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LEADER was a landmark cardiovascular outcome trial with the GLP-1 receptor agonist liraglutide, which demonstrated significant reductions in major adverse cardiovascular events (MACE, a composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke), driven by a reduction in cardiovascular deaths and accompanied by a significant reduction in all-cause mortality. Shortly afterwards, the SUSTAIN-6 trial with once-weekly semaglutide demonstrated non-inferiority for MACE, with a nominal reduction in MACE that was driven by a reduction in the risk of non-fatal strokes. Since then, a further six cardiovascular trials have been published with GLP-1 receptor agonists, with major differences in study design and outcomes. Four trials have been performed with once-weekly formulations. The EXSCEL trial with once-weekly exenatide showed non-inferiority for MACE, but not superiority, with a reduction in all-cause mortality which was an exploratory outcome. The Harmony Outcomes trial with albiglutide demonstrated significant reductions in MACE, driven by reductions in fatal or non-fatal myocardial infarction. REWIND, with dulaglutide, also demonstrated significant reductions in MACE, this time driven by reductions in strokes. The AMPLITUDE-O trial with efpeglenatide showed significant reductions in MACE, but none of the individual components of MACE was significantly reduced as a secondary endpoint, and in contrast to other trials there was also a significant reduction in heart failure events. The fifth trial was the PIONEER 6 trial with the oral formulation of semaglutide, and this showed non-inferiority for MACE, but not superiority, with reductions in cardiovascular deaths and all-cause mortality which were secondary outcomes. Finally, FREEDOM-CVO with a subcutaneous mini-pump of exenatide showed non-inferiority for MACE and MACE plus hospitalisation for unstable angina. A reduction in albuminuria was seen in several of these trials, but there was no definite effect on eGFR or end-stage renal disease. Meta-analysis of the cardiovascular outcome trials with GLP-1 receptor agonists has demonstrated significant reductions in MACE, cardiovascular death, fatal or non-fatal stroke, fatal or non-fatal myocardial infarction, and all-cause mortality. It remains unclear why updated guidance from NICE on the management of T2DM in adults fails to acknowledge these evidence-based cardiovascular benefits.

EMPA-REG OUTCOME was an FDA-mandated cardiovascular outcome trial with empagliflozin and was the first completed trial with a sodium-glucose co-transporter-2 (SGLT2) inhibitor. EMPA-REG OUTCOME compared empagliflozin and placebo in 7,020 subjects with type 2 diabetes and established atherosclerotic cardiovascular disease. The results were astounding as EMPA-REG OUTCOME demonstrated superiority for major cardiovascular events (cardiovascular death, myocardial infarction, stroke) and cardiovascular deaths were significantly reduced, as was all-cause mortality. Hospitalisation for heart failure, which was a secondary outcome, was also significantly reduced. Later trials with SGLT2 inhibitors have demonstrated reductions in major adverse cardiovascular events (MACE) and hospitalisation for heart failure, and trials with glucagon-like peptide 1 receptor agonists have demonstrated reductions in MACE. Collectively, these trials could transform the management of people with type 2 diabetes.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are effective antidiabetic therapies in patients with type 2 diabetes mellitus and are associated with improved glycaemic control as well as with reductions in body mass and blood pressure. In large cardiovascular outcome trials in patients with diabetes, SGLT2 inhibitors improve cardiovascular and renal outcomes, including hospitalization for heart failure, with this benefit extending to patients without diabetes who have heart failure with reduced ejection fraction. The possible mechanisms of benefit are being extensively investigated because they are unlikely to be related to improved glycaemic control. Early natriuresis with a reduction in plasma volume, a consequent rise in haematocrit, improved vascular function, a reduction in blood pressure and changes in tissue sodium handling are all likely to have a role. Additional mechanisms of SGLT2 inhibitors that might be beneficial include a reduction in adipose tissue-mediated inflammation and pro-inflammatory cytokine production, a shift towards ketone bodies as the metabolic substrate for the heart and kidneys, reduced oxidative stress, lowered serum uric acid level, reduced glomerular hyperfiltration and albuminuria, and suppression of advanced glycation end-product signalling. Further outcome trials and mechanistic studies, including in patients with heart failure with preserved ejection fraction or non-diabetic kidney disease, might identify other possible mechanisms of benefit of SGLT2-inhibitor therapy.

SUSTAIN-6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes) was a pre-licensing FDA-mandated cardiovascular outcome trial with subcutaneous semaglutide and was the first completed trial with a once-weekly glucagon-like peptide-1 receptor agonist. SUSTAIN-6 compared semaglutide and placebo in 3,297 people with type 2 diabetes and established cardiovascular disease, chronic kidney disease, or both, or who were aged over 60 years and had subclinical evidence of cardiovascular disease (persistent microalbuminuria or proteinuria, hypertension with left ventricular hypertrophy, left ventricular dysfunction by imaging, ankle/brachial index less than 0.9). As SUSTAIN-6 was performed as a pre-licensing safety study, non-inferiority for major cardiovascular events (MACE; cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) was the primary outcome and testing for superiority for MACE was not pre-specified or adjusted for multiplicity. SUSTAIN-6 confirmed non-inferiority for MACE, with nominal superiority, and demonstrated a significant reduction in the risk of non-fatal stroke. There was no significant difference in non-fatal myocardial infarction, cardiovascular death, all-cause mortality or hospitalisation for heart failure. Rates of retinopathy complications were unexpectedly higher in the semaglutide group. Further outcome trials with subcutaneous semaglutide are in progress, including a cardiovascular outcome trial in non-diabetic subjects with overweight or obesity.

