Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial.

BACKGROUND: This trial assessed the efficacy and safety of the GLP-1 analogue once a week subcutaneous semaglutide 2·4 mg versus semaglutide 1·0 mg (the dose approved for diabetes treatment) and placebo for weight management in adults with overweight or obesity, and type 2 diabetes. METHODS: This double-blind, double-dummy, phase 3, superiority study enrolled adults with a body-mass index of at least 27 kg/m2 and glycated haemoglobin 7-10% (53-86 mmol/mol) who had been diagnosed with type 2 diabetes at least 180 days before screening. Patients were recruited from 149 outpatient clinics in 12 countries across Europe, North America, South America, the Middle East, South Africa, and Asia. Patients were randomly allocated (1:1:1) via an interactive web-response system and stratified by background glucose-lowering medication and glycated haemoglobin, to subcutaneous injection of semaglutide 2·4 mg, or semaglutide 1·0 mg, or visually matching placebo, once a week for 68 weeks, plus a lifestyle intervention. Patients, investigators, and those assessing outcomes were masked to group assignment. Coprimary endpoints were percentage change in bodyweight and achievement of weight reduction of at least 5% at 68 weeks for semaglutide 2·4 mg versus placebo, assessed by intention to treat. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03552757 and is closed to new participants. FINDINGS: From June 4 to Nov 14, 2018, 1595 patients were screened, of whom 1210 were randomly assigned to semaglutide 2·4 mg (n=404), semaglutide 1·0 mg (n=403), or placebo (n=403) and included in the intention-to-treat analysis. Estimated change in mean bodyweight from baseline to week 68 was -9·6% (SE 0·4) with semaglutide 2·4 mg vs -3·4% (0·4) with placebo. Estimated treatment difference for semaglutide 2·4 mg versus placebo was -6·2 percentage points (95% CI -7·3 to -5·2; p<0·0001). At week 68, more patients on semaglutide 2·4 mg than on placebo achieved weight reductions of at least 5% (267 [68·8%] of 388 vs 107 [28·5%] of 376; odds ratio 4·88, 95% CI 3·58 to 6·64; p<0·0001). Adverse events were more frequent with semaglutide 2·4 mg (in 353 [87·6%] of 403 patients) and 1·0 mg (329 [81·8%] of 402) than with placebo (309 [76·9%] of 402). Gastrointestinal adverse events, which were mostly mild to moderate, were reported in 256 (63·5%) of 403 patients with semaglutide 2·4 mg, 231 (57·5%) of 402 with semaglutide 1·0 mg, and 138 (34·3%) of 402 with placebo. INTERPRETATION: In adults with overweight or obesity, and type 2 diabetes, semaglutide 2·4 mg once a week achieved a superior and clinically meaningful decrease in bodyweight compared with placebo. FUNDING: Novo Nordisk.

The updated Pedersen-Bjergaard method for assessment of awareness of hypoglycaemia in type 1 diabetes.

INTRODUCTION: Loss of awareness of hypoglycaemia is the major risk factor for severe hypoglycaemia in type 1 diabetes. Three methods for assessment of self-reported awareness have been validated and used more widely: the Gold, the Clarke and the Pedersen-Bjergaard classification. Comparisons between the methods are hampered by the latter operating with three classes, whereas the other methods are bimodal. We have therefore updated the Pedersen-Bjergaard classification and here present a comparison of the three methods. METHODS: Adult people with type 1 diabetes (n = 325) completed a validated questionnaire. Hypoglycaemia awareness was self-reported by the three methods: Gold, Clarke and Pedersen-Bjergaard scores. The latter was updated by renaming the previous "impaired" class to "intermediate". RESULTS: A total of 24%, 17% and 14% of patients were classified as having loss of awareness by the Gold, Clarke and updated Pedersen-Bjergaard methods, respectively, with reasonably good agreement and all with increased rates of severe hypoglycaemia. The latter classified 43% with normal and 43% with intermediate awareness and low and average rate of severe hypoglycaemia, respectively. CONCLUSION: The three classifications identified people with loss of awareness with a reasonably high degree of concordance. In contrast to the others, the updated Pedersen-Bjergaard method identified groups with normal and intermediate awareness with clinically significant different risks of severe hypoglycaemia. FUNDING: The Research Foundation of Nordsjællands Hospital and the Beckett Foundation. TRIAL REGISTRATION: not relevant.

