Carol Wysham - Academia.edu (original) (raw)

Papers by Carol Wysham

BMJ Open Diabetes Research & Care

IntroductionInvestigate the effects of switching from two times per day exenatide to once-weekly ... more IntroductionInvestigate the effects of switching from two times per day exenatide to once-weekly exenatide administered by autoinjector (exenatide once-weekly suspension by autoinjector (QWS-AI)) or treatment with exenatide QWS-AI for 1 year.Research design and methodsIn this phase III open-label study, adults with type 2 diabetes were randomized to receive exenatide QWS-AI (2 mg) or exenatide two times per day (5 mcg for 4 weeks, followed by 10 mcg) for 28 weeks. During a subsequent non-randomized 24-week extension, patients who received exenatide two times per day were switched to exenatide QWS-AI and those randomized to exenatide QWS-AI continued this treatment. Efficacy measures included changes from baseline in glycated hemoglobin (A1C), fasting plasma glucose (FPG), and body weight.ResultsIn total, 315 patients (mean baseline A1C of 8.5%) completed the initial 28 weeks of randomized treatment with exenatide QWS-AI (n=197) or exenatide two times per day (n=118) and were include...

Diabetes, Obesity and Metabolism

Tirzepatide is a novel glucose‐dependent insulinotropic polypeptide/glucagon‐like peptide 1 (GLP‐... more Tirzepatide is a novel glucose‐dependent insulinotropic polypeptide/glucagon‐like peptide 1 (GLP‐1) receptor agonist approved in the United States as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes and under investigation for use in chronic weight management, major adverse cardiovascular events and the management of other conditions, including heart failure with preserved ejection fraction and obesity and non‐cirrhotic non‐alcoholic steatohepatitis. The Phase 3 SURPASS 1‐5 clinical trial programme was designed to assess efficacy and safety of once‐weekly subcutaneously injected tirzepatide (5, 10 and 15 mg), as monotherapy or combination therapy, across a broad spectrum of people with type 2 diabetes. Use of tirzepatide in clinical studies was associated with marked reductions of glycated haemoglobin (−1.87 to −2.59%, −20 to −28 mmol/mol) and body weight (−6.2 to −12.9 kg), as well as reductions in parameters commonly associated with heigh...

Cardiovascular Diabetology

The 7th Cardiovascular Outcome Trial (CVOT) Summit on Cardiovascular, Renal, and Glycemic Outcome... more The 7th Cardiovascular Outcome Trial (CVOT) Summit on Cardiovascular, Renal, and Glycemic Outcomes, was held virtually on November 18–19, 2021. Pursuing the tradition of the previous summits, this reference congress served as a platform for in-depth discussion and exchange on recently completed CVOTs. This year’s focus was placed on the outcomes of EMPEROR-Preserved, FIGARO-DKD, AMPLITUDE-O, SURPASS 1–5, and STEP 1–5. Trial implications for diabetes and obesity management and the impact on new treatment algorithms were highlighted for endocrinologists, diabetologists, cardiologists, nephrologists, and general practitioners. Discussions evolved from outcome trials using SGLT2 inhibitors as therapy for heart failure, to CVOTs with nonsteroidal mineralocorticoid receptor antagonists and GLP-1 receptor agonists. Furthermore, trials for glycemic and overweight/obesity management, challenges in diabetes management in COVID-19, and novel guidelines and treatment strategies were discussed.T...

Additional file 1. Study design.

Postgraduate Medicine, 2020

It is well known that type 2 diabetes mellitus (T2D) is a globally increasing health burden. Desp... more It is well known that type 2 diabetes mellitus (T2D) is a globally increasing health burden. Despite recent therapeutic advances and the availability of many different classes of antihyperglycemic therapy, a large proportion of people do not achieve glycemic control. A decline in pancreatic beta-cell function has been defined as a key contributing factor to progression of T2D. In fact, a significant proportion of beta-cell secretory capacity is thought to be lost well before the diagnosis of T2D is made. Several models have been proposed to explain the reduction in beta-cell function, including reduced beta-cell number, beta-cell exhaustion, and dedifferentiation or transdifferentiation into other cell types. However, there have been reports that suggest remission of T2D is possible, and it is believed that beta-cell dysfunction may be, in part, reversible. As such, the question of whether beta cells are committed to failure in people with T2D is complex. It is now widely accepted that early restoration of normoglycemia may protect beta-cell function. Key to the successful implementation of this approach in clinical practice is the appropriate assessment of individuals at risk of beta-cell failure, and the early implementation of appropriate treatment options. In this review, we discuss the progression of T2D in the context of beta-cell failure and describe how C-peptide testing can be used to assess beta-cell function in primary care practice. In conclusion, significant beta-cell dysfunction is likely in individuals with certain clinical characteristics of T2D, such as long duration of disease, high glycated hemoglobin (≥9%), and/or long-term use of therapies that continuously stimulate the beta cell. In these people, measurement of beta-cell status could assist with choice of appropriate therapy to delay or potentially reverse beta-cell dysfunction and the progression of T2D.