DEVOTE (Trial Comparing Cardiovascular Safety of Insulin Degludec versus Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardio-vascular Events) was an FDA-mandated cardiovascular outcome trial and was the first – and at present the only – completed trial comparing two insulins. DEVOTE compared insulin degludec and insulin glargine (U100) in 7,637 people with type 2 diabetes with established cardiovascular disease, chronic kidney disease, or both, and older diabetic patients with increased cardiovascular risk. DEVOTE demonstrated non-inferiority for major cardiovascular events (MACE), a composite of death from cardiovascular causes, non-fatal myocardial infarction and non-fatal stroke, with a pre-specified non-inferiority margin of 1.3. At 24 months the mean HbA1c was similar in the two groups. Mean fasting plasma glucose was significantly lower in the degludec group than in the glargine group, and pre-specified severe hypoglycaemia was also significantly lower in the degludec group. DEVOTE satisfied the FDA cardiovascular safety requirements for new antidiabetic therapies.

EMPA-REG OUTCOME was a landmark trial with the sodium-glucose co-transporter-2 (SGLT2) inhibitor empagliflozin, which demonstrated significant reductions in major adverse cardiovascular events (MACE, a composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke) driven by reductions in cardiovascular deaths and accompanied by an early reduction in hospitalisation for heart failure. This was followed by cardiovascular outcome trials with canagliflozin, dapagliflozin and ertugliflozin. The CANVAS Program was an integrated analysis of the CANVAS and CANVAS-R trials with canagliflozin. It demonstrated a significant reduction in MACE, but not in any of the components, and there was an unexpected increase in amputations and fractures with canagliflozin. The DECLARE-TIMI 58 trial with dapagliflozin had two co-primary endpoints. A composite endpoint of cardiovascular death or hospitalisation for heart failure was significantly reduced, but there was no significant difference in MACE comparing dapagliflozin with placebo. Analysis of patients with a prior myocardial infarction, however, demonstrated significant reductions in MACE. The VERTIS CV trial with ertugliflozin was disappointing as there was no difference in MACE comparing ertugliflozin and placebo. In all four trials a reduction in hospitalisation for heart failure was observed in patients with type 2 diabetes, regardless of whether they had existing atherosclerotic cardiovascular disease or increased cardiovascular risk. Pre-specified renal outcomes were reduced with empagliflozin, canagliflozin and dapagliflozin, and these drugs are now commonly used in the management of people with type 2 diabetes. It is hard to envisage an ongoing role for ertugliflozin in routine clinical management as the evidence for its cardiovascular benefit is not convincing.

LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) was an FDA-mandated cardiovascular outcome trial with liraglutide and was the first trial with a glucagon-like peptide-1 (GLP-1) receptor agonist to demonstrate a significant reduction in cardiovascular events. It compared liraglutide and placebo in 9,340 people with type 2 diabetes and either existing cardiovascular disease or age >60 years with at least one cardiovascular risk factor. LEADER demonstrated superiority for major cardiovascular events (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke), and cardiovascular deaths were significantly reduced, as was all-cause mortality. Hospitalisation for heart failure, which was a secondary outcome, was not significantly reduced. Compared with the EMPA-REG OUTCOME trial, the curves for major adverse cardiovascular events in LEADER separated later, and the absence of a clear effect on hospitalisation for heart failure or on estimated glomerular filtration rate suggests that the mechanism of cardiovascular benefit for liraglutide was different from that for empagliflozin

ELIXA (Evaluation of Lixisenatide in Acute Coronary Syndrome) was an FDA mandated cardiovascular outcome trial with lixisenatide. In contrast to later cardiovascular outcome trials with glucagon-like peptide-1 (GLP-1) receptor agonists, it was performed in subjects with a recent myocardial infarction or hospitalisation for unstable angina within the previous 180 days. ELIXA compared lixisenatide and placebo in 6,068 subjects with type 2 diabetes and demonstrated non-inferiority for major cardiovascular events plus unstable angina (cardiovascular death, myocardial infarction, stroke, unstable angina) but not superiority. Similarly, there was no difference in hospitalisation for heart failure which was a secondary outcome. A subsequent exploratory analysis showed that lixisenatide reduced progression of the urinary albumin to creatinine ratio in patients with macroalbuminuria, and was associated with a lower risk of new-onset macroalbuminuria. No clear clinical benefit has been established for lixisenatide, and there are alternative GLP-1 receptor agonists such as liraglutide, semaglutide and dulaglutide that are associated with a reduction in major adverse cardiovascular events.