High serum ACE activity predicts severe hypoglycaemia over time in patients with type 1 diabetes.

AIMS/HYPOTHESIS: High serum angiotensin-converting enzyme (ACE) activity is associated with increased risk of severe hypoglycaemia (SH) within 1 year in type 1 diabetes. We wanted to find out whether ACE activity is stable over time and predicts SH beyond 1 year, and if gender differences exist in the association between ACE activity and risk of SH. METHODS: A follow-up study of 128 adult patients with type 1 diabetes was conducted. At entry, ACE activity was measured. For 12 months, patients prospectively recorded events of severe hypoglycaemia (SH). At a median of 40 months, ACE activity was measured again and participants recalled the number of SH in the last year. RESULTS: ACE activity is reproducible over 40 months (p < 0.00001). Patients with SH during the baseline study also had SH during follow-up (p < 0.00001). Serum ACE activity measured at baseline was positively associated with the rate of SH at follow-up (p = 0.0003) with a 3.2-fold increased rate of SH in subjects belonging to the upper ACE quartile compared to subjects in the three lowest quartiles (p < 0.00001). The association between high serum ACE activity and increased risk of SH did not differ significantly in women and men. CONCLUSION: In type 1 diabetes individual serum ACE activity is reproducible over time. High ACE activity predicts recurrent SH over at least 40 months with no differences between genders.

Impact of Genetic Polymorphism in the ß2-Receptor Gene on Risk of Severe Hypoglycemia in Patients With Type 1 Diabetes.

Context: Severe hypoglycemic events are unevenly distributed in people with type 1 diabetes, making a genetic influence probable. Of the common adrenoceptor ß-2 receptor gene (ADRB2) polymorphisms, the Arg16 allele is associated with receptor downregulation and reduced agonist-mediated endogenous glucose production. Objective: We tested the hypothesis that the Arg16 variant is associated with severe hypoglycemia. Method: A cohort of 311 patients with type 1 diabetes reported severe hypoglycemic events retrospectively in a validated questionnaire. The patients were characterized by diabetes history, state of hypoglycemia awareness, C-peptide status, HbA1c, and ADRB2 genotype. Results: The ADRB2 Gly16Arg genotype distribution was in Hardy-Weinberg equilibrium. The rate of severe hypoglycemia differed among all genotypes (P = 0.01). Patients homozygous for the Arg16 genotype (AA; n = 60) had a relative rate (RR) of severe hypoglycemia of 2.2 (95% CI, 1.3 to 3.6) compared with patients homozygous for the Gly16 genotype (GG; n = 116; P = 0.002). Among patients with impaired awareness or unawareness (n = 175), those with the AA genotype (n = 33) had an RR of severe hypoglycemia of 3.2 (95% CI, 1.7 to 6.0) compared with patients with the GG genotype (n = 58; P < 0.000). Genotype was not associated with state of hypoglycemia awareness per se, as assessed by any of three classification methods. The difference was not explained by other risk factors. Conclusion: Genetic polymorphism in ADRB2 is associated with risk of severe hypoglycemia in individuals with type 1 diabetes, especially in those with impaired hypoglycemia awareness.

Long-Term Prediction of Severe Hypoglycemia in Type 1 Diabetes: Is It Really Possible?

BACKGROUND: Prediction of risk of severe hypoglycemia (SH) in patients with type 1 diabetes is important to prevent future episodes, but it is unknown if it is possible to predict the long-term risk of SH. The aim of the study is to assess if long-term prediction of SH is possible in type 1 diabetes. METHODS: A follow-up study was performed with 98 patients with type 1 diabetes. At baseline and at follow-up, the patients filled in a questionnaire about diabetes history and complications, number of SH in the preceding year and state of awareness, and HbA1c and C-peptide levels were measured. RESULTS: During the 12 years of follow-up, there was a decrease in HbA1c, C-peptide levels, and incidence of SH (1.1 to 0.4 episodes per patient-year; P < .001). At baseline, the relative rate of SH was 3.6 (P = .001) and 10.9 (P < .0001) in patients with impaired awareness and unawareness of hypoglycemia, respectively, as compared to patients with normal awareness. At follow-up, patients with unawareness at baseline tended to have maintained an increased rate of SH (RR = 3.1; P = .07). Impaired awareness, HbA1c and C-peptide determined at baseline did not correspond with an increased rate of SH at follow-up. CONCLUSIONS: Long-term prediction of severe hypoglycemia in type 1 diabetes was not possible, although baseline hypoglycemia unawareness tended to remain a predictor for risk of SH at follow-up. Therefore, it is important repeatedly to assess the different risk factors of SH to determine the actual risk.

