Abstract Purpose Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the newest class of antihyperglycemic agents available on the market. Regulator warnings and concerns regarding the risk of ...developing diabetic ketoacidosis (DKA), however, have dampened enthusiasm for the class despite the combined glycemic, blood pressure, and occasional weight benefits of SGLT2 inhibitors. With the goal of improving patient safety, a cross-Canada expert panel and writing group were convened to review the evidence to-date on reported SGLT2 inhibitor–related DKA incidents and to offer recommendations for preventing and recognizing patients with SGLT2 inhibitor–associated DKA. Methods Reports covering DKA events in subjects taking SGLT2 inhibitors that were published in PubMed, presented at professional conferences, or in the public domain from January 2013 to mid-August 2016 were reviewed by the group independently and collectively. Practical recommendations for diagnosis and prevention were established by the panel. Findings DKA is rarely associated with SGLT2 inhibitor therapy. Patients with SGLT2 inhibitor–associated DKA may be euglycemic (plasma glucose level <14 mmol/L). DKA is more likely in patients with insulin-deficient diabetes, including those with type 2 diabetes, and is typically precipitated by insulin omission or dose reduction, severe acute illness, dehydration, extensive exercise, surgery, low-carbohydrate diets, or excessive alcohol intake. SGLT2 inhibitor–associated DKA may be prevented by withholding SGLT2 inhibitors when precipitants develop, avoiding insulin omission or inappropriate insulin dose reduction, and by following sick day protocols as recommended. Implications Preventive strategies should help avoid SGLT2 inhibitor–associated DKA. All SGLT2 inhibitor–treated patients presenting with signs or symptoms of DKA should be suspected to have DKA and be investigated for DKA, especially euglycemic patients. If DKA is diagnosed, SGLT2 inhibitor treatment should be stopped, and the DKA should be treated with a traditional treatment protocol.
This multicenter, treat-to-target, phase 3 trial evaluated the efficacy and safety of fast-acting insulin aspart (faster aspart) versus conventional insulin aspart (IAsp) in adults with type 1 ...diabetes.
The primary end point was change from baseline in HbA
after 26 weeks. After an 8-week run-in, subjects were randomized (1:1:1) to double-blind mealtime faster aspart (
= 381), IAsp (
= 380), or open-label postmeal faster aspart (
= 382)-each with insulin detemir.
HbA
was reduced in both treatment groups, and noninferiority to IAsp was confirmed for both mealtime and postmeal faster aspart (estimated treatment difference ETD faster aspart-IAsp, mealtime, -0.15% 95% CI -0.23; -0.07, and postmeal, 0.04% -0.04; 0.12); mealtime faster aspart statistically significantly reduced HbA
versus IAsp (
= 0.0003). Postprandial plasma glucose (PPG) increments were statistically significantly lower with mealtime faster aspart at 1 h (ETD -1.18 mmol/L 95% CI -1.65; -0.71, -21.21 mg/dL -29.65; -12.77;
< 0.0001) and 2 h (-0.67 mmol/L -1.29; -0.04, -12.01 mg/dL -23.33; -0.70;
= 0.0375) after the meal test; superiority to IAsp for the 2-h PPG increment was confirmed. The overall rate of severe or blood glucose-confirmed (plasma glucose <3.1 mmol/L 56 mg/dL) hypoglycemic episodes and safety profiles were similar between treatments.
Faster aspart effectively improved HbA
, and noninferiority to IAsp was confirmed, with superior PPG control for mealtime faster aspart versus IAsp. Subjects randomized to postmeal faster aspart for all meals maintained HbA
noninferior to that obtained with mealtime IAsp.
Recent phase 3 clinical trials have evaluated the impact of adding sodium‐glucose co‐transporter (SGLT) inhibitors to the type 1 diabetes armamentarium. These trials studied SGLT2 inhibitors ...(dapagliflozin and empagliflozin) and a dual SGLT1 and SGLT2 inhibitor (sotagliflozin), and demonstrated that these oral non‐insulin antihyperglycaemic medications are able not only to improve glycaemic control, but also to reduce body weight and extend time in range without increasing rates of hypoglycaemia in type 1 diabetes. Diabetic ketoacidosis (DKA) is a feature of type 1 diabetes and the risk is increased when SGLT inhibitors are used in type 1 diabetes. To minimize the risk of DKA and still gain the multiple benefits, we developed the “STOP DKA Protocol “, an easily accessible and practical tool, that provides a risk mitigation strategy for reducing DKA in patients with type 1 diabetes being treated with SGLT inhibitors.
