Evaluating glucose‐lowering treatment in older people with diabetes : lessons from the IMPERIUM trial

Understanding the benefits and risks of treatments to be used by older individuals (≥65 years old) is critical for informed therapeutic decisions. Glucose‐lowering therapy for older patients with diabetes should be tailored to suit their clinical condition, comorbidities and impaired functional status, including varying degrees of frailty. However, despite the rapidly growing population of older adults with diabetes, there are few dedicated clinical trials evaluating glucose‐lowering treatment in older people. Conducting clinical trials in the older population poses multiple significant challenges. Despite the general agreement that individualizing treatment goals and avoiding hypoglycaemia is paramount for the therapy of older people with diabetes, there are conflicting perspectives on specific glycaemic targets that should be adopted and on use of specific drugs and treatment strategies. Assessment of functional status, frailty and comorbidities is not routinely performed in diabetes trials, contributing to insufficient characterization of older study participants. Moreover, significant operational barriers and problems make successful enrolment and completion of such studies difficult. In this review paper, we summarize the current guidelines and literature on conducting such trials, as well as the learnings from our own clinical trial (IMPERIUM) that assessed different glucose‐lowering strategies in older people with type 2 diabetes. We discuss the importance of strategies to improve study design, enrolment and attrition. Apart from summarizing some practical advice to facilitate the successful conduct of studies, we highlight key gaps and needs that warrant further research

Glycaemic outcomes of an Individualised treatMent aPproach for oldER vulnerable patIents: A randomised, controlled stUdy in type 2 diabetes Mellitus (IMPERIUM).

AIM: To compare the glycaemic outcomes of 2 glucose-lowering treatment strategies in vulnerable (moderately ill and/or frail) patients aged ≥65 years with type 2 diabetes whose individual HbA1c targets were not met with diet/exercise and/or oral antihyperglycaemic medications (OAMs). METHODS: The primary endpoint of this study was a composite of achieving/maintaining individualised HbA1c targets without 'clinically significant' hypoglycaemia (severe hypoglycaemia or repeated hypoglycaemia causing interruption of patients' activities or blood glucose <54 mg/dL). Strategy-A comprised glucose-dependent therapies (N = 99) with a non-sulphonylurea OAM and a glucagon-like peptide-1 receptor agonist as the first injectable. Strategy-B comprised non-glucose-dependent therapies (N = 93) with sulphonylurea as the preferred OAM and insulin glargine as the first injectable. RESULTS: There was no significant difference between Strategies A and B in percentages of patients achieving the primary endpoint (64.5% vs 54.9%; P=0.190). Mean incidences (A vs B) of total (10.2% vs 53.8%), documented symptomatic (5.1% vs 36.6%), and asymptomatic (8.2% vs 32.3%) hypoglycaemia were lower for Strategy-A (P<0.001 each). Proportions of patients achieving/maintaining HbA1c target (A, 63.3% vs B, 55.9%) were similar. CONCLUSIONS: Similar proportions of older, vulnerable aged ≥65 years patients with type 2 diabetes achieved/maintained glycaemic treatment goals without clinically significant hypoglycaemia with Strategies A or B. However, Strategy-A resulted in lower risk of total, documented symptomatic, and asymptomatic hypoglycaemia. These results identify an approach of potential clinical benefit in this age group and will inform future clinical research in older patients with type 2 diabetes. This trial is registered with ClinTrials.gov, number NCT02072096

Emerging role of insulin with incretin therapies for management of type 2 diabetes

Type 2 diabetes mellitus (T2DM) is a progressive disease warranting intensification of treatment, as beta-cell function declines over time. Current treatment algorithms recommend metformin as the first-line agent, while advocating the addition of either basal-bolus or premixed insulin as the final level of intervention. Incretin therapy, including incretin mimetics or enhancers, are the latest group of drugs available for treatment of T2DM. These agents act through the incretin axis, are currently recommended as add-on agents either as second-or third-line treatment, without concurrent use of insulin. Given the novel role of incretin therapy in terms of reducing postprandial hyperglycemia, and favorable effects on weight with reduced incidence of hypoglycemia, we explore alternative options for incretin therapy in T2DM management. Furthermore, as some evidence alludes to incretins potentially increasing betacell mass and altering disease progression, we propose introducing these agents earlier in the treatment algorithm. In addition, we suggest the concurrent use of incretins with insulin, given the favorable effects especially in relation to weight gain