TECOS (Trial Evaluating Cardiovascular Outcomes with Sitagliptin) was an investigator-initiated cardiovascular outcome trial with sitagliptin. It compared sitagliptin and placebo in 14,671 subjects with type 2 diabetes and demonstrated non-inferiority for major cardiovascular events plus hospitalisation for unstable angina (cardiovascular death, myocardial infarction, stroke, unstable angina) but not superiority. Rates of hospitalisation for heart failure did not differ between the sitagliptin and placebo groups, and there were no significant between-group differences in rates of acute pancreatitis or pancreatic cancer. The clinical role for dipeptidyl peptidase-4 (DPP-4) inhibitors is diminishing as they have not been demonstrated to reduce cardiovascular events and are not associated with weight reduction, but if a DPP-4 inhibitor is indicated, the results of TECOS show that sitagliptin appears safer than saxagliptin or alogliptin.

The EDITION trials in type 2 diabetes demonstrated comparable glycaemic control with less nocturnal and anytime (24-hour) hypoglycaemia for insulin glargine 300 U/mL (Gla-300) versus glargine 100 U/mL (Gla-100). However, the predefined nocturnal window (0:00-5:59 AM) may not be the most relevant for clinical practice. This post-hoc analysis compared expansions of the predefined nocturnal interval during basal insulin treatment without prandial insulin. Patient-level, 6-month data, pooled from the EDITION 2 and 3 trials and the EDITION JP 2 trial (N = 1922, basal insulin only) were analysed. Accompanying hypoglycaemia during treatment with Gla-300 was compared to that during treatment with Gla-100, using predefined (0:00-5:59 AM) and expanded (10:00 PM-5:59 AM, 0:00-7:59 AM, 10:00 PM to pre-breakfast SMPG) windows. Confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycaemic events were reported most frequently between 6:00 AM and 8:00 AM. Windows expanded beyond 6:00 AM included more events than other windows. The percentage of participants with at least one event was lower with Gla-300 than Gla-100 in all windows examined. Expanding the nocturnal interval allows better assessment of the risk of hypoglycaemia associated with basal insulin. The risk of nocturnal hypoglycaemia was consistently lower with Gla-300 versus Gla-100 using all four windows.

Statin therapy is proven to reduce cardiovascular morbidity and mortality in people with diabetes, and high-dose statins are recommended for people with established atherosclerotic vascular disease. In two dedicated studies in people with diabetes, fibrates did not significantly reduce cardiovascular events and were associated with serious side effects. A similar lack of benefit was seen in two large studies of niacin. Ezetimibe, when added to statins, may further reduce LDL cholesterol and non-fatal vascular events. The PCSK9 inhibitors are a new class of subcutaneous lipid- lowering drugs which cause profound reductions in LDL cholesterol when added to statins. Evolocumab reduced non-fatal cardiovascular events when added to background statin therapy in a larger group of subjects and the benefits were confirmed in a diabetes subgroup. In another large trial alirocumab reduced major adverse cardiovascular events and total mortality. The clinical use of ezetimibe and PCSK9 inhibitors is currently limited by cost.

Treatment with statins is one of the most effective ways of reducing cardiovascular events in those with diabetes. Many studies containing thousands of subjects with diabetes have demonstrated that statins reduce cardiovascular events when there is no known cardiovascular disease (primary prevention) and in those with confirmed atherosclerotic disease (secondary prevention). High-dose statins appear to be even more effective in established cardiovascular disease, but at the expense of increased drug side effects. In this paper we review the evidence for the benefits of statins in diabetes. In a second review we will examine the evidence for possible benefits of other lipid-lowering therapies when these are added to background statin therapy in diabetes.

EXAMINE was an FDA mandated cardiovascular outcome trial with alogliptin. In contrast to other cardiovascular outcome trials with DPP-4 inhibitors, it was performed in subjects with a recent acute coronary syndrome. EXAMINE compared alogliptin and placebo in 5,380 subjects with type 2 diabetes and demonstrated non-inferiority for major cardiovascular events (cardiovascular death, myocardial infarction, stroke) but not superiority. Data on hospitalisation for heart failure were not included in the principal publication. A subsequent publication showed no overall increase in hospitalisation for heart failure with alogliptin, but when subjects with and without baseline heart failure were separated there was a significant increase in the group without heart failure at baseline. No clear clinical benefit has been established for alogliptin, and there are alternatives such as sitagliptin and linagliptin that are not associated with an increase in hospitalisation for heart failure.