In many large gatherings of priests, seminaries, and formation houses, daily concelebration among priests has become the default option in recent decades. A canonical question arises. Can a priest ...who has daily access to a concelebrated Mass legitimately choose to celebrate alone due to his devotion to the Eucharist? Contrary to the prevalent misconception that Vatican II aimed at eliminating private Mass through the promotion of concelebration, canon 904 encourages priests to offer daily Masses even when the faithful cannot be present. Canon 906 allows priests to celebrate Mass alone for a just and reasonable cause. Canon 902 stipulates that a priest has the complete freedom to offer Mass individually. This article shows that it is licit for a priest to celebrate alone even if there is a concelebration available, as long as the concelebration does not take place simultaneously in the same church or oratory. A Mass celebrated even without the participation of the faithful remains the center of the entire Church and the heart of priestly existence. The canonical right of a priest to celebrate alone, based on Vatican II's teachings on daily Mass in the life of a priest, must be safeguarded.
To investigate whether liraglutide added to treat-to-target insulin improves glycemic control and reduces insulin requirements and body weight in subjects with type 1 diabetes.
A 52-week, ...double-blind, treat-to-target trial involving 1,398 adults randomized 3:1 to receive once-daily subcutaneous injections of liraglutide (1.8, 1.2, or 0.6 mg) or placebo added to insulin.
HbA1c level was reduced 0.34-0.54% (3.7-5.9 mmol/mol) from a mean baseline of 8.2% (66 mmol/mol), and significantly more for liraglutide 1.8 and 1.2 mg compared with placebo (estimated treatment differences ETDs: 1.8 mg liraglutide -0.20% 95% CI -0.32; -0.07; 1.2 mg liraglutide -0.15% 95% CI -0.27; -0.03; 0.6 mg liraglutide -0.09% 95% CI -0.21; 0.03). Insulin doses were reduced by the addition of liraglutide 1.8 and 1.2 mg versus placebo (estimated treatment ratios: 1.8 mg liraglutide 0.92 95% CI 0.88; 0.96; 1.2 mg liraglutide 0.95 95% CI 0.91; 0.99; 0.6 mg liraglutide 1.00 95% CI 0.96; 1.04). Mean body weight was significantly reduced in all liraglutide groups compared with placebo ETDs (1.8 mg liraglutide -4.9 kg 95% CI -5.7; -4.2; 1.2 mg liraglutide -3.6 kg 95% CI -4.3; -2.8; 0.6 mg liraglutide -2.2 kg 95% CI -2.9; -1.5). The rate of symptomatic hypoglycemia increased in all liraglutide groups (estimated rate ratios: 1.8 mg liraglutide 1.31 95% CI 1.07; 1.59; 1.2 mg liraglutide 1.27 95% CI 1.03; 1.55; 0.6 mg liraglutide 1.17 95% CI 0.97; 1.43), and hyperglycemia with ketosis increased significantly for liraglutide 1.8 mg only (event rate ratio 2.22 95% CI 1.13; 4.34).
Liraglutide added to insulin therapy reduced HbA1c levels, total insulin dose, and body weight in a population that was generally representative of subjects with type 1 diabetes, accompanied by increased rates of symptomatic hypoglycemia and hyperglycemia with ketosis, thereby limiting clinical use in this group.
Adults with type 2 diabetes mellitus can benefit from pharmacotherapies that lower their risk for cardiovascular disease. This review describes the salient findings from sodium-glucose ...cotransporter-2 (SGLT2) inhibitor cardiovascular outcome trials that serendipitously revealed the cardiorenal benefits of SGLT2 inhibitors in adults with type 2 diabetes mellitus who either have established cardiovascular disease or multiple cardiovascular risk factors. It also summarizes the findings from other phase 3 clinical studies that measured the cardiovascular effects of SGLT2 inhibitors and real-world evidence reports that compared the cardiovascular impact of SGLT2 inhibitors with other antihyperglycemic agents. The collective data indicate that SGLT2 inhibitors are pleiotropic agents that offer important cardiovascular, metabolic and renal benefits beyond glucose lowering with low incidences of hypoglycemia. Specifically, the placebo-controlled SGLT2 inhibitor cardiovascular outcome trials documented either fewer major adverse cardiac events (nonfatal myocardial infarction, nonfatal stroke and cardiovascular death) or a reduction in the composite endpoint of cardiovascular death or hospitalization for heart failure in participants with type 2 diabetes mellitus and established cardiovascular disease. Amongst those with type 2 diabetes mellitus who did not have established cardiovascular disease but did present with multiple risk factors, SGLT2 inhibitors lowered the combined endpoint of cardiovascular death or hospitalization for heart failure but had little impact on the occurrence of major adverse cardiac events. Ongoing clinical trials and subanalyses of the trials that have been reported should shed further light on the clinical benefits and utility of SGLT2 inhibitors.
Adultes atteints du diabète sucré de type 2 peuvent bénéficier des pharmacothérapies qui abaissent leur risque de maladies cardiovasculaires. La présente revue décrit les principaux résultats des essais sur les résultats cardiovasculaires des inhibiteurs du cotransporteur sodium-glucose de type 2 (SGLT2) qui ont fortuitement révélé les bénéfices cardio-rénaux des inhibiteurs du SGLT2 chez les adultes atteints du diabète sucré de type 2 ayant soit une maladie cardiovasculaire établie ou de multiples facteurs de risque cardiovasculaire. De plus, elle récapitule les résultats d’autres études cliniques de phase III qui portaient sur la mesure des effets cardiovasculaires des inhibiteurs du SGLT2 et fait la synthèse des données probantes du monde réel sur la comparaison des répercussions cardiovasculaires des inhibiteurs du SGLT2 aux autres antihyperglycémiants. L’ensemble des données indiquent que les inhibiteurs du SGLT2 sont des agents à effets pléiotropiques qui, outre la réduction de la glycémie, apportent des bénéfices cardiovasculaires, métaboliques et rénaux, et entraînent un faible risque d’hypoglycémie. Particulièrement, les essais sur les résultats cardiovasculaires des inhibiteurs du SGLT2 contre placebo ont démontré soit une moindre survenue d’événements cardiaques indésirables majeurs (infarctus du myocarde non fatal, accident vasculaire cérébral non fatal et décès d’origine cardiovasculaire) soit une diminution de la survenue du critère combiné de décès d’origine cardiovasculaire ou d’hospitalisation pour insuffisance cardiaque chez les participants atteints de diabète sucré de type 2 et d’une maladie cardiovasculaire établie. Parmi les individus atteints du diabète sucré de type 2 qui n’avaient pas de maladie cardiovasculaire établie, mais présentaient de multiples facteurs de risque, les inhibiteurs du SGLT2 ont fait réduire les critères combinés de décès d’origine cardiovasculaire ou d’hospitalisation pour insuffisance cardiaque, mais avaient peu de répercussions sur la survenue d’événements cardiaques indésirables majeurs. Les essais cliniques et les sous-analyses d’essais en cours rapportées devraient davantage élucider les avantages cliniques et l’utilité des inhibiteurs du SGLT2.
Abstract Purpose The treatment of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) using insulin is not ideal at this time. Despite advances made with basal insulin analogues, many ...individuals achieve less than optimal glycemic control or are at risk for hypoglycemia. Currently available basal insulin analogues do not deliver steady, peakless, continuous insulin for >24 hours and are associated with adverse events, including hypoglycemia. The objective of this paper was to review the clinical efficacy and safety of upcoming long-acting insulin analogues such as insulin degludec and insulin glargine 300 U/mL (Gla-300). Methods A comprehensive literature search of PubMed and Google Scholar was conducted from 1966 to 2015. The search included randomized controlled trials that specifically assessed the efficacy and safety of insulin degludec and Gla-300 in patients with T1DM and T2DM. Findings The efficacy of insulin degludec and Gla-300 in achieving glycemic control has been reported in clinical trials in adults with T1DM and T2DM. Not only did a large number of patients succeed in meeting glycosylated hemoglobin targets, but they also experienced reductions in hypoglycemic events. These 2 therapies are associated with a reduced risk of nocturnal hypoglycemia and are generally well tolerated. Implications The long-acting insulin analogues insulin degludec and Gla-300 are promising therapies in the treatment of T1DM and T2DM. Their improved insulin delivery for >24 hours offers glycemic control with a good safety profile.
Although canon 1010 of the 1983 CIC states the Church's preference to conduct ordinations on Sundays and holy days of obligation, ordinations are mostly conferred on Saturdays in the United States. ...In fact, the Church historically restricted ordinations to six designated Saturdays. Four of these six days were ember Saturdays, which were mandatory days of fasting in the Latin Church before Vatican II. This article explains the reasons behind ember Saturday ordinations, particularly the inherent connection between fasting and ordinations. It also delineates the historical development regarding the times of ordinations from the Acts of the Apostles until the 1983 CIC . The recent revival of ember days in various US dioceses provides an impetus for re-associating ember Saturdays with ordinations. This article suggests ways for priests, diocesan bishops, and conferences of bishops to promote ember Saturday ordinations as a way to foster vocations.
