liraglutide and an increase of 0.1% for placebo. Body weight decreased in all liraglutide groups (1.8-2.8 kg) compared with an increase in the glimepiride group (1.0 kg; P < 0.0001). The incidence of minor hypoglycemia with liraglutide ( approximately 3%) was comparable to that with placebo but less than that with glimepiride (17%; P < 0.001). Nausea was reported by 11-19% of the liraglutide-treated subjects versus 3-4% in the placebo and glimepiride groups. The incidence of nausea declined over time. CONCLUSIONS: In subjects with type 2 diabetes, once-daily liraglutide induced similar glycemic control, reduced body weight, and lowered the occurrence of hypoglycemia compared with glimepiride, when both had background therapy of metformin.

Delayed breast reconstruction with implants after invasive breast cancer does not impair prognosis.

We investigated if delayed breast implant reconstruction after breast cancer impairs prognosis. Using data from the Danish Breast Cancer Cooperative Group register, we identified all women <70 years who underwent breast reconstruction with implants after mastectomy after invasive breast cancer during 1978 to 1992, on average 2.2 years (range, 3 days-9.4 years) after mastectomy. The reconstructed women were closely matched to breast cancer patients without reconstruction on age and calendar time of diagnosis, tumor size, regional lymph node involvement, and adjuvant radiation therapy. Overall, 580 reconstructed women and 1158 individually matched controls were followed-up for disease-free survival within the first 10 years and for overall survival for an average of 20.1 year (range, 12.8-27.5 years). Disease-free survival was significantly improved hazard ratio 0.78; 95% confidence interval 0.64-0.95 and overall survival was nonsignificantly improved (hazard ratio, 0.90; 95% confidence interval 0.76-1.06) among the breast reconstructed women. This is likely because of differences in socioeconomic and health factors.

Long-term results of breast conserving surgery vs. mastectomy for early stage invasive breast cancer: 20-year follow-up of the Danish randomized DBCG-82TM protocol.

The main objective of the present study aims at comparing the long-term efficacy of breast conserving surgery (BCS) vs. mastectomy (M) based on a randomized design. The Danish Breast Cancer Cooperative Group (DBCG) conducted the trial (DBCG-82TM) from January 1983 to March 1989 recruiting 1154 patients with invasive breast carcinoma. Follow-up time ended 1(st) May 2006 with a median follow-up time of 19.6 years (time span 17.1-23.3 years). Eligibility criteria included a one-sided, unifocal, primary operable breast carcinoma, patient age below 70 years, probability of satisfactory cosmetic outcome with BCS, and no evidence of disseminated disease. The patients accrued were grouped into three subsets: correctly randomized, suspicion of randomization error, and declining randomization. The main analyses focus on the subgroup of 793 correctly randomized patients representing 70% of the complete series. 10-year recurrence free survival (RFS) and 20-year overall survival (OS) based on intent to treat did not reveal significant differences in outcome between breast conserving surgery vs. mastectomy, p=0.95 and p=0.10, respectively. Including the complete series comprising 1133 eligible patients based on treatment in fact given similarly no significant difference between surgical options could be traced in outcome of 10-year RFS and 20-year OS, p=0.94 and p=0.24, respectively. The pattern of recurrences as a first event in breast conservation vs. mastectomy did not differ significantly irrespective of site, p=0.27. Looking into the type of local relapse, viz., new primaries vs. true recurrences, it appeared that new primaries were significantly associated to BCS, while true recurrences dominated among M treated patients (p<0.001). In conclusion, long-term data indicate that BCS in eligible patients proves as effective as mastectomy both regarding local tumour control, RFS and OS. Local failures as a first event consistent with new primaries are strongly associated with BCS, whereas true recurrence predominates after mastectomy.

Breast conserving treatment in Denmark, 1989-1998. A nationwide population-based study of the Danish Breast Cancer Co-operative Group.