The influence of new European Union driver's license legislation on reporting of severe hypoglycemia by patients with type 1 diabetes.

OBJECTIVE: We test the hypotheses that the implementation in Denmark of new, stricter European Union (EU) legislation on driver's licensing, with the purpose to improve traffic safety in January 2012, has reduced the self-reported rate of severe hypoglycemia in a routine clinical setting and that anonymous reporting results in higher event rates. RESEARCH DESIGN AND METHODS: A cohort of 309 patients with type 1 diabetes was recruited in the outpatient clinic at Nordsjællands University Hospital Hillerød, Denmark. Yearly numbers of severe hypoglycemic events defined by need for treatment assistance from another person were retrieved from medical records in the years 2010 to 2012 and retrospectively reported in an anonymous questionnaire. Data from medical records in 2012 were compared with those from 2010 and 2011 and with data from the questionnaire. RESULTS: Reported rates of severe hypoglycemia in the medical records were reduced by 55% in 2012 compared with the prior years (P = 0.034). The proportion of subjects reporting recurrent episodes was grossly reduced from 5.6 to 1.5% (P = 0.014). Compared with anonymous reporting in the questionnaire, the rate of severe hypoglycemia in 2012 was 70% lower (P < 0.001). CONCLUSIONS: Reporting of severe hypoglycemia by patients with type 1 diabetes is significantly reduced following implementation of EU driver's licensing legislation that implies withdrawal of driver's licensing in case of recurrent episodes within 1 year. The resulting burden of concealed severe hypoglycemia may impair the safety of affected patients and unintentionally paradoxically reduce the general traffic safety.

ACE genotype, phenotype and all-cause mortality in different cohorts of patients with type 1 diabetes.

AIMS: Carrying the D-allele of the angiotensin-converting enzyme (ACE) I/D polymorphism and high ACE activity are prognostic factors in diabetic nephropathy, which predicts mortality in type 1 diabetes. We studied the association between the ACE D-allele and ACE phenotype and long-term all-cause mortality in three single-institution outpatient cohorts. METHODS: Genotype-based analyses were performed in 269 patients from Hillerød Hospital (HIH) (follow-up: 12 years) and in 439 patients with diabetic nephropathy and 437 patients with persistent normoalbuminuria from the Steno Diabetes Center (SDC) (follow-up: 9.5 years). Patients not on renin-angiotensin system (RAS)-blocking treatment were included in analyses of serum ACE activity (HIH: n = 208) and plasma ACE concentration (SDC: n=269). RESULTS: In the HIH cohort, carrying a D-allele was associated with excess mortality (hazard ratio (HR) = 4.0 (95% confidence interval (CI) 1.0-16)), but not in the SDC cohorts. At HIH, serum ACE activity was associated with excess mortality (HR=1.04 (95% CI 1.0-1.1 per unit increase)), but in the SDC cohort plasma ACE concentration was not. CONCLUSION: In unselected patients with type 1 diabetes, carrying the ACE D-allele and high spontaneous serum ACE activity were associated with 12-year excess mortality. These findings could not be reproduced in two other cohorts with persistent normoalbuminuria or diabetic nephropathy.

Effects of angiotensin II receptor blockade on cerebral, cardiovascular, counter-regulatory, and symptomatic responses during hypoglycaemia in patients with type 1 diabetes.

