Effect of Insulin Degludec vs Insulin Glargine U100 on Hypoglycemia in Patients With Type 1 Diabetes: The SWITCH 1 Randomized Clinical Trial.

IMPORTANCE: Hypoglycemia, common in patients with type 1 diabetes, is a major barrier to achieving good glycemic control. Severe hypoglycemia can lead to coma or death. OBJECTIVE: To determine whether insulin degludec is noninferior or superior to insulin glargine U100 in reducing the rate of symptomatic hypoglycemic episodes. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, randomized, crossover noninferiority trial involving 501 adults with at least 1 hypoglycemia risk factor treated at 84 US and 6 Polish centers (January 2014-January 12, 2016) for two 32-week treatment periods, each with a 16-week titration and a 16-week maintenance period. INTERVENTIONS: Patients were randomized 1:1 to receive once-daily insulin degludec followed by insulin glargine U100 (n = 249) or to receive insulin glargine U100 followed by insulin degludec (n = 252) and randomized 1:1 to morning or evening dosing within each treatment sequence. MAIN OUTCOMES AND MEASURES: The primary end point was the rate of overall severe or blood glucose-confirmed (<56 mg/dL) symptomatic hypoglycemic episodes during the maintenance period. Secondary end points included the rate of nocturnal symptomatic hypoglycemic episodes and proportion of patients with severe hypoglycemia during the maintenance period. The noninferiority criterion for the primary end point and for the secondary end point of nocturnal hypoglycemia was defined as an upper limit of the 2-sided 95% CI for a rate ratio of 1.10 or lower; if noninferiority was established, 2-sided statistical testing for superiority was conducted. RESULTS: Of the 501 patients randomized (mean age, 45.9 years; 53.7% men), 395 (78.8%) completed the trial. During the maintenance period, the rates of overall symptomatic hypoglycemia were 2200.9 episodes per 100 person-years' exposure (PYE) in the insulin degludec group vs 2462.7 episodes per 100 PYE in the insulin glargine U100 group for a rate ratio (RR) of 0.89 (95% CI, 0.85-0.94; P < .001 for noninferiority; P < .001 for superiority; rate difference, -130.31 episodes per 100 PYE; 95% CI, -193.5 to -67.16). The rates of nocturnal symptomatic hypoglycemia were 277.1 per 100 PYE in the insulin degludec group vs 428.6 episodes per 100 PYE in the insulin glargine U100 group, for an RR of 0.64 (95% CI, 0.56-0.73; P < .001 for noninferiority; P < .001 for superiority; rate difference, -61.94 episodes per 100 PYE; 95% CI, -83.85 to -40.03). A lower proportion of patients in the insulin degludec than in the insulin glargine U100 group experienced severe hypoglycemia during the maintenance period (10.3%, 95% CI, 7.3%-13.3% vs 17.1%, 95% CI, 13.4%-20.8%, respectively; McNemar P = .002; risk difference, -6.8%; 95% CI, -10.8% to -2.7%). CONCLUSIONS AND RELEVANCE: Among patients with type 1 diabetes and at least 1 risk factor for hypoglycemia, 32 weeks' treatment with insulin degludec vs insulin glargine U100 resulted in a reduced rate of overall symptomatic hypoglycemic episodes. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02034513.

Insulin Degludec 200 Units/mL Is Associated With Lower Injection Frequency and Improved Patient-Reported Outcomes Compared With Insulin Glargine 100 Units/mL in Patients With Type 2 Diabetes Requiring High-Dose Insulin.

IN BRIEF Many patients with type 2 diabetes require high basal insulin doses, necessitating multiple injections, increasing patient burden, and resulting in reduced treatment adherence. This randomized, controlled, crossover trial compared the efficacy, safety, and patient-reported outcomes for a concentrated formulation of insulin degludec (200 units/mL) to those of insulin glargine in patients requiring high doses of basal insulin. By offering equivalent glycemic control while reducing the rate of confirmed hypoglycemia and the number of injections required for administration, insulin degludec 200 units/mL may be preferred by patients with type 2 diabetes who require high basal insulin doses.

Cigarette smoking is associated with adverse survival among women with ovarian cancer: Results from a pooled analysis of 19 studies.

Cigarette smoking is associated with an increased risk of developing mucinous ovarian tumors but whether it is associated with ovarian cancer survival overall or for the different histotypes is unestablished. Furthermore, it is unknown whether the association between cigarette smoking and survival differs according to strata of ovarian cancer stage at diagnosis. In a large pooled analysis, we evaluated the association between various measures of cigarette smoking and survival among women with epithelial ovarian cancer. We obtained data from 19 case-control studies in the Ovarian Cancer Association Consortium (OCAC), including 9,114 women diagnosed with ovarian cancer. Cox regression models were used to estimate adjusted study-specific hazard ratios (HRs), which were combined into pooled hazard ratios (pHR) with corresponding 95% confidence intervals (CIs) under random effects models. Overall, 5,149 (57%) women died during a median follow-up period of 7.0 years. Among women diagnosed with ovarian cancer, both current (pHR = 1.17, 95% CI: 1.08-1.28) and former smokers (pHR = 1.10, 95% CI: 1.02-1.18) had worse survival compared with never smoking women. In histotype-stratified analyses, associations were observed for mucinous (current smoking: pHR = 1.91, 95% CI: 1.01-3.65) and serous histotypes (current smoking: pHR = 1.11, 95% CI: 1.00-1.23; former smoking: pHR = 1.12, 95% CI: 1.04-1.20). Further, our results suggested that current smoking has a greater impact on survival among women with localized than disseminated disease. The identification of cigarette smoking as a modifiable factor associated with survival has potential clinical importance as a focus area to improve ovarian cancer prognosis.