Diabetes is an important risk factor for cardiovascular morbidity and mortality, and atrial fibrillation is linked to cardiovascular complications. The prevalence of both is increasing and they commonly co‐exist with a longer duration of diabetes and poorer control putting individuals at higher risk of atrial fibrillation. The complications of atrial fibrillation include heart failure and thromboembolism. There is an association between diabetes and atrial fibrillation and there are many theories as to the specific pathophysiology, including sharing similar precursors, but it is not clearly understood. What is understood is that the risk of developing the main consequences of atrial fibrillation can be reduced by treatment. Broadly speaking, this involves controlling the heart rhythm and/or heart rate to improve cardiac function in addition to anticoagulation. The development of risk stratification strategies and direct oral anticoagulants has led to safer anticoagulation with more individuals thought to benefit balanced against any potential risk of bleeding. The evidence base for treatment of atrial fibrillation includes many individuals with diabetes and, in this group, prevention of complications is equally as relevant. In those with diabetes and atrial fibrillation the evidence overwhelmingly supports a treatment strategy similar to that for individuals with atrial fibrillation but without diabetes. This should be done in addition to identifying and treating other cardiovascular risk factors.

SAVOR-TIMI 53 was the first FDA-mandated cardiovascular outcome trial to be presented and published. It compared saxagliptin and placebo in 16,492 patients with type 2 diabetes. SAVOR-TIMI 53 demonstrated non-inferiority for major cardiovascular events (cardiovascular death, myocardial infarction, stroke) but not superiority. An unexpected statistically significant increase in adjudicated hospitalisation for heart failure was seen in the saxagliptin group. Post hoc analysis demonstrated that subjects at greatest risk for hospitalisation for heart failure had previous heart failure, an estimated glomerular filtration rate

The first insulin biosimilar, Abasaglar, is now available in the UK and several more are in development. Biosimilars are manufactured copies of previously approved biopharmaceuticals no longer under patent protection. They are not identical versions of their reference product due to the complexity of their production and resultant protein product. The present article reviews the current biosimilar landscape including manufacture, regulatory requirements, safety and prescribing issues. Abasaglar is used to illustrate the process of biosimilar development and approval. Copyright © 2017 John Wiley & Sons.

Aims To revisit the data analysis used to inform National Institute of Health and Care Excellence (NICE) NG17 guidance for initiating basal insulin in adults with type 1 diabetes mellitus (diabetes). Methods We replicated the data, methodology and analysis used by NICE diabetes in the NG17 network meta‐analysis (NMA). We expanded this data cohort to a more contemporary data set (extended 2017 NMA) and restricted the studies included to improve the robustness of the data set (restricted 2017 NMA) and in a post hoc analysis, changed the index comparator from neutral protamine Hagedorn (NPH) insulin twice daily to insulin detemir twice daily. Results The absolute changes in HbA1c were similar to those reported in the NG17. However, all 95% credible intervals for change in HbA1c point estimates crossed the line of null effect, except for detemir twice daily (in the NICE and extended 2017 NMAs) and NPH four times daily. In the detemir twice‐daily centred post hoc analysis, the 95% credible intervals for change in HbA1c crossed the line of null effect for all basal therapies, except NPH. Conclusions In NG17, comparisons of basal insulins were based solely on efficacy of glycaemic control. Many of the trials used in this analysis were treat‐to‐target, which minimize differences in HbA1c. In the NMAs, statistical significance was severely undermined by the wide credible intervals. Despite these limitations, point estimates of HbA1c were used to rank the insulins and formed the basis of NG17 guidance. This study queries whether such analyses should be used to make specific clinical recommendations., What's new? This study found no significant differences in HbA1c reduction between twice‐daily detemir and modern basal insulin comparators in efficacy trials; the apparent wide variation in HbA1c undermines the statistical robustness and the clinical relevance of the recommendation in the current National Institute of Health and Care Excellence (NICE) guidelines for type 1 diabetes in adults (NG17).The analyses highlight the importance of the quantity and quality of data used in network meta‐analyses to allow clinically meaningful recommendations.With the lack of differentiating evidence to support twice‐daily detemir as the basal insulin of choice for type 1 diabetes, selection of basal insulin should be personalized to individual needs.

No abstract available.

