Once-weekly insulin icodec versus once-daily insulin degludec as part of a basal-bolus regimen in individuals with type 1 diabetes (ONWARDS 6): a phase 3a, randomised, open-label, treat-to-target trial.

BACKGROUND: ONWARDS 6 compared the efficacy and safety of once-weekly subcutaneous insulin icodec (icodec) and once-daily insulin degludec (degludec) in adults with type 1 diabetes. METHODS: This 52-week (26-week main phase plus a 26-week safety extension), randomised, open-label, treat-to-target, phase 3a trial was done at 99 sites across 12 countries. Adults with type 1 diabetes (glycated haemoglobin [HbA1c] <10·0% [86 mmol/mol]) were randomly assigned (1:1) to once-weekly icodec or once-daily degludec, both in combination with insulin aspart (two or more daily injections). The primary endpoint was change in HbA1c from baseline to week 26, tested for non-inferiority (0·3 percentage point margin) in all randomly assigned participants. This trial is registered with ClinicalTrials.gov, NCT04848480, and is now complete. FINDINGS: Between April 30 and Oct 15, 2021, of 655 participants screened, 582 participants were randomly assigned to icodec (n=290) or degludec (n=292). At week 26, from baseline values of 7·59% (icodec) and 7·63% (degludec), estimated mean changes in HbA1c were -0·47 percentage points and -0·51 percentage points, respectively (estimated treatment difference 0·05 percentage points [95% CI -0·13 to 0·23]), confirming non-inferiority of icodec to degludec (p=0·0065). Overall rate of combined clinically significant or severe hypoglycaemia (baseline to week 26) was statistically significantly higher with icodec than degludec (19·9 vs 10·4 events per patient-year of exposure; estimated rate ratio 1·9 [95% CI 1·5 to 2·3]; p<0·0001). The rate was also statistically significantly higher with icodec than degludec when evaluated over 57 weeks (52 weeks plus a 5-week follow-up period). 39 serious adverse events were reported in 24 (8%) participants receiving icodec, and 25 serious adverse events were reported in 20 (7%) participants receiving degludec. One participant in the icodec group died; this was judged unlikely to be due to the trial product. INTERPRETATION: In adults with type 1 diabetes, once-weekly icodec showed non-inferiority to once-daily degludec in HbA1c reduction at week 26, with statistically significantly higher rates of combined clinically significant or severe hypoglycaemia. For icodec, time below 3·0 mmol/L (<54 mg/dL) was at the threshold of the internationally recommended target (<1%) during weeks 22-26 and below target during weeks 48-52. FUNDING: Novo Nordisk.

Frequency of hypoglycaemia with basal insulin treatments in adults with type 1 diabetes treated with basal-bolus insulin regimens in treat-to-target trials: A narrative review.

AIM: To summarise, in a narrative review, published data on hypoglycaemia occurrence with basal insulin therapy in adults with type 1 diabetes treated with basal-bolus insulin regimens in treat-to-target randomised controlled trials. METHODS: Data were included from 21 eligible trials, which mainly used self-measured blood glucose or plasma glucose to detect hypoglycaemia. RESULTS: All-day self-measured blood glucose or plasma glucose level 2 (glucose threshold of 3.1 or 3.0 mmol/L) and level 3 (severe, requiring assistance) hypoglycaemic events were reported, respectively, by a range of 69.0%-97.5% and 0%-13.4% adults when receiving basal-bolus insulin therapy, with rates of 10.6-68.1 and 0.0-0.4 events per patient-year of exposure, respectively. Hypoglycaemia rates measured using continuous glucose monitoring (three studies) were numerically, yet consistently, higher than with either other method, except when limiting to symptomatic events. Nocturnal hypoglycaemia rates were generally less than 30% of the equivalent all-day rates. CONCLUSIONS: Differences across the studies in design (e.g., titration targets) and participant characteristics hindered comparison of hypoglycaemia rates by insulin formulation. Consequently, few trends were identified by insulin formulation, study methodology or individuals' characteristics, suggesting that further research is required to identify treatment strategies that facilitate development of individualised recommendations to lower hypoglycaemia risk. These findings are useful to understand hypoglycaemia risk with available basal insulin therapies when used in a multiple daily injection regimen, as well as to provide context for the results of ongoing and future clinical trials, including those for two once-weekly basal insulins, insulin icodec and basal insulin Fc.