OBJECTIVE: Dapagliflozin, a novel inhibitor of renal sodium-glucose cotransporter 2, allows an insulin-independent approach to improve type 2 diabetes hyperglycemia. In this multiple-dose study we ...evaluated the safety and efficacy of dapagliflozin in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: Type 2 diabetic patients were randomly assigned to one of five dapagliflozin doses, metformin XR, or placebo for 12 weeks. The primary objective was to compare mean change from baseline in A1C. Other objectives included comparison of changes in fasting plasma glucose (FPG), weight, adverse events, and laboratory measurements. RESULTS: After 12 weeks, dapagliflozin induced moderate glucosuria (52-85 g urinary glucose/day) and demonstrated significant glycemic improvements versus placebo (ΔA1C -0.55 to -0.90% and ΔFPG -16 to -31 mg/dl). Weight loss change versus placebo was -1.3 to -2.0 kg. There was no change in renal function. Serum uric acid decreased, serum magnesium increased, serum phosphate increased at higher doses, and dose-related 24-h urine volume and hematocrit increased, all of small magnitude. Treatment-emergent adverse events were similar across all groups. CONCLUSIONS: Dapagliflozin improved hyperglycemia and facilitates weight loss in type 2 diabetic patients by inducing controlled glucosuria with urinary loss of ~200-300 kcal/day. Dapagliflozin treatment demonstrated no persistent, clinically significant osmolarity, volume, or renal status changes.
Summary Background For patients with type 2 diabetes who do not achieve target glycaemic control with conventional insulin treatment, advancing to a basal–bolus insulin regimen is often recommended. ...We aimed to compare the efficacy and safety of long-acting glucagon-like peptide-1 receptor agonist dulaglutide with that of insulin glargine, both combined with prandial insulin lispro, in patients with type 2 diabetes. Methods We did this 52 week, randomised, open-label, phase 3, non-inferiority trial at 105 study sites in 15 countries. Patients (aged ≥18 years) with type 2 diabetes inadequately controlled with conventional insulin treatment were randomly assigned (1:1:1), via a computer-generated randomisation sequence with an interactive voice-response system, to receive once-weekly dulaglutide 1·5 mg, dulaglutide 0·75 mg, or daily bedtime glargine. Randomisation was stratified by country and metformin use. Participants and study investigators were not masked to treatment allocation, but were unaware of dulaglutide dose assignment. The primary outcome was a change in glycated haemoglobin A1c (HbA1c ) from baseline to week 26, with a 0·4% non-inferiority margin. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT01191268. Findings Between Dec 9, 2010, and Sept 21, 2012, we randomly assigned 884 patients to receive dulaglutide 1·5 mg (n=295), dulaglutide 0·75 mg (n=293), or glargine (n=296). At 26 weeks, the adjusted mean change in HbA1c was greater in patients receiving dulaglutide 1·5 mg (−1·64% 95% CI −1·78 to −1·50, −17·93 mmol/mol −19·44 to −16·42) and dulaglutide 0·75 mg (−1·59% −1·73 to −1·45, −17·38 mmol/mol −18·89 to −15·87) than in those receiving glargine (−1·41% −1·55 to −1·27, −15·41 mmol/mol −16·92 to −13·90). The adjusted mean difference versus glargine was −0·22% (95% CI −0·38 to −0·07, −2·40 mmol/mol –4·15 to −0·77; p=0·005) for dulaglutide 1·5 mg and −0·17% (–0·33 to −0·02, −1·86 mmol/mol –3·61 to −0·22; p=0·015) for dulaglutide 0·75 mg. Five (<1%) patients died after randomisation because of septicaemia (n=1 in the dulaglutide 1·5 mg group); pneumonia (n=1 in the dulaglutide 0·75 mg group); cardiogenic shock; ventricular fibrillation; and an unknown cause (n=3 in the glargine group). We recorded serious adverse events in 27 (9%) patients in the dulaglutide 1·5 mg group, 44 (15%) patients in the dulaglutide 0·75 mg group, and 54 (18%) patients in the glargine group. The most frequent adverse events, arising more often with dulaglutide than glargine, were nausea, diarrhoea, and vomiting. Interpretation Dulaglutide in combination with lispro resulted in a significantly greater improvement in glycaemic control than did glargine and represents a new treatment option for patients unable to achieve glycaemic targets with conventional insulin treatment. Funding Eli Lilly and Company.
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