Aim: To compare time spent in pre-specified glycemic ranges in day and night-time during intensive training in professional cyclists with type 1 diabetes (T1D). Methods: Fifteen male professional cyclists with T1D on multiple daily injections (age 27±4 years, duration T1D 11±5 years, BMI 21.6±1.5 kg·min-2, HbA1c 7.2±0.7%, O2max 73±4 ml·kg·min-1) performed road cycle sessions (50-90% of the anaerobic threshold, duration 1-6 hours) over 9 consecutive days. Time spent in pre-specified glycemic ranges was compared between day and night time using paired t-test and Wilcoxon matched-pairs signed rank test, P≤0.05. Results: Overall glycemia is shown in Figure 1. More time was spent in level 1 (54-70 mg·dl-1) (6±5% vs. 4±3%, P=0.05) and level 2 hypoglycemia (299 mg dL-1) (night 0.2±0.4% vs. day 1.4±2.3%, P=0.02). Conclusion: Professional cyclists with T1D spent more time in hypoglycemia during the night compared to day-time during intensified training. Long-lasting insulin-sensitizing effects of endurance exercise may suggest a greater need for additional pre-bed carbohydrates and/or insulin dose reductions. Disclosure O. Moser: Research Support; Self; Abbott, Dexcom, Inc., Novo Nordisk A/S. M.L. Eckstein: Research Support; Self; Novo Nordisk A/S. O. McCarthy: None. M. Riddell: Advisory Panel; Self; Xeris Pharmaceuticals, Inc. Consultant; Self; Lilly Diabetes. Research Support; Self; Dexcom, Inc., Insulet Corporation, Novo Nordisk Inc., Sanofi. Speaker’s Bureau; Self; Medtronic MiniMed, Inc., OmniPod. Stock/Shareholder; Self; Zucara Therapeutics Inc. F.Y. Fontana: None. K. Skroce: None. L. Festa: None. P.H. Lagrou: None. P. Southerland: Other Relationship; Self; Novo Nordisk Inc. M.P. Christiansen: Research Support; Self; Abbott, Biolinq, Dexcom, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Medtronic MiniMed, Inc., Novo Nordisk A/S, Sanofi-Aventis, Xeris Pharmaceuticals, Inc. B.W. Bode: Consultant; Self; ADOCIA, Lexicon Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; Becton, Dickinson and Company, Dexcom, Inc., Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Eyenuk Inc., Insulet Corporation, National Institutes of Health, Novo Nordisk Inc., Sanofi Research & Development, Senseonics, Xeris Pharmaceuticals, Inc. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi US, Senseonics. Stock/Shareholder; Self; AgaMatrix, Glytec, LLC. C. Stettler: None. S.N. Scott: None. M. Fisher: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Mylan, NAPP Pharmaceuticals Limited, Novo Nordisk A/S. Speaker’s Bureau; Self; Eli Lilly and Company, Sanofi. C.A. Hayes: Other Relationship; Self; Novo Nordisk A/S. R.M. Bracken: None. Funding Novo Nordisk A/S

Aim: This study investigated whether markers related to type 1 diabetes (T1D) influence cardiopulmonary exercise (CPX) test performance in a group of world class road cyclists with T1D. Methods: Fifteen elite male road cyclists with T1D (age 27±4 years, T1D duration 11±5 years, BMI 21.6±1.5 kg·min-2, HbA1c 6.8±0.6%) performed a ramped (10 W per min) CPX test to exhaustion. Adjusted stepwise linear regression analysis was performed to investigate relationships between markers of T1D control and absolute maximum markers of performance, maximum oxygen consumption (V O2max), maximum power output (Pmax) and maximum heart rate (HRmax). Associations between submaximal CPX parameters and V O2max, Pmax and HRmax were also investigated. Results: Starting-CPX blood glucose (BG), post-CPX BG, ΔBG, T1D duration, HbA1c and BMI were not associated with V O2max (r2=0.51, P=0.32) and Pmax (r2=0.48, P=0.37) during CPX testing. However, HRmax was associated with T1D duration (r2=0.31, P=0.03). CO2 expiration at the lactate turn point 2 (V CO2LTP2) and power at the heart rate turn point (PHRTP) were associated with V O2max (r2=0.87, P Conclusion: This is the first dataset presenting CPX data from a world class cycle team with T1D. The study shows that not all markers of maximum physiological performance are influenced by T1D, solely HRmax by T1D duration. Yet, maximum performance is dependent on several submaximal cardiopulmonary markers of performance. Disclosure M.L. Eckstein: Research Support; Self; Novo Nordisk A/S. O. Moser: Research Support; Self; Abbott, Dexcom, Inc., Novo Nordisk A/S. O. McCarthy: None. S.N. Scott: None. M. Riddell: Advisory Panel; Self; Xeris Pharmaceuticals, Inc. Consultant; Self; Lilly Diabetes. Research Support; Self; Dexcom, Inc., Insulet Corporation, Novo Nordisk Inc., Sanofi. Speaker’s Bureau; Self; Medtronic MiniMed, Inc., OmniPod. Stock/Shareholder; Self; Zucara Therapeutics Inc. F.Y. Fontana: None. K. Skroce: None. M.P. Christiansen: Research Support; Self; Abbott, Biolinq, Dexcom, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Medtronic MiniMed, Inc., Novo Nordisk A/S, Sanofi-Aventis, Xeris Pharmaceuticals, Inc. L. Festa: None. M. Fisher: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Mylan, NAPP Pharmaceuticals Limited, Novo Nordisk A/S. Speaker’s Bureau; Self; Eli Lilly and Company, Sanofi. C.A. Hayes: Other Relationship; Self; Novo Nordisk A/S. P. Southerland: Other Relationship; Self; Novo Nordisk Inc. C. Stettler: None. P.H. Lagrou: None. B.W. Bode: Consultant; Self; ADOCIA, Lexicon Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; Becton, Dickinson and Company, Dexcom, Inc., Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Eyenuk Inc., Insulet Corporation, National Institutes of Health, Novo Nordisk Inc., Sanofi Research & Development, Senseonics, Xeris Pharmaceuticals, Inc. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi US, Senseonics. Stock/Shareholder; Self; AgaMatrix, Glytec, LLC. R.M. Bracken: None. Funding Novo Nordisk A/S