A Model-Informed Method for the Purpose of Precision Dosing of Isoniazid in Pulmonary Tuberculosis

BACKGROUND AND OBJECTIVE: This study aimed to develop and evaluate a population pharmacokinetic model and limited sampling strategy for isoniazid to be used in model-based therapeutic drug monitoring. METHODS: A population pharmacokinetic model was developed based on isoniazid and acetyl-isoniazid pharmacokinetic data from seven studies with in total 466 patients from three continents. Three limited sampling strategies were tested based on the available sampling times in the dataset and practical considerations. The tested limited sampling strategies sampled at 2, 4, and 6 h, 2 and 4 h, and 2 h after dosing. The model-predicted area under the concentration-time curve from 0 to 24 h (AUC(24)) and the peak concentration from the limited sampling strategies were compared to predictions using the full pharmacokinetic curve. Bias and precision were assessed using the mean error (ME) and the root mean square error (RMSE), both expressed as a percentage of the mean model-predicted AUC(24) or peak concentration on the full pharmacokinetic curve. RESULTS: Performance of the developed model was acceptable and the uncertainty in parameter estimations was generally low (the highest relative standard error was 39% coefficient of variation). The limited sampling strategy with sampling at 2 and 4 h was determined as most suitable with an ME of 1.1% and RMSE of 23.4% for AUC(24) prediction, and ME of 2.7% and RMSE of 23.8% for peak concentration prediction. For the performance of this strategy, it is important that data on both isoniazid and acetyl-isoniazid are used. If only data on isoniazid are available, a limited sampling strategy using 2, 4, and 6 h can be employed with an ME of 1.7% and RMSE of 20.9% for AUC(24) prediction, and ME of 1.2% and RMSE of 23.8% for peak concentration prediction. CONCLUSIONS: A model-based therapeutic drug monitoring strategy for personalized dosing of isoniazid using sampling at 2 and 4 h after dosing was successfully developed. Prospective evaluation of this strategy will show how it performs in a clinical therapeutic drug monitoring setting

Pharmacokinetics of Anidulafungin in Obese and Normal-Weight Adults

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Pharmacokinetics and probability of target attainment for micafungin in normal-weight and morbidly obese adults

Contains fulltext : 202593.pdf (publisher's version ) (Closed access)OBJECTIVES: The rising pandemic of obesity means an increasing number of obese patients who require antimicrobial therapy for serious infections. Micafungin is an echinocandin drug frequently used as therapy or prophylaxis for fungal infections, predominantly with Candida species. In order to maximize the efficacy of micafungin in obese patients, the dose that corresponds to optimal exposure for each obese individual needs to be identified. METHODS: We performed a prospective study in 16 obese and 8 normal-weight healthy subjects with a weight ranging from 61.5-184 kg (ClinicalTrials.gov Identifier: NCT03102658). A population pharmacokinetic model was developed and used to simulate several dosing regimens to evaluate the PTA for relevant MICs to define the optimal dose using the pharmacokinetic/pharmacodynamic target of an AUC/MIC ratio above 5000. RESULTS: Total body weight was found to be most predictive for CL and V. Simulations showed that a 100 mg dose results in a PTA of >90% in patients weighing 125 kg infected with a Candida species with an MIC of 0.016 mg/L. For an MIC of 0.032 mg/L, a 300 mg maintenance dose is recommended above 125 kg weight. Furthermore, we demonstrate that patients can benefit from a loading dose (i.e. twice the maintenance dose). CONCLUSIONS: We present easy-to-use dose recommendations for obese patients, based on both weight and target MIC, that result in adequate exposure in patients with body weight up to 190 kg