INTRODUCTION: High spontaneous activity of the renin-angiotensin system (RAS) results in more pronounced cognitive impairment and more prolonged QTc interval during hypoglycaemia in type 1 diabetes. We tested whether angiotensin II receptor blockade improves cerebral and cardiovascular function during hypoglycaemia. METHODS: Nine patients with type 1 diabetes and high spontaneous RAS activity were included in a double-blind, randomised, cross-over study on the effect of angiotensin II receptor antagonist (candesartan 32 mg) or placebo for one week on cognitive function, cardiovascular parameters, hormonal counter-regulatory response, substrate mobilisation, and symptoms during hypoglycaemia induced by two hyperinsulinaemic, hypoglycaemic clamps. RESULTS: Compared to placebo, candesartan did neither change performance of the cognitive tests nor the EEG at a plasma glucose concentration of 2.6±0.2 mmol/l. During candesartan treatment, the QT interval in the ECG was not affected. No effect of candesartan was observed in the hormonal counter-regulatory responses, in substrate concentrations, or in symptom scores. A 36% reduced glucose infusion rate during hypoglycaemia with candesartan was observed. CONCLUSION: In conclusion candesartan has no effect on cerebral function during mild experimental hypoglycaemia in subjects with type 1 diabetes and high RAS activity. Candesartan may reduce glucose utilisation or increase endogenous glucose production during hypoglycaemia.

Association of IGF1 with glycemic control and occurrence of severe hypoglycemia in patients with type 1 diabetes mellitus.

OBJECTIVE: GH is implicated in the counter-regulatory response to hypoglycemia. We tested whether IGF1 levels are associated with occurrence of severe hypoglycemic events in patients with type 1 diabetes and whether the IGF1 concentration is influenced by glycemic control. METHODS: A total of 228 outpatients with type 1 diabetes were included in a post hoc analysis of a 1-year observational study on severe hypoglycemia. Serum total IGF1 was measured at entry into the study. The occurrence of severe episodes of hypoglycemia, mild symptomatic, and biochemical as well as hypoglycemia awareness status was assessed. Also patients were included in a multiple regression analysis to investigate the role of HbA1c in the IGF1 concentration. RESULTS: IGF1 levels were associated with neither severe hypoglycemia in the entire cohort (P=0.30) nor in any gender nor when confining the analysis to those with long-standing diabetes (>20 years) (n=112, P=0.68) and those with both long-standing diabetes and undetectable C-peptide (n=51, P=0.067). Levels of IGF1 were associated with neither mild symptomatic hypoglycemia (P=0.24) nor biochemical hypoglycemia (0.089) nor hypoglycemia awareness (P=0.16). At a multiple regression analysis, HbA1c was negatively associated with IGF1 (P=0.001). CONCLUSION: In type 1 diabetes, circulating IGF1 levels are negatively associated with glycemic control. However, IGF1 levels were not associated with occurrence of hypoglycemia or hypoglycemia awareness in these patients.

Testing the validity of the Danish urban myth that alcohol can be absorbed through feet: open labelled self experimental study.

OBJECTIVE: To determine the validity of the Danish urban myth that it is possible to get drunk by submerging feet in alcohol. DESIGN: Open labelled, self experimental study, with no control group. SETTING: Office of a Danish hospital. PARTICIPANTS: Three adults, median age 32 (range 31-35), free of chronic skin and liver disease and non-dependent on alcohol and psychoactive drugs. MAIN OUTCOME MEASURES: The primary end point was the concentration of plasma ethanol (detection limit 2.2 mmol/L (10 mg/100 mL)), measured every 30 minutes for three hours while feet were submerged in a washing-up bowl containing the contents of three 700 mL bottles of vodka. The secondary outcome was self assessment of intoxication related symptoms (self confidence, urge to speak, and number of spontaneous hugs), scored on a scale of 0 to 10. RESULTS: Plasma ethanol concentrations were below the detection limit of 2.2 mmol/L (10 mg/100 mL) throughout the experiment. No significant changes were observed in the intoxication related symptoms, although self confidence and urge to speak increased slightly at the start of the study, probably due to the setup. CONCLUSION: Our results suggest that feet are impenetrable to the alcohol component of vodka. We therefore conclude that the Danish urban myth of being able to get drunk by submerging feet in alcoholic beverages is just that; a myth. The implications of the study are many though.