Aim: This observational study examined in-ride interstitial glucose data and nutritional intake in a UCI-accredited professional cycling team with type 1 diabetes (T1D) over a nine-day training camp. Methods: Sixteen male professional road cyclists with T1D (age 27±4 years, T1D duration 11±5 years, BMI 21.6±1.5 kg·min-2, HbA1c 6.8±0.6 %, O2max 71.3±3.9 ml·kg·min-1) on multiple daily injections performed eight rides over nine days lasting between 2 and 6 h, traversing 56 to 182 km/day. Cycle glycemic information (G6, Dexcom) was collected, stratified into glycemic time in ranges; hypoglycemia (Level 1: 54-70, Level 2: 299 mg/dL) and analyzed for time spent (%) within each range. Nutritional intake during each ride was determined and reported as median (range). Results: Average percentage time spent in euglycemia during cycling was 78±6% (daily range 70-86%). Hypoglycemia during cycling was 3±4% (range 0-11%, Level 1), and 1±2% (range 0-2%, Level 2). No hypoglycemic event required assistance. Percentage time spent in hyperglycemia during cycling was 17±7% (range 8-27%, Level 1), and 1±2 % (range 0-5%, Level 2). The contribution of carbohydrates, fat and protein to total in-ride energy intake was 83.8±15.4, 12.6±8.1 and 1.2±0.6 %, respectively. Macronutrient intake was dependent on cycle duration with greater carbohydrate intake rate on longer rides (2-hour cycle: 20 (4-82) g/h vs. 6-hour cycle: 51 (17-86) g/h). Conclusions: Professional cyclists with T1D maintained a large proportion of time in a euglycemic range during intense cycling sessions over a nine-day training period. The low occurrence of in-ride hypoglycemia, mostly at Level 1, suggests a protective role for consumption of carbohydrate-rich foods to maintain glycaemia, especially during longer rides. However, time spent in Level 1 hyperglycemia during cycling was notable and should be monitored. Disclosure O. McCarthy: None. O. Moser: Research Support; Self; Abbott, Dexcom, Inc., Novo Nordisk A/S. M.L. Eckstein: Research Support; Self; Novo Nordisk A/S. S.N. Scott: None. M. Riddell: Advisory Panel; Self; Xeris Pharmaceuticals, Inc. Consultant; Self; Lilly Diabetes. Research Support; Self; Dexcom, Inc., Insulet Corporation, Novo Nordisk Inc., Sanofi. Speaker’s Bureau; Self; Medtronic MiniMed, Inc., OmniPod. Stock/Shareholder; Self; Zucara Therapeutics Inc. M. Fisher: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Mylan, NAPP Pharmaceuticals Limited, Novo Nordisk A/S. Speaker’s Bureau; Self; Eli Lilly and Company, Sanofi. F.Y. Fontana: None. K. Skroce: None. L. Festa: None. P.H. Lagrou: None. P. Southerland: Other Relationship; Self; Novo Nordisk Inc. C.A. Hayes: Other Relationship; Self; Novo Nordisk A/S. M.P. Christiansen: Research Support; Self; Abbott, Biolinq, Dexcom, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Medtronic MiniMed, Inc., Novo Nordisk A/S, Sanofi-Aventis, Xeris Pharmaceuticals, Inc. B.W. Bode: Consultant; Self; ADOCIA, Lexicon Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; Becton, Dickinson and Company, Dexcom, Inc., Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Eyenuk Inc., Insulet Corporation, National Institutes of Health, Novo Nordisk Inc., Sanofi Research & Development, Senseonics, Xeris Pharmaceuticals, Inc. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi US, Senseonics. Stock/Shareholder; Self; AgaMatrix, Glytec, LLC. C. Stettler: None. R.M. Bracken: None.

The association between diabetes and stroke is well established. Recent large‐scale, international population studies suggest that diabetes is one of the most important modifiable risk factors for cerebrovascular disease. Despite this, we still have a relative paucity of evidence around the management of diabetes in stroke. The landscape is evolving and recent studies are helping establish best practice and suggesting new therapeutic opportunities. It is possible to develop a practical and clinical synthesis of the evidence around managing diabetes in adult patients with stroke and cerebrovascular disease, based on large trials, systematic reviews and guidelines, and focusing on the scenarios most often encountered in clinical practice. It is also important to recognise that there are common situations where robust evidence is lacking, but practical guidance for clinicians can be suggested.

The association between diabetes and cardiovascular disease is now well accepted. For the Arnold Bloom lecture 2016 I described the great improvements in the management of cardiovascular disease that have occurred in the last 20 years in people with diabetes. Meta-analysis has shown reductions in microvascular and macrovascular complications with control of blood pressure, but there is still some uncertainty as to how low the target systolic blood pressure should be. Meta-analysis has also demonstrated that reductions in cholesterol decrease macrovascular complications, and larger doses of statins should be used in people with established atherosclerotic disease. The initial results of intensive glycaemic control trials in diabetes did not demonstrate reductions in macrovascular outcomes during the study period, but long-term epidemiological follow up has shown long-lasting benefits. Follow up of DCCT and UKPDS has shown reductions in cardiovascular events and total mortality, and shorter follow up of VADT and ADVANCE has shown reductions in a composite of cardiovascular outcomes and end-stage renal disease respectively. Metformin, pioglitazone, empagliflozin and liraglutide have demonstrated specific effects, although use of pioglitazone is falling because of side effects. Future reductions in cardiovascular events in people with diabetes can be anticipated if these beneficial antidiabetes drugs can be used more widely in appropriate patients. Copyright © 2016 John Wiley & Sons.