BACKGROUND: Randomised studies have shown that breast conserving surgery followed by radiotherapy is associated with a prognosis similar to mastectomy alone. This formed the basis for recommending breast conserving surgery combined with radiotherapy as a standard treatment for suited breast cancer patients in Denmark. PATIENTS AND METHODS: To evaluate the results of this treatment, we performed a nationwide population-based follow-up study of patients aged less than 75 years treated in Denmark from 1989 to 1998 based on the database of Danish Breast Cancer Cooperative Group. RESULTS: At 15 years of follow-up, the Kaplan-Meier estimate of overall survival was 69% among 3 758 patients who received the recommended treatment. Within the first 10 years of follow-up, the cumulative incidences of loco-regional recurrences, distant metastases or other malignant disease, or death as a first event were 9.0, 19.9, and 6.0% respectively, when analysed in a competing risk setting. The risk of loco-regional recurrences was significantly decreased in patients aged 50 years or more and increased with increasing tumour size. There was a pronounced beneficial effect of adjuvant radiotherapy with those not receiving radiotherapy having a hazard ratio of 3.52 (95% CI 2.21-5.61). The effect of resection margins was significant for loco-regional recurrences only in node negative patients. CONCLUSION: In conclusion, the present study shows that results similar to those from randomised clinical trials can be obtained when breast conserving treatment is applied as a standard treatment in an entire population.

Prognostic effect of estrogen receptor status across age in primary breast cancer.

Estrogen receptor (ER) status is considered as an important prognostic factor as well as a predictive factor for endocrine responsiveness in breast cancer. We analyzed the distribution of ER status across age and estimated variations in the prognostic impact of ER status related to patients' age and time since diagnosis. Overall, 26,944 patients with primary breast cancer diagnosed from 1989 to 2004 were included. The proportion of ER positive tumors increased over age from 51 to 82%. In multivariate analysis of overall survival, ER positive status was found to be a significantly positive prognostic factor over all age groups. This effect was limited to the first 5 years after diagnosis, RR: 2.08 (95% CI: 1.95-2.22, p < 0.0001). Overall survival during the following 5 years was slightly superior for women with ER negative tumors, RR of death: 0.89 (95% CI: 0.79-1.00, p = 0.049). Results were unchanged in patients who did not receive adjuvant systemic therapy (n = 6,272). Thus, positive ER status does not confer a negative impact on survival in young women as has been previously reported. The inferior prognosis for ER negative patients during the first 5 years after diagnosis changes into a slightly superior residual prognosis compared to ER positive patients independent of use of adjuvant systemic therapy. This may have an impact on future designing of guidelines for adjuvant endocrine therapy beyond 5 years.

Influence of socioeconomic factors on survival after breast cancer--a nationwide cohort study of women diagnosed with breast cancer in Denmark 1983-1999.

The reasons for social inequality in breast cancer survival are far from established. Our study aims to study the importance of a range of socioeconomic factors and comorbid disorders on survival after breast cancer surgery in Denmark where the health care system is tax-funded and uniform. All 25,897 Danish women who underwent protocol-based treatment for breast cancer in 1983-1999 were identified in a clinical database and information on socioeconomic variables and both somatic and psychiatric comorbid disorders was obtained from population-based registries. We used Cox proportional hazards models to estimate the association between socioeconomic position and overall survival and further to analyse breast cancer specific deaths in a competing risk set-up regarding all other causes of death as competing risks. The adjusted hazard ratio (HR) for death was reduced in women with higher education (HR, 0.91; 95% confidence interval (CI), 0.85-0.98), with higher income (HR, 0.93; 95% CI, 0.87-0.98) and with larger dwellings (HR, 0.90; 95% CI, 0.85-0.96 for women living in houses larger than 150 m(2)). Presence of comorbid disorders increased the HR. An interaction between income and comorbid disorders resulting in a 15% lower survival 10 year after primary surgery in poor women with low-risk breast cancer having comorbid conditions ( approximately 65%) compared to rich women with similar breast cancer prognosis and comorbid conditions ( approximately 80%) suggests that part of the explanation for the social inequality in survival after breast cancer surgery in Denmark lies in the access to and/or compliance with management of comorbid conditions in poorer women.