Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Conservative treatment of acute appendicitis: heresy or an effective and acceptable alternative to surgery?

For more than a century, emergency appendectomy has been a ‘surgical dogma’ in the management of acute appendicitis (AA). During recent decades, however, there is an increasing body of evidence suggesting that selected patients with AA could be treated conservatively. This approach has many advantages, including high success and low recurrence rates, reduced morbidity and mortality, less pain, shorter hospitalization and sick leave, and reduced costs. Despite that conservative management of AA cannot be used for all patients with AA (for example, in the presence of peritonitis), it could be preferred in a large percentage of patients with mild infection (as evidenced by clinical, laboratory, and imaging findings). Eur J Gastroenterol Hepatol 23:121-127 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins

Postexercise phosphocreatine recovery, an index of mitochondrial oxidative phosphorylation, is reduced in diabetic patients with lower extremity complications

To identify differences in postexercise phosphocreatine (PCr) recovery, an index of mitochondrial function, in diabetic patients with and without lower extremity complications. METHODS: We enrolled healthy control subjects and three groups of patients with type 2 diabetes mellitus: without complications, with peripheral neuropathy, and with both peripheral neuropathy and peripheral arterial disease. We used magnetic resonance spectroscopic measurements to perform continuous measurements of phosphorous metabolites (PCr and inorganic phosphate [Pi]) during a 3-minute graded exercise at the level of the posterior calf muscles (gastrocnemius and soleus muscles). Micro- and macrovascular reactivity measurements also were performed. RESULTS: The resting Pi/PCr ratio and PCr at baseline and the maximum reached during exercise were similar in all groups. The postexercise time required for recovery of Pi/PCr ratio and PCr levels to resting levels, an assessment of mitochondrial oxidative phosphorylation, was significantly higher in diabetic patients with neuropathy and those with both neuropathy and peripheral arterial disease (P < .01 for both measurements). These two groups also had higher levels of tumor necrosis factor-\u3b1 (P < .01) and granulocyte colony-stimulating factor (P < .05). Multiple regression analysis showed that only granulocyte colony-stimulating factor, osteoprotegerin, and tumor necrosis factor-\u3b1 were significant contributing factors in the variation of the Pi/PCr ratio recovery time. No associations were observed between micro- and macrovascular reactivity measurements and Pi/PCr ratio or PCr recovery time. CONCLUSIONS: Mitochondrial oxidative phosphorylation is impaired only in type 2 diabetes mellitus patients with neuropathy whether or not peripheral arterial disease is present and is associated with the increased proinflammatory state observed in these groups

A Greek registry of current type 2 diabetes management, aiming to determine core clinical approaches, patterns and strategies

Abstract Background To analyze data in terms of the glycaemic control and therapeutic regimens used for Type-2 Diabetes Mellitus (T2DM) management in Greece, identify factors that influence clinical decisions and determine the level of compliance of T2DM management with the latest international and local guidelines. Methods ‘AGREEMENT’ was a national-multicenter, non-interventional, cross-sectional disease registry. A total of 1191 adult T2DM patients were enrolled consecutively from 59 sites of the National Health System (NHS) or University Hospitals, representing the majority of Diabetes centers or Diabetes outpatient clinics in Greece with a broad geographic distribution. Patients were stratified by gender and analysis was done according to 3 treatment strategies: A (lifestyle changes or use of one oral antidiabetic agent), B (up to 3 antidiabetic agents including injectables but not insulin) and C (any regimens with insulin). Results Mean (±SD) HbA1c % of the total population was 7.1 (±1.2) while mean (±SD) FPG (mg/dl) was measured at 136 (±42). The proportion of patients who achieved HbA1c < 7% was 53% and ranged from 74.2% for group A, to 60.6% for group B and 35.5% for group C. Median age of the studied population was 65.0 year old (Interquartile Range-IQR 14.0) with an equal distribution of genders between groups. Patients on insulin therapy (treatment strategy C) were older (median age: 67 years vs 63 or 65 for A and B, respectively) with longer diabetes duration (mean duration: 15.3 years vs 5.2 and 10.1 for A and B, respectively). Patients who received insulin presented poor compliance. There was a consensus for a series of decision criteria and factors that potentially influence clinical decisions, used by physicians for selection of the therapeutic strategy among the three groups. Compliance with international and Greek guidelines received a high score among groups A, B and C. No significant differences were presented as per sites’ geographic areas, NHS or University centers and physicians’ specialty (endocrinologists, diabetologists and internists). Conclusions The presented findings suggest the need for improvement of the glycaemic control rate, especially among insulin treated patients as this group seems to achieve low glycaemic control, by setting appropriate HbA1c targets along with timely and individualised intensification of treatment as well as post-therapy evaluation of the compliance with the proposed treatment

A Greek registry of current type 2 diabetes management, aiming to determine core clinical approaches, patterns and strategies

Background: To analyze data in terms of the glycaemic control and therapeutic regimens used for Type-2 Diabetes Mellitus (T2DM) management in Greece, identify factors that influence clinical decisions and determine the level of compliance of T2DM management with the latest international and local guidelines. Methods: &apos;AGREEMENT&apos; was a national-multicenter, non-interventional, cross-sectional disease registry. A total of 1191 adult T2DM patients were enrolled consecutively from 59 sites of the National Health System (NHS) or University Hospitals, representing the majority of Diabetes centers or Diabetes outpatient clinics in Greece with a broad geographic distribution. Patients were stratified by gender and analysis was done according to 3 treatment strategies: A (lifestyle changes or use of one oral antidiabetic agent), B (up to 3 antidiabetic agents including injectables but not insulin) and C (any regimens with insulin). Results: Mean (±SD) HbA1c % of the total population was 7.1 (±1.2) while mean (±SD) FPG (mg/dl) was measured at 136 (±42). The proportion of patients who achieved HbA1c &lt; 7% was 53% and ranged from 74.2% for group A, to 60.6% for group B and 35.5% for group C. Median age of the studied population was 65.0 year old (Interquartile Range-IQR 14.0) with an equal distribution of genders between groups. Patients on insulin therapy (treatment strategy C) were older (median age: 67 years vs 63 or 65 for A and B, respectively) with longer diabetes duration (mean duration: 15.3 years vs 5.2 and 10.1 for A and B, respectively). Patients who received insulin presented poor compliance. There was a consensus for a series of decision criteria and factors that potentially influence clinical decisions, used by physicians for selection of the therapeutic strategy among the three groups. Compliance with international and Greek guidelines received a high score among groups A, B and C. No significant differences were presented as per sites&apos; geographic areas, NHS or University centers and physicians&apos; specialty (endocrinologists, diabetologists and internists). Conclusions: The presented findings suggest the need for improvement of the glycaemic control rate, especially among insulin treated patients as this group seems to achieve low glycaemic control, by setting appropriate HbA1c targets along with timely and individualised intensification of treatment as well as post-therapy evaluation of the compliance with the proposed treatment. © 2019 The Author(s)