Rationale and design of the phase 3a development programme (ONWARDS 1-6 trials) investigating once-weekly insulin icodec in diabetes.

AIM: To describe the phase 3a ONWARDS clinical development programme investigating insulin icodec (icodec), a once-weekly basal insulin, including the design and rationale for each of the ONWARDS 1-6 trials. MATERIALS AND METHODS: Six randomized controlled trials have been initiated in adults with type 2 diabetes (T2D) (insulin-naive: ONWARDS 1, 3 and 5; previously insulin-treated: ONWARDS 2 and 4) and type 1 diabetes (T1D) (ONWARDS 6). Each trial will investigate icodec use in a unique clinical scenario, with consideration of long-term safety and varied comparator treatments (insulin glargine U100 or U300 or insulin degludec). ONWARDS 5 will incorporate real-world elements and a digital dose titration solution to guide icodec dosing. The primary objective for each of the trials is to compare the change in HbA1c from baseline to week 26 or week 52 between icodec and comparator arms. Secondary objectives include investigating other glycaemic control and safety parameters, such as fasting glucose, time in glycaemic range and hypoglycaemia. Patient-reported outcomes will assess treatment satisfaction. CONCLUSIONS: The ONWARDS 1-6 trials will evaluate the efficacy and safety of once-weekly icodec compared with currently available daily basal insulin analogues in T2D and T1D. These trials will generate comprehensive evidence of icodec use in diverse populations across the spectrum of diabetes progression and treatment experience.

Discovery of insulin 100 years on.

The discovery of insulin 100 years ago ranks among the greatest medical achievements ever. This sparked a revolution of scientific discovery and therapeutic intervention to treat people suffering with diabetes. A light was shone for other areas of medicine to illuminate what was possible with detailed scientific endeavour. There followed a range of firsts leading to the current time in which we now know more about this peptide hormone than almost any other protein in existence. This has allowed therapeutic advancement from a positon of knowledge leading to stunning innovation. This innovation is likely to lead to more physiological insulin replacement reducing the disease burden to individuals and society as whole.

Efficacy of iGlarLixi in adults with type 2 diabetes inadequately controlled (glycated haemoglobin ≥8%, ≥64 mmol/mol) on two oral antidiabetes drugs: Post hoc analysis of the LixiLan-O randomized trial.

AIMS: To assess the efficacy and safety of iGlarLixi (the titratable fixed-ratio combination of insulin glargine 100 U/mL [iGlar] plus lixisenatide [Lixi]), in adults with type 2 diabetes (T2D) with glycated haemoglobin (HbA1c) levels ≥8% (≥64 mmol/mol). MATERIALS AND METHODS: The LixiLan-O study (NCT02058147) compared iGlarLixi with iGlar or Lixi in adults with T2D inadequately controlled on metformin ± a second oral antidiabetes drug (OAD). This exploratory analysis evaluated the LixiLan-O subgroup of participants with baseline HbA1c levels of ≥8% (≥64 mmol/mol) who were receiving metformin plus a second OAD at screening. RESULTS: The mean diabetes duration was 10.0 years, and the mean duration of second OAD use was 4.5 years. iGlarLixi demonstrated greater mean reductions from baseline in HbA1c and 2-hour postprandial glucose (PPG) compared with iGlar or Lixi (HbA1c -1.9% vs. -1.6% or -1.0% [-20 vs. -17 or -10 mmol/mol; 2-hour PPG -7.2 vs. -4.6 or -5.5 mmol/L). Greater proportions of participants achieved HbA1c <7% (<53 mmol/mol) with iGlarLixi versus iGlar or Lixi (67% vs. 51% or 18%), and the composite endpoints of HbA1c <7% (<53 mmol/mol) with no body weight gain (36% vs. 19% or 16%), and HbA1c <7% (<53 mmol/mol) with no body weight gain and no documented symptomatic hypoglycaemia (plasma glucose ≤3.9 mmol/L; 28% vs. 15% or 15%). The incidence rates of documented symptomatic hypoglycaemia were 29.0%, 27.9% and 12.1% for iGlarLixi, iGlar and Lixi, respectively. CONCLUSIONS: Adults with T2D and HbA1c ≥64 mmol/mol (≥8%) despite two OADs at screening achieved better glycaemic control with iGlarLixi versus iGlar or Lixi, without increased risk of hypoglycaemia versus iGlar.

