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Aims/hypothesis This 52-week multinational, randomised, open-label, parallel-group, non-inferiority trial compared clinical outcomes following supplementation of oral glucose-lowering drugs with basal insulin analogues detemir and glargine in type 2 diabetic patients. Methods Insulin-naive adults (n = 582, HbA₁c 7.5-10.0%, BMI <= 40.0 kg/m²) were randomised 1:1 to receive insulin detemir or glargine once daily (evening) actively titrated to target fasting plasma glucose (FPG) <= 6.0 mmol/l. An additional morning insulin detemir dose was permitted if pre-dinner plasma glucose (PG) was >7.0 mmol/l after achieving FPG < 7.0 mmol/l. Due to labelling restrictions, no second glargine dose was allowed. Results Baseline HbA₁c decreased from 8.6 to 7.2 and 7.1% (NS) with detemir and glargine, respectively. FPG improved from 10.8 to 7.1 and 7.0 mmol/l (NS), respectively. With detemir, 45% of participants completed the study on once daily dosing and 55% on twice daily dosing, with no difference in HbA₁c. Overall, 52% of participants achieved HbA₁c <= 7.0%: 33% (detemir) and 35% (glargine) without hypoglycaemia. Within-participant variability for self-monitored FPG and pre-dinner PG did not differ by insulin treatment, nor did the relative risk of overall or nocturnal hypoglycaemia. Modest reductions in weight gain were seen with detemir vs glargine in completers (3.0 vs 3.9 kg, p = 0.01) and in the intention-to-treat population (2.7 vs 3.5 kg, p = 0.03), primarily related to completers on once-daily detemir. Mean daily detemir dose was higher (0.78 U/kg [0.52 with once daily dosing, 1.00 U/kg with twice daily dosing]) than glargine (0.44 IU/kg). Injection site reactions were more frequent with detemir (4.5 vs 1.4%). Conclusions/interpretation Supplementation of oral agents with detemir or glargine achieves clinically important improvements in glycaemic control with low risk of hypoglycaemia. Non-inferiority was demonstrated for detemir using higher insulin doses (mainly patients on twice daily dosing); weight gain was somewhat reduced with once daily insulin detemir. ClinicalTrials.gov ID no.: NCT00283751.

Background Type 2 diabetes mellitus is associated with cognitive dysfunction and an increased risk of dementia. Linagliptin is a glucose-lowering agent of the dipeptidyl peptidase-IV (DPP-IV) inhibitor class that is of particular interest for the prevention of accelerated cognitive decline, because it may potentially benefit the brain through pleiotropic effects, beyond glucose lowering. This paper presents the design of a study that aims to establish if linagliptin is superior to the sulfonylurea glimepiride in the prevention of accelerated cognitive decline in patients with type 2 diabetes mellitus. Methods The cognition substudy is an integral part of the ongoing event-driven, randomised, double blind CARdiOvascular safety of LINAgliptin (CAROLINA®) trial, which evaluates the effect of treatment with linagliptin versus glimepiride on cardiovascular outcomes. CAROLINA® includes patients with type 2 diabetes mellitus with sub-optimal glycaemic control at elevated cardiovascular risk. The substudy will evaluate patients randomised and treated who have a baseline Mini Mental State Examination (MMSE) score ≥ 24, documented years of formal education with at least one valid cognitive assessment at baseline and during follow-up. The primary cognitive outcome is the occurrence of accelerated cognitive decline at the end of follow-up. The two treatment groups will be compared by using a logistic regression. Accelerated cognitive decline is defined as a rate of cognitive decline that falls at or below the 16th percentile of decline for the whole cohort on either the MMSE or a combined score of the trail making and verbal fluency test. Potential confounders are taken into account at an individual patient level, using a regression based index. Discussion Between December 2010 and December 2012, 6042 patients were randomised and treated with either linagliptin (5 mg) or glimepiride (1-4 mg) once daily in CAROLINA®. Cognitive tests were conducted in nearly 4500 participants at baseline and are scheduled for two subsequent assessments, after 160 weeks of follow-up and end of follow-up. This substudy of the ongoing CAROLINA® trial will establish if linagliptin is superior to glimepiride in the prevention of accelerated cognitive decline in patients with type 2 diabetes mellitus. Final results are expected in 2019. Trial registration ClinicalTrials.gov Identifier: NCT 01243424 .

Background: Lebanon is part of the global DISCOVER study, a global, noninterventional, multicentre, prospective study with 3-years of follow-up. Aims: The aim of this study is to describe real-world clinical practice in terms of type 2 diabetes mellitus (T2DM) disease management and treatment patterns within Lebanon. Methods: Baseline demographic and clinical parameters were captured on a standardized case report form, according to routine clinical practice at each clinical site. Results: We recruited 348 patients. At the initiation of second-line therapy, mean duration of diabetes was 6.7 [standard deviation (SD) 6.5] years; mean HbA1c and fasting plasma glucose levels were 8.5% (SD 1.6%) and 178.7 (SD 56.5) mg/dL respectively. Almost half the patients were hypertensive (45.1%) or had dyslipidaemia (48.6%). Metformin monotherapy was used as first-line therapy in 56.9% of the patients and upfront dual therapy in 25%. The primary reason for changing first-line therapy was poor glycaemic control. The main factors in choosing the second-line therapy were efficacy, tolerability and hypoglycaemia. Conclusion: Clinical inertia was evident in this cohort of patients as they had suboptimal glycaemic control at the time of enrolment and the initiation of second-line therapy. Treatment intensification is required to reduce diabetes-related adverse outcomes.

Introduction Systematic patient education has been reported to improve adherence to treatment, leading to better clinical outcomes. This cluster randomized real-world study investigated the effect of a systematic education program and telephone support on self-reported adherence to oral glucose-lowering treatment in patients with type 2 diabetes mellitus (T2DM). Methods Centers were randomized (1:1) to provide either standard-of-care (control group) or standard-of-care along with the education program and telephone support (empowerment group). Adherence to treatment and satisfaction with treatment were assessed using the four-item Morisky Medication Adherence Scale (MMAS-4) and the Diabetes Treatment Satisfaction Questionnaire (DTSQ). The study population included 457 patients (258/199 male/female) with T2DM and non-optimal glycemic control, on oral antidiabetic treatment (age 62.7 [11.4]; disease duration 8.5 [6.5] years). Results MMAS-4 high adherence rates for the control and empowerment groups were increased by 3.8% and 16.8% at 4 months (Breslow-Day test p  = 0.04) and by 8.5% and 18.8% at 8 months of follow-up, respectively (Breslow-Day test p  = 0.09), compared to baseline. Intense physical activity was increased in both control and empowerment groups by 2.3% and 13.9% at 4 months (Breslow-Day test p  = 0.082) and by 4.0% and 22.5% at 8 months of follow-up (Breslow-Day test p  < 0.001). Baseline mean (SD) HbA1c was significantly lower in the control group compared with the empowerment group [7.7% versus 8.0%, p  = 0.001] and decreased in both groups at 4 months by 0.7% and 0.9%, respectively. The change from baseline in the mean DTSQ status score at 4 months was greater in the empowerment group, and the effect was sustained at 8 months (control group: 29.1, 30.5, and 30.9; empowerment group: 25.0, 28.7, and 29.4 at baseline, 4 and 8 months, respectively, p  < 0.001). Conclusion Systematic education combined with telephone support delivered by physicians might be associated with improvement in treatment adherence and treatment satisfaction in patients with T2DM. Funding MSD, Greece.

Introduction The duration of uncontrolled type 2 diabetes mellitus (T2DM) can adversely impact small and large vessels, eventually leading to microvascular and macrovascular complications. Failure of therapeutic lifestyle changes, monotherapy, and clinical inertia contribute to persistent hyperglycemia and disease progression. The aim was to review the complex pathophysiology of type 2 diabetes and how different oral agents can be used effectively as first-line therapy in combination with metformin, as well as in patients not achieving glycemic goals with metformin therapy. Methods For this review, a non-systematic literature search of PubMed, NCBI, and Google Scholar was conducted. Results New oral agents have made it possible to improve glycemic control to near-normal levels with a low risk of hypoglycemia and without weight gain, and sometimes with weight loss. Early combination therapy is effective and has been shown to have a favorable legacy effect. A number of agents are available in a single-pill combination (SPC) that provides fewer pills and better adherence. Compared with adding a sulfonylurea, still the most common oral combination used, empagliflozin has been shown to decrease cardiovascular (CV) events in a dedicated CV outcome study, and pioglitazone has been effective in reducing the risk of secondary CV endpoints, whereas sulfonylureas have been associated with an increased risk of CV disease. In those failing metformin, triple oral therapy by adding a non-metformin SPC such as empagliflozin/linagliptin or pioglitazone/alogliptin is a good option for reducing glycated hemoglobin (HbA1c) without significant hypoglycemia. Conclusion Clinicians have a comprehensive armamentarium of medications to treat patients with T2DM. Clinical evidence has shown that dual or triple oral combination therapy is effective for glycemic control, and early treatment is effective in getting patients to goal more quickly. Use of SPCs is an option for double or triple oral combination therapy and may result in better adherence.

Diabetes mellitus (DM) is a metabolic disorder that requires medical diagnosis and treatment. Type 2 DM is due to a combination of defective secretion of and responsiveness to insulin. In early stages, the predominant abnormality is reduced insulin sensitivity, and hyperglycemia can be reversed by a variety of measures and medications. In this stage, the cornerstone of glucose-lowering therapy is lifestyle modification, but when counseling does not adequately achieve the recommended glycemic targets, at least five classes of oral drugs are available. In general, α-glucosidase inhibitors delay carbohydrate absorption, metiglinides and sulfonylureas increase insulin supply, and biguanides and thiazolidinediones enhance insulin action. Given the high cardiovascular morbidity and mortality in type 2 DM patients, the attempt to reduce cardiovascular complications, beyond the glucose lowering itself, is an extremely relevant task. Indeed, the role of oral glucose-lowering agents concerning hyperglycemia reduction is defined; however, they have not clearly demonstrated to reduce micro- and macrovascular disease, and hitherto, no firm evidence favors one pharmacological treatment over another. The aim of this update is to describe the existing experiences with oral glucose-lowering agents for type 2 DM treatment with respect to cardiovascular prevention.

Management of type 2 diabetes mellitus (T2DM) is complex and challenging, particularly for clinicians working in primary care who are faced with many competing clinical priorities. The range of available T2DM treatments has diversified significantly in recent years, generating a busy and data-rich environment in which evidence is rapidly evolving. Sodium-glucose cotransporter-2 inhibitor (SGLT2i) agents are a relatively new class of oral glucose-lowering therapy that have been available in the UK for approximately 5 years. These agents reduce the reabsorption of glucose in the kidney and increase its excretion via the urine. Conflicting messages and opinions within the clinical community have led to misconceptions concerning the efficacy, safety and appropriate position of SGLT2i therapies within the T2DM treatment pathway. To help address some of these concerns and provide advice regarding the appropriate place of these medicines in clinical practice, the Improving Diabetes Steering Committee was formed. The Committee worked together to develop this review article, providing a summary of relevant data regarding the use of SGLT2i medicines and focusing on specific considerations for appropriate prescribing within the T2DM management pathway. In addition, a benefit/risk tool has been provided (see Fig. 3 ) that summarises many of the aspects discussed in this review. The tool aims to support clinicians in identifying the people most likely to benefit from SGLT2i treatments, as well as situations where caution may be required. Funding Napp Pharmaceuticals Limited.

A substantial evidence base supports the use of sodium-glucose cotransporter-2 inhibitors (SGLT2is) in the treatment of type 2 diabetes mellitus (T2DM). This class of medicines has demonstrated important benefits that extend beyond glucose-lowering efficacy to protective mechanisms capable of slowing or preventing the onset of long-term cardiovascular, renal and metabolic (CVRM) complications, making their use highly applicable for organ protection and the maintenance of long-term health outcomes. SGLT2is have shown cost-effectiveness in T2DM management and economic savings over other glucose-lowering therapies due to reduced incidence of cardiovascular and renal events. National and international guidelines advocate SGLT2i use early in the T2DM management pathway, based upon a plethora of supporting data from large-scale cardiovascular outcome trials, renal outcomes trials and real-world studies. While most people with T2DM would benefit from CVRM protection through SGLT2i use, prescribing hesitancy remains, potentially due to confusion concerning their place in the complex therapeutic paradigm, variation in licensed indications or safety perceptions/misunderstandings associated with historical data that have since been superseded by robust clinical evidence and long-term pharmacovigilance reporting. This latest narrative review developed by the Improving Diabetes Steering Committee (IDSC) outlines the place of SGLT2is within current evidence-informed guidelines, examines their potential as the standard of care for the majority of newly diagnosed people with T2DM and sets into context the perceived risks and proven advantages of SGLT2is in terms of sustained health outcomes. The authors discuss the cost-effectiveness case for SGLT2is and provide user-friendly tools to support healthcare professionals in the correct application of these medicines in T2DM management. The previously published IDSC SGLT2i Prescribing Tool for T2DM Management has undergone updates and reformatting and is now available as a Decision Tool in an interactive pdf format as well as an abbreviated printable A4 poster/wall chart.

Aims/hypothesisThe long-term effects of metformin in individuals with type 2 diabetes who are at increased risk of severe respiratory infections are unknown. This study aimed to evaluate the effects of metformin use on the risk of first pneumonia hospitalisation and pneumonia-related death in a cohort of Chinese individuals with type 2 diabetes.MethodsWe performed a retrospective analysis of a consecutive cohort of 22,638 individuals with type 2 diabetes in the Hong Kong Diabetes Register enrolled between 2001 and 2018, with follow-up until 31 December 2019. Overlap propensity-score weighting was performed to balance baseline characteristics.ResultsOf 22,638 individuals with type 2 diabetes, after excluding those who had not been prescribed any glucose-lowering drugs (GLDs) and/or with eGFR ≤30 ml min−1 [1.73 m]−2 or treated by dialysis and/or treated with insulin at baseline, we identified 15,784 either prevalent or incident metformin users and 917 users of other GLDs during a mean follow-up period of 7.5 years. Overlap-weighted analysis showed an HR of 0.63 (95% CI 0.52, 0.77) for first pneumonia hospitalisation and 0.49 (95% CI 0.33, 0.73) for pneumonia-related death in metformin users vs users of other GLDs; similar observations resulted following stratification by sex and kidney function. There was also a negative association between metformin exposure over time (proportion of duration of metformin prescriptions during the total follow-up time) and pneumonia events using the penalised spline analysis. Metformin users had a lower neutrophil/lymphocyte ratio at first pneumonia hospitalisation vs non-metformin users (mean [95% CI]: 12.8 [12.1, 13.5] vs 14.8 [12.3, 17.3], p = 0.032). The rate of metformin-associated lactic acidosis was 2.5 per 100,000 person-years. The lower risk of pneumonia events was also observed among incident metformin users vs other GLD users.Conclusions/interpretationLong-term use of metformin was associated with reduced risk of pneumonia and pneumonia-related death among Chinese individuals with diabetes. The relevance of these results to other respiratory infections merits further investigation.

Cardiovascular disease (CVD), including heart failure (HF), is a leading cause of morbidity and mortality in people with type 2 diabetes mellitus (T2DM). CVD and T2DM share common risk factors for development and progression, and there is significant overlap between the conditions in terms of worsening outcomes. In assessing the cardiovascular (CV) safety profiles of anti-diabetic drugs, sodium-glucose co-transporter-2 inhibitor (SGLT2i) therapies have emerged with robust evidence for reducing the risk of adverse CVD outcomes in people with T2DM who have either established CVD or are at risk of developing CVD. A previous consensus document from the Improving Diabetes Steering Committee has examined the potential role of SGLT2is in T2DM management and considered the risk–benefit profile of the class and the appropriate place for these medicines within the T2DM pathway. This paper builds on these findings and presents practical guidance for maximising the pleiotropic benefits of this class of medicines in people with T2DM in terms of reducing adverse CVD outcomes. The Improving Diabetes Steering Committee aims to offer evidence-based practical guidance for the use of SGLT2i therapies in people with T2DM stratified by CVD risk. This is of particular importance currently because some treatment guidelines have not been updated to reflect recent evidence from cardiovascular outcomes trials (CVOTs) and real-world studies that complement the CVOTs. The Improving Diabetes Steering Committee seeks to support healthcare professionals (HCPs) in appropriate treatment selection for people with T2DM who are at risk of developing or have established CVD and examines the role of SGLT2i therapy for these people. Funding : Napp Pharmaceuticals Limited.