Trends in all-cause five-year mortality after head and neck cancers diagnosed over a period of 33 years. Focus on estimated degree of association with human papillomavirus.

BACKGROUND: Factors influencing survival after head and neck cancer (HNC) include among others stage, age, and sex. More recently, human papillomavirus (HPV) positivity has been described as a favorable prognostic factor in relation to some HNCs. MATERIAL AND METHODS: In this nationwide register-based cohort study of all 20 925 individuals diagnosed with squamous cell carcinoma of the head and neck (HNSCC) in Denmark 1978-2010, we investigate secular trends in all-cause five-year mortality after HNSCC according to the anticipated degree of association with HPV using a Cox proportional hazards model. Furthermore, we examine whether any trend over time differed according to sex, stage, and age at diagnosis. RESULTS: All-cause five-year mortality after HNSCC has decreased over time. The greatest decrease was seen in the last decade (2000-2010) among patients with HNSCC at sites estimated to be strongly associated with HPV, i.e. the base of the tongue and the tonsils, where a 28% decrease per five years (e.g. HRbase of tongue/tonsils=0.72; 95% CI 0.64-0.81) was observed. When examining sex- and age-specific time trends, the decrease in mortality was most pronounced among male patients and patients below 60 years at diagnosis. In contrast, no clear pattern was observed when examining five-year all-cause mortality trends according to stage. CONCLUSION: All-cause five-year mortality after HNSCC has decreased significantly in Denmark from 1978 to 2010, especially for HNSCCs at sites anticipated to be strongly associated with HPV, possibly due to an increasing proportion of HPV-positive HNSCCs.

Mortality Among Women With Cervical Cancer During or Shortly After a Pregnancy in Denmark 1968 to 2006.

OBJECTIVE: Cervical cancer diagnosed in relation to a pregnancy is rare; however, the current trend to have children later in life increases the risk of pregnancy and cervical cancer coinciding. We investigated the mortality of women diagnosed with cervical cancer during or in relation to a pregnancy. MATERIALS AND METHODS: From the nationwide Danish Cancer Registry, we identified women diagnosed with a primary cervical cancer at ages 15 to 44 years during 1968 to 2006 born after April 1, 1935. The women were linked to several Danish national registries to obtain information on births and abortions. In addition, linkage was made to the Cause of Death Register. Overall and cause-specific hazards ratios (HRs) were assessed by Cox proportional hazards regression with adjustment for age, calendar year, and extent of disease. RESULTS: A total of 6135 cervical cancers were identified. Among these, 126 women were diagnosed with cervical cancer during pregnancy, 1856 were diagnosed with cervical cancer 0 to 4 years after a pregnancy, and 4153 were diagnosed with cervical cancer more than 30 days before or 5 years or more after a pregnancy or had no known pregnancies. The latter group was used as reference. The adjusted HR for death due to cervical cancer was 1.77 (95% confidence interval, 1.21-2.60) among women diagnosed with cervical cancer during pregnancy compared with that in the reference group, while the corresponding HR among women with cervical cancer 0 to 4 years after pregnancy was 0.96 (95% confidence interval, 0.83-1.10) compared with that in the reference group. CONCLUSIONS: Our results suggest an increased mortality for women diagnosed with cervical cancer during pregnancy, but not among those diagnosed shortly after pregnancy. This finding should be explored further in larger populations.

The association between socioeconomic status and tumour stage at diagnosis of ovarian cancer: A pooled analysis of 18 case-control studies.

PURPOSE: Socioeconomic status (SES) is a known predictor of survival for several cancers and it has been suggested that SES differences affecting tumour stage at diagnosis may be the most important explanatory factor for this. However, only a limited number of studies have investigated SES differences in tumour stage at diagnosis of ovarian cancer. In a pooled analysis, we investigated whether SES as represented by level of education is predictive for advanced tumour stage at diagnosis of ovarian cancer, overall and by histotype. The effect of cigarette smoking and body mass index (BMI) on the association was also evaluated. METHODS: From 18 case-control studies, we obtained information on 10,601 women diagnosed with epithelial ovarian cancer. Study specific odds ratios (ORs) with corresponding 95% confidence intervals (CI) were obtained from logistic regression models and combined into a pooled odds ratio (pOR) using a random effects model. RESULTS: Overall, women who completed ≤high school had an increased risk of advanced tumour stage at diagnosis compared with women who completed >high school (pOR 1.15; 95% CI 1.03-1.28). The risk estimates for the different histotypes of ovarian cancer resembled that observed for ovarian cancers combined but did not reach statistical significance. Our results were unchanged when we included BMI and cigarette smoking. CONCLUSION: Lower level of education was associated with an increased risk of advanced tumour stage at diagnosis of ovarian cancer. The observed socioeconomic difference in stage at diagnosis of ovarian cancer calls for further studies on how to reduce this diagnostic delay.