100 years of physiology, discrimination and wonder.

There has been 100 years of research detailing the role of insulin in glucose, protein and free fatty acid metabolism. We explore the learnings though evolution and changes in management with an understanding of how it has impacted the care of people with diabetes. The discrimination endured is described and recent advances to empower and counter this are highlighted.

Pilots flying with insulin-treated diabetes.

People with diabetes treated with insulin have often faced blanket bans from safety-critical occupations, largely because of fear of incapacitation due to hypoglycaemia. Recent advances in insulin therapies, modes of administration, monitoring, and noninvasive monitoring techniques have allowed stereotypical views to be challenged. The aviation sector has led the way, in allowing pilots to fly while on insulin. Recently, countries that have traditionally been opposed to this have changed their minds, largely due to the increasing evidence of safety. The purpose of this review was to gather all available information to update clinicans. The physiology and pathophysiology underpinning glucose regulation and the management of diabetes in the air allowing certain insulin-treated pilots to fly are discussed.

Blood glucose monitoring by insulin-treated pilots of commercial and private aircraft: An analysis of out-of-range values.

AIM: To examine blood glucose measurements recorded as part of the diabetes protocol operated by the UK, Ireland and Austria, which allows commercial airline pilots with insulin-treated diabetes to fly. METHODS: An observational study was conducted in pilots with insulin-treated diabetes, granted medical certification to fly commercial or noncommercial aircraft, who recorded pre-flight and hourly in-flight blood glucose measurements. These values were correlated to a traffic light system (green 5.0 to 15.0 mmol/L; amber 4.0 to 4.9 mmol/L and 15.1 to 20.0 mmol/L; and red <4.0 mmol/L or >20.0 mmol/L) and studied for trends in glucose concentrations, time course within flight and any consequences. Pilot demographics were also analysed. RESULTS: Forty-four pilots (90%) recorded one or more blood glucose value outside the green range during the 7 years of the study. Pilot age, diabetes type and duration, and follow-up period were comparable among subgroups, and mean glycated haemoglobin did not differ before and after certification in a way which would indicate poorer glycaemic control in any subgroup. A total of 892 blood glucose values (2.31%) were outside the green range, with half reported in-flight at various time intervals. There were 48 (0.12%) low red range values recorded, 14 (0.04%) of which occurred in-flight; all but four were restored to within the green range by the time of the next measurement. Appropriate corrective action was taken for all out-of-range values, with no reports of pilot incapacitation from any cause. CONCLUSIONS: The traffic light system appears effective in identifying and reducing the frequency and severity of out-of-range values.

Take Control: A randomized trial evaluating the efficacy and safety of self- versus physician-managed titration of insulin glargine 300 U/mL in patients with uncontrolled type 2 diabetes.

AIM: To compare the efficacy and safety of self- versus physician-managed titration of insulin glargine 300 U/mL (Gla-300) in people with inadequately controlled type 2 diabetes. METHODS: Take Control (EudraCT number: 2015-001626-42) was a 24-week, multi-national, open-label, controlled, two-arm, parallel-group study in insulin-naïve and pre-treated participants, randomized 1:1 to a self- or physician-managed titration of Gla-300. The fasting self-monitored plasma glucose (SMPG) target was 4.4 to 7.2 mmol/L. The primary outcome was non-inferiority of glycated haemoglobin (HbA1c) change from baseline to week 24. Secondary outcomes included SMPG target achievement without hypoglycaemia, hypoglycaemia incidence, adverse events and participant-reported outcomes (PROs). RESULTS: At week 24, the least squares (LS) mean HbA1c reduction was 0.97% (10.6 mmol/mol) and 0.84% (9.2 mmol/mol) in the self- and physician-managed groups, respectively, with an LS mean difference of -0.13% [95% confidence interval -0.2619 to -0.0004] (-1.4 mmol/mol [-2.863 to -0.004]), demonstrating non-inferiority (P < 0.0001) and superiority (P = 0.0247) of self- versus physician-managed titration. Significantly more of the self- than physician-managed group achieved SMPG target without hypoglycaemia (67% vs 58%; P = 0.0187). Overall, hypoglycaemia incidence was similar in each group. No safety concerns were reported. In both groups, similar PRO improvements were observed for distress related to diabetes disease burden and for confidence in diabetes self-management, with even more individuals achieving a clinically relevant reduction in emotional burden and fewer individuals with high emotional burden in the self-managed group. CONCLUSIONS: Self-managed titration of Gla-300 was superior to physician-managed titration in terms of HbA1c reduction, accompanied by similar total PRO scores, with a clinically relevant reduction in emotional burden, and similar hypoglycaemia frequency.