The drug development process is long and expensive. Regulatory approval is granted following assessment of efficacy and safety, and drugs intended for use in the treatment of type 2 diabetes are also required to demonstrate cardiovascular safety. Once marketing approval has been granted in the UK, an additional step is required prior to a drug's use: cost-benefit assessment by the Scottish Medicines Consortium and by the National Institute for Health and Care Excellence. Empagliflozin, an SGLT-2 inhibitor, has recently been granted marketing authorisation and approval for use in the UK. It will be used to illustrate the processes of drug development and licensing. Copyright © 2016 John Wiley & Sons.

Patients with cardiovascular disease have an increased risk of severe COVID‐19 disease and an increased mortality. Clinical observations have described cardiovascular complications of COVID‐19 in patients without prior cardiovascular disease, including acute cardiac injury, myocarditis, heart failure, arrhythmias, and acute coronary syndromes. These are also associated with a worse outcome from COVID‐19. Several of the potential treatments for COVID‐19 may also have cardiovascular consequences. Some of the acute cardiovascular complications resolve on recovery from the infection and it is uncertain how many people will suffer permanent cardiovascular damage. During the emergency lockdown that was introduced to deal with the pandemic it has been observed that hospital admissions with other cardiovascular conditions, such as acute coronary syndromes and heart failure, have been greatly reduced. Copyright © 2020 John Wiley & Sons.

IntroductionThis prospective observational study sought to establish the glycemic, physiological and dietary demands of strenuous exercise training as part of a 9-day performance camp in a professional cycling team with type 1 diabetes (T1D).Research design and methodsSixteen male professional cyclists with T1D on multiple daily injections (age: 27±4 years; duration of T1D: 11±5 years; body mass index: 22±2 kg/m2; glycated hemoglobin: 7%±1% (50±6 mmol/mol); maximum rate of oxygen consumption: 73±4 mL/kg/min) performed road cycle sessions (50%–90% of the anaerobic threshold, duration 1–6 hours) over 9 consecutive days. Glycemic (Dexcom G6), nutrition and physiological data were collected throughout. Glycemic data were stratified into predefined glycemic ranges and mapped alongside exercise physiology and nutritional parameters, as well as split into daytime and night-time phases for comparative analysis. Data were assessed by means of analysis of variance and paired t-tests. A p value of ≤0.05 (two-tailed) was statistically significant.ResultsHigher levels of antecedent hypoglycemia in the nocturnal hours were associated with greater time spent in next-day hypoglycemia overall (p=0.003) and during exercise (p=0.019). Occurrence of nocturnal hypoglycemia was associated with over three times the risk of next-day hypoglycemia (pConclusionThe higher prevalence of nocturnal hypoglycemia was associated with an increased risk of next-day hypoglycemia, which extended to cycle training sessions. These data highlight the potential need for additional prebed carbohydrates and/or insulin dose reduction strategies around exercise training in professional cyclists with T1D.Trial registration numberDRKS00019923.

Summary Background Albiglutide is a glucagon-like peptide-1 receptor agonist, a new class of drugs used to treat type 2 diabetes. We did a prospective meta-analysis of the cardiovascular safety of albiglutide as stipulated by the US Food and Drug Administration recommendations for the assessment of new treatments for diabetes. Methods We did a meta-analysis of eight phase 3 trials and one phase 2b trial in which patients were randomly assigned to albiglutide, placebo, or active comparators (glimepiride, insulin glargine, insulin lispro, liraglutide, pioglitazone, or sitagliptin). The safety population included 5107 patients, of whom 2524 took albiglutide (4870 person-years) and 2583 took comparators (5213 person-years). Possible major cardiovascular events were recorded prospectively and adjudicated by an independent endpoint committee masked to treatment allocation. The primary endpoint was a composite of first occurrence of major adverse cardiovascular events (ie, cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) or hospital admission for unstable angina. Secondary endpoints were major adverse cardiovascular events alone, all-cause mortality, silent myocardial infarction, hospital admission for heart failure, chest pain, other angina, and subdural or extradural haemorrhage. The occurrence of all other adverse events classified by the investigators as cardiovascular events were documented, but these were not adjudicated. Findings The primary endpoint was not significantly different between albiglutide and all comparators (58 events vs 58 events; hazard ratio [HR] 1·00, 95% CI 0·68–1·49, p=0·0019 for non-inferiority). Major adverse cardiovascular event alone was also not significantly different (52 events vs 53; HR, 0·99; 95% CI, 0·65–1·49). When albiglutide was compared separately with placebo or active comparators, we noted no significant differences. We detected no significant differences in the other secondary endpoints. More patients had atrial fibrillation or atrial flutter in the albiglutide group (35 [1·4%] of 2524 patients; 8·6 events per 1000 patient-years) than in the all-comparators group (16 [0·6%] of 2583 patients; 3·4 events per 1000 patient-years). Interpretation Cardiovascular events were not significantly more likely to occur with albiglutide than with all comparators. Because the upper bound of the 95% CI for major adverse cardiovascular event plus hospital admission for unstable angina was greater than 1·3, a dedicated study with a cardiovascular endpoint is underway to confirm the safety of albiglutide. Funding GlaxoSmithKline.