Diabetes, Obesity and Metabolism, 2020

AimTreat‐to‐target, randomized controlled trials have confirmed lower rates of hypoglycaemia at e... more AimTreat‐to‐target, randomized controlled trials have confirmed lower rates of hypoglycaemia at equivalent glycaemic control with insulin degludec (degludec) versus insulin glargine 100 units/mL (glargine U100) in patients with type 1 (T1D) or type 2 diabetes (T2D). Treat‐to‐target trials are designed to enable comparisons of safety and tolerability at a similar HbA1c level. In this post hoc analysis of the SWITCH 1 and 2 trials, we utilised a patient‐level modelling approach to compare how glycaemic control might differ between basal insulins at a similar rate of hypoglycaemia.Materials and MethodsData for HbA1c and symptomatic hypoglycaemia from the SWITCH 1 and SWITCH 2 trials were analyzed separately for patients with type 1 diabetes and type 2 diabetes, respectively. The association between the individual patient‐level risk of hypoglycaemia and HbA1c was investigated using a Poisson regression model and used to estimate potential differences in glycaemic control with degludec v...

Current Medical Research and Opinion, 2019

Duh & James B. Young (2019): Development of risk models for major adverse chronic renal outcomes ... more Duh & James B. Young (2019): Development of risk models for major adverse chronic renal outcomes among patients with type 2 diabetes mellitus using insurance claims: a retrospective observational study, Current Medical Research and Opinion,

Diabetes, Obesity and Metabolism, 2018

AimsTo investigate the association between day‐to‐day fasting self‐monitored blood glucose (SMBG)... more AimsTo investigate the association between day‐to‐day fasting self‐monitored blood glucose (SMBG) variability and risk of hypoglycaemia in type 1 (T1D) and type 2 diabetes (T2D), and to compare day‐to‐day fasting SMBG variability between treatments with insulin degludec (degludec) and insulin glargine 100 units/mL (glargine U100).Materials and MethodsData were retrieved from two double‐blind, randomized, treat‐to‐target, two‐period (32 weeks each) crossover trials of degludec vs glargine U100 in T1D (SWITCH 1, n = 501) and T2D (SWITCH 2, n = 720). Available fasting SMBGs were used to determine the standard deviation (SD) of day‐to‐day fasting SMBG variability for each patient and the treatment combination. The association between day‐to‐day fasting SMBG variability and overall symptomatic, nocturnal symptomatic and severe hypoglycaemia was analysed for the pooled population using linear regression, with fasting SMBG variability included as a three‐level factor defined by population ...

Diabetes care, 2016

This study investigated the efficacy and safety of multiple exenatide once-monthly suspension (QM... more This study investigated the efficacy and safety of multiple exenatide once-monthly suspension (QMS) doses of exenatide-containing microspheres in Miglyol referenced against the clinical dose of exenatide once-weekly (QW) microspheres in aqueous solution. In this phase II, randomized, controlled, single-blind study, 121 adults (∼30/arm) with type 2 diabetes and HbA1c 7.1-11.0% (54-97 mmol/mol) were randomized 1:1:1:1 to subcutaneous exenatide QW 2 mg (self-administered) or exenatide QMS 5, 8, or 11 mg (caregiver-administered) for 20 weeks. The primary end point was change in HbA1c. At baseline, mean age was 50 years, HbA1c was 8.5% (69 mmol/mol), fasting plasma glucose (FPG) was 184 mg/dL, and body weight was 98 kg. At week 20, mean ± SD HbA1c reductions were -1.54% ± 1.26% with exenatide QW and -1.29% ± 1.07%, -1.31% ± 1.66%, and -1.45% ± 0.93% with exenatide QMS 5, 8, and 11 mg, respectively (evaluable population: n = 110). There were no significant differences in HbA1c reductions ...

Postgraduate medicine, 2017

To consolidate the evidence from randomized controlled trials evaluating the use of glucagon-like... more To consolidate the evidence from randomized controlled trials evaluating the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) as add-on to basal insulin therapy in type 2 diabetes (T2D) patients. We searched the EMBASE® and NCBI PubMed (Medline) databases and relevant congress abstracts for randomized controlled trials evaluating the efficacy and safety of GLP-1 RAs as add-on to basal insulin compared with basal insulin with or without rapid-acting insulin (RAI) through 23 May 2016. The pooled data were analyzed using a random-effects meta-analysis model. A subanalysis was performed for trials investigating basal insulin plus GLP-1 RAs versus basal insulin plus RAI. Of the 2617 retrieved records, 19 randomized controlled trials enrolling 