Glycaemic benefit of iGlarLixi in insulin-naive type 2 diabetes patients with high HbA1c or those with inadequate glycaemic control on two oral antihyperglycaemic drugs in the LixiLan-O randomized trial.

In this post hoc analysis of the randomized controlled LixiLan-O trial in insulin-naive patients with type 2 diabetes mellitus (T2DM) not controlled with metformin, with or without a second oral antihyperglycaemic drug (OAD), the efficacy and safety of the fixed-ratio combination, iGlarLixi (insulin glargine 100 U [iGlar] and lixisenatide [Lixi]), compared to its individual components was assessed in two patient subgroups: group 1) baseline HbA1c ≥9% (n = 134); group 2) inadequate control (HbA1c ≥7.0% and ≤9.0%) despite administration of two OADs at screening (n = 725). Treatment with iGlarLixi resulted in significantly greater reduction in least squares mean HbA1c compared to treatment with iGlar or Lixi alone in both subgroups (group 1: 2.9%, 2.5%, 1.7% and group 2: 1.5%, 1.2%, 0.7%, respectively). Target HbA1c less than 7% was achieved in more than 70% of patients using iGlarLixi in both subgroups, while mitigating the weight gain observed with use of iGlar alone. Rates of hypoglycaemic events were low overall. These results suggest that treatment with iGlarLixi achieves superior glycaemic control compared to treatment with iGlar or Lixi alone in T2DM patients with HbA1c ≥9% or in those inadequately controlled with two OADs.

Identification of barriers to insulin therapy and approaches to overcoming them.

Poor glycaemic control in type 2 diabetes (T2D) is a global problem despite the availability of numerous glucose-lowering therapies and clear guidelines for T2D management. Tackling clinical or therapeutic inertia, where the person with diabetes and/or their healthcare providers do not intensify treatment regimens despite this being appropriate, is key to improving patients' long-term outcomes. This gap between best practice and current level of care is most pronounced when considering insulin regimens, with studies showing that insulin initiation/intensification is frequently and inappropriately delayed for several years. Patient- and physician-related factors both contribute to this resistance at the stages of insulin initiation, titration and intensification, impeding achievement of optimal glycaemic control. The present review evaluates the evidence and reasons for this delay, together with available methods for facilitation of insulin initiation or intensification.

Efficacy and safety of fast-acting insulin aspart in comparison with insulin aspart in type 1 diabetes (onset 1): A 52-week, randomized, treat-to-target, phase III trial.

AIMS: To compare the safety and efficacy of fast-acting insulin aspart (faster aspart) with conventional insulin aspart (IAsp) in adults with type 1 diabetes (T1D). MATERIALS AND METHODS: onset 1 was a randomized, multicentre, treat-to-target, phase III, 52-week (initial 26 weeks + additional 26 weeks) trial conducted at 165 sites across 9 countries. Adults with T1D were randomly allocated to double-blind mealtime faster aspart or IAsp, each with once- or twice-daily insulin detemir. The primary endpoint, change in glycated haemoglobin (HbA1c) from baseline after the initial 26 weeks, has been reported previously. In the present paper, we report data from the full 52-week study period. RESULTS: Between August 2013 and June 2015, 381 participants were assigned to double-blind faster aspart and 380 participants to IAsp. After 52 weeks, estimated mean changes from baseline in HbA1c levels were -0.08% (faster aspart) and +0.01% (IAsp); estimated treatment difference significantly favoured faster aspart (-0.10% [95% confidence interval {CI} -0.19;-0.00]; P = .0424). Changes from baseline in 1-hour postprandial plasma glucose (PPG) increment (meal test; faster aspart -1.05 mmol/L; IAsp -0.14 mmol/L) also significantly favoured faster aspart (estimated treatment difference -0.91 mmol/L [95% CI -1.40;-0.43]; -16.48 mg/dL [95% CI -25.17;-7.80]; P = .0002). There was no difference in overall severe or blood glucose-confirmed hypoglycaemic episodes or treatment-emergent adverse events between treatments. CONCLUSIONS: At 52 weeks, overall glycaemic control had significantly improved with faster aspart vs IAsp, consistent with the 26-week study findings. Achieving an insulin profile closer to physiological insulin secretion with faster aspart translates into lower PPG and HbA1c levels compared with those achieved with IAsp in people with T1D.

Projected long-term outcomes in patients with type 1 diabetes treated with fast-acting insulin aspart vs conventional insulin aspart in the UK setting.

AIM: To assess the impact of faster aspart vs insulin aspart on long-term clinical outcomes and costs for patients with type 1 diabetes mellitus (T1DM) in the UK setting. METHODS: The QuintilesIMS CORE Diabetes Model was used to project clinical outcomes and costs over patient lifetimes in a cohort with data on baseline characteristics from the "onset 1" trial. Treatment effects were taken from the 26-week main phase of the onset 1 trial, with costs and utilities based on literature review. Future costs and clinical benefits were discounted at 3.5% annually. RESULTS: Projections indicated that faster aspart was associated with improved discounted quality-adjusted life expectancy (by 0.13 quality-adjusted life-years) vs insulin aspart. Improved clinical outcomes resulted from fewer diabetes-related complications and a delayed time to their onset with faster aspart. Faster aspart was found to be associated with reduced costs vs insulin aspart (cost savings of £1715), resulting from diabetes-related complications avoided and reduced treatment costs. CONCLUSIONS: Faster aspart was associated with improved clinical outcomes and cost savings vs insulin aspart for patients with T1DM in the UK setting.

Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): a phase 3, randomised, open-label, treat-to-target non-inferiority trial.

BACKGROUND: Intensive basal-bolus insulin therapy has been shown to improve glycaemic control and reduce the risk of long-term complications that are associated with type 1 diabetes mellitus. Insulin degludec is a new, ultra-longacting basal insulin. We therefore compared the efficacy and safety of insulin degludec and insulin glargine, both administered once daily with mealtime insulin aspart, in basal-bolus therapy for type 1 diabetes. METHODS: In an open-label, treat-to-target, non-inferiority trial, undertaken at 79 sites (hospitals and centres) in six countries, adults (aged ≥18 years) with type 1 diabetes (glycated haemoglobin [HbA(1c)] ≤10% [86 mmol/mol]), who had been treated with basal-bolus insulin for at least 1 year, were randomly assigned in a 3:1 ratio, with a computer-generated blocked allocation sequence, to insulin degludec or insulin glargine without stratification by use of a central interactive response system. The primary outcome was non-inferiority of degludec to glargine, assessed as a reduction in HbA(1c) after 52 weeks, with the intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT00982228. FINDINGS: Of 629 participants, 472 were randomly assigned to insulin degludec and 157 to insulin glargine; all were analysed in their respective treatment groups. At 1 year, HbA(1c) had fallen by 0·40% points (SE 0·03) and 0·39% points (0·07), respectively, with insulin degludec and insulin glargine (estimated treatment difference -0·01% points [95% CI -0·14 to 0·11]; p<0·0001 for non-inferiority testing) and 188 (40%) and 67 (43%) participants achieved a target HbA(1c) of less than 7% (<53 mmol/mol). Rates of overall confirmed hypoglycaemia (plasma glucose <3·1 mmol/L or severe) were similar in the insulin degludec and insulin glargine groups (42·54 vs 40·18 episodes per patient-year of exposure; estimated rate ratio [degludec to glargine] 1·07 [0·89 to 1·28]; p=0·48). The rate of nocturnal confirmed hypoglycaemia was 25% lower with degludec than with glargine (4·41 vs 5·86 episodes per patient-year of exposure; 0·75 [0·59 to 0·96]; p=0·021). Overall serious adverse event rates (14 vs 16 events per 100 patient-years of exposure) were similar for the insulin degludec and insulin glargine groups. INTERPRETATION: Insulin degludec might be a useful basal insulin for patients with type 1 diabetes because it provides effective glycaemic control while lowering the risk of nocturnal hypoglycaemia, which is a major limitation of insulin therapy. FUNDING: Novo Nordisk.

Continuous Glucose Monitoring by Insulin-Treated Pilots Flying Commercial Aircraft Within the ARA.MED.330 Diabetes Protocol: A Preliminary Feasibility Study.

Background and Aims: A preliminary study compared the use of continuous glucose monitoring (CGM) with the use of self-monitored blood glucose (SMBG) by aircraft pilots with insulin-treated diabetes in the United Kingdom, Ireland, and Austria, certified to fly commercial aircraft within the European Aviation Safety Agency ARA.MED.330 protocol. Methods: SMBG and simultaneous interstitial glucose measurements using CGM (Dexcom G6®) were recorded during pre- and in-flight periods. Results: Eight male pilots (seven with type 1 diabetes and one with type 3c diabetes), median age of 48.5 years and median diabetes duration of 11.5 years, participated. The correlation coefficient (R) between 874 contemporaneously recorded SMBG and CGM values was 0.843, P < 0.001. The mean glucose concentration was 8.78 mmol/L (standard deviation [SD] 0.67) using SMBG compared with 8.71 mmol/L (SD 0.85) recorded using CGM. The mean absolute relative difference was 9.39% (SD 3.12). Conclusions: CGM using Dexcom G6 systems is a credible alternative to SMBG for monitoring glucose levels when insulin-treated pilots fly commercial aircraft. The study was registered with Clinical Trials.gov NCT04395378.

Effect of Dapagliflozin on Cardiac Function and Metabolic and Hormonal Responses to Exercise.

OBJECTIVE: This work aimed to investigate the effect of the SGLT2 inhibitor, dapagliflozin (DAPA), on cardiac function and the metabolic and hormonal response to moderate exercise in people with type 2 diabetes. METHODS: This was a double-blind, placebo-controlled crossover study with a 4-week washout period. Nine participants were randomly assigned to receive either 4 weeks of DAPA or 4 weeks of placebo. After each treatment, they underwent an exercise protocol with 2 consecutive 10-minute stages at a constant load corresponding to 40% and 70% maximal oxygen consumption (VO2max), coupled with hormonal and metabolic analysis. A blinded transthoracic echocardiogram was performed 3 days later. RESULTS: During the exercise protocol, glucose and lactate were lower (P < .0001 and P < .05, respectively) and ß-hydroxybutyrate (BOBH) and growth hormone (GH) were higher (P < .0005 and P = .01) following DAPA treatment compared to placebo. There was a trend for lower insulin with DAPA. Adrenalin, noradrenalin, and glucagon were not different. Following DAPA participants demonstrated an increased mean peak diastolic mitral annular velocity (e') in comparison to placebo (P = .03). The indexed left atrial volume and right ventricular e" were reduced following DAPA compared with placebo (P = .045 and P = .042, respectively). Arterial stiffness was not different between treatments (DAPA 9.35 ± 0.60 m/s; placebo 9.07 ± 0.72 m/s). CONCLUSION: During exercise, GH may be more important than catecholamines in driving the shift from glucose to fatty acid metabolism by SGLT2 inhibitors. The 4-week crossover design showed changes in cardiac function were rapid in onset and reversible.

Recent advances in incretin-based therapies.

The global burden of type 2 diabetes is growing. Traditional therapies are suboptimal and there is a clear unmet need for treatments that offer effective glucose control while addressing the comorbid factors associated with diabetes, such as obesity and risk of cardiovascular disease, without the fear of hypoglycaemia. Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors offer a novel way of reducing hyperglycaemia by targeting the incretin system. This review provides an overview of the development of incretin-based therapies and explains their differing modes of action compared with traditional interventions. A comparison of the clinical profiles of current glucagon-like peptide-1 receptor agonists [liraglutide and exenatide (twice-daily and once-weekly)] and dipeptidyl peptidase-4 inhibitors (sitagliptin, saxagliptin, vildagliptin and linagliptin) is performed alongside a discussion of the placement of incretin-based therapies in treatment guidelines. Further improvements in this class are expected, and we will examine some of the novel glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors currently under development.

A prospective, randomized pilot study evaluating the effects of metformin and lifestyle intervention on patients with prostate cancer receiving androgen deprivation therapy.

UNLABELLED: Study Type - Therapy (RCT) Level of Evidence 1b What's known on the subject? and What does the study add? Men with prostate cancer have higher rates of non-cancer mortality and CV morbidity and some of that excess risk has been attributed to the treatment they receive. ADT is an established treatment option for men with locally-advanced and metastatic prostate cancer and, although it has been shown to confer a disease-free survival advantage, it has also been associated with an increased incidence of CV disease and the metabolic syndrome (characterized by a cluster of CV risk factors, including insulin resistance). The benefits of the insulin sensitizer metformin and lifestyle intervention for reducing the incidence of metabolic syndrome have been shown in patients with impaired glucose tolerance. At the time of writing, the present study is the first to use metformin and lifestyle intervention in men with prostate cancer with the aim of reducing the risk of developing ADT-related CV morbidity and the metabolic syndrome. The study shows that lifestyle changes and metformin may indeed reduce the complications of androgen suppression in these men. Although further investigations are needed to establish which of the two interventions may be most beneficial, the favourable effects of a combination of these interventions on patients' quality of life and the potential for improved overall survival are of clinical significance. OBJECTIVE: To investigate the effects of metformin and lifestyle changes on the development of androgen deprivation therapy (ADT)-related metabolic syndrome. PATIENTS AND METHODS: Men with prostate cancer due to receive ADT were recruited and randomized. Controls received ADT alone. Men in the intervention arm received ADT with 6 months of metformin, a low glycaemic index diet and an exercise programme. All patients were investigated pretreatment and at 6 months for the metabolic syndrome, as well as for related biochemical and physical parameters. RESULTS: In total, 40 men were recruited and randomized (20 to each arm). After 6 months, significant improvements in abdominal girth (P= 0.05), weight (P < 0.001), body mass index (P < 0.001) and systolic blood pressure (P= 0.01) were seen in the intervention arm compared to controls. Biochemical markers of insulin resistance did not differ significantly. CONCLUSIONS: The present study shows the potential benefits of metformin and lifestyle changes in ADT-treated men. Further studies will aim to determine which intervention is most important, and may show that overall survival can be improved.

The SGLT2 Inhibitor Dapagliflozin Increases the Oxidation of Ingested Fatty Acids to Ketones in Type 2 Diabetes.

OBJECTIVE: To investigate the mechanism for increased ketogenesis following treatment with the SGLT2 inhibitor dapagliflozin in people with type 2 diabetes. RESEARCH DESIGN AND METHODS: The design was a double-blind, placebo-controlled, crossover study with a 4-week washout period. Participants received dapagliflozin or placebo in random order for 4 weeks. After each treatment, they ingested 30 mL of olive oil containing [U-13C]palmitate to measure ketogenesis, with blood sampling for 480 min. Stable isotopes of glucose and glycerol were infused to measure glucose flux and lipolysis, respectively, at 450-480 min. RESULTS: Glucose excretion rate was higher and peripheral glucose uptake lower with dapagliflozin than placebo. Plasma ß-hydroxybutyrate (BOHB) concentrations and [13C2]BOHB concentrations were higher and glucose concentrations lower with dapagliflozin than placebo. Nonesterified fatty acids (NEFAs) were higher with dapagliflozin at 300 and 420 min, but lipolysis at 450-480 min was not different. Triacylglycerol at all time points and endogenous glucose production rate at 450-480 min were not different between treatments. CONCLUSIONS: The increase in ketone enrichment from the ingested palmitic acid tracer suggests that meal-derived fatty acids contribute to the increase in ketones during treatment with dapagliflozin. The increase in BOHB concentration with dapagliflozin occurred with only minimal changes in plasma NEFA concentration and no change in lipolysis. This finding suggests a metabolic switch to increase ketogenesis within the liver.