Background The effect of the α-glucosidase inhibitor acarbose on cardiovascular outcomes in patients with coronary heart disease and impaired glucose tolerance is unknown. We aimed to assess whether acarbose could reduce the frequency of cardiovascular events in Chinese patients with established coronary heart disease and impaired glucose tolerance, and whether the incidence of type 2 diabetes could be reduced. Methods The Acarbose Cardiovascular Evaluation (ACE) trial was a randomised, double-blind, placebo-controlled, phase 4 trial, with patients recruited from 176 hospital outpatient clinics in China. Chinese patients with coronary heart disease and impaired glucose tolerance were randomly assigned (1:1), in blocks by site, by a centralised computer system to receive oral acarbose (50 mg three times a day) or matched placebo, which was added to standardised cardiovascular secondary prevention therapy. All study staff and patients were masked to treatment group allocation. The primary outcome was a five-point composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospital admission for unstable angina, and hospital admission for heart failure, analysed in the intention-to-treat population (all participants randomly assigned to treatment who provided written informed consent). The secondary outcomes were a three-point composite outcome (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke), death from any cause, cardiovascular death, fatal or non-fatal myocardial infarction, fatal or non-fatal stroke, hospital admission for unstable angina, hospital admission for heart failure, development of diabetes, and development of impaired renal function. The safety population comprised all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT00829660, and the International Standard Randomised Controlled Trial Number registry, number ISRCTN91899513. Findings Between March 20, 2009, and Oct 23, 2015, 6522 patients were randomly assigned and included in the intention-to-treat population, 3272 assigned to acarbose and 3250 to placebo. Patients were followed up for a median of 5·0 years (IQR 3·4–6·0) in both groups. The primary five-point composite outcome occurred in 470 (14%; 3·33 per 100 person-years) of 3272 acarbose group participants and in 479 (15%; 3·41 per 100 person-years) of 3250 placebo group participants (hazard ratio 0·98; 95% CI 0·86–1·11, p=0·73). No significant differences were seen between treatment groups for the secondary three-point composite outcome, death from any cause, cardiovascular death, fatal or non-fatal myocardial infarction, fatal or non-fatal stroke, hospital admission for unstable angina, hospital admission for heart failure, or impaired renal function. Diabetes developed less frequently in the acarbose group (436 [13%] of 3272; 3·17 per 100 person-years) compared with the placebo group (513 [16%] of 3250; 3·84 per 100 person-years; rate ratio 0·82, 95% CI 0·71–0·94, p=0·005). Gastrointestinal disorders were the most common adverse event associated with drug discontinuation or dose changes (215 [7%] of 3263 patients in the acarbose group vs 150 [5%] of 3241 in the placebo group [p=0·0007]; safety population). Numbers of non-cardiovascular deaths (71 [2%] of 3272 vs 56 [2%] of 3250, p=0·19) and cancer deaths (ten [ Interpretation In Chinese patients with coronary heart disease and impaired glucose tolerance, acarbose did not reduce the risk of major adverse cardiovascular events, but did reduce the incidence of diabetes.

In this post hoc analysis we compared glycaemic control and hypoglycaemia between insulin glargine 300 U/mL (Gla-300) and glargine 100 U/mL (Gla-100) administered once daily in people with type 2 diabetes (T2DM) from the EDITION 1 (basal plus mealtime insulin) and EDITION 2 (basal insulin plus oral antihyperglycaemic drugs) trials who were previously receiving twice-daily insulin. At randomization, 16.9% and 20.0% of people in EDITION 1 and 2, respectively, were receiving twice-daily basal insulin. Glycated haemoglobin change from baseline to Month 6 was similar over 6 months with Gla-300 or Gla-100 (least squares mean difference -0.01%; 95% confidence interval [CI] -0.27 to 0.24] in EDITION 1 and 0.16%; 95% CI -0.25 to 0.57, in EDITION 2). Participants previously receiving twice-daily insulin in EDITION 1 had a lower risk of confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycaemia with Gla-300 vs Gla-100 at night (00:00-05:59 hours), but not at any time (24 hours); in EDITION 2 the risk was reduced at night and any time (24 hours). In conclusion, Gla-300 provided similar glycaemic control with less hypoglycaemia compared with Gla-100 in people with T2DM switching from twice-daily to once-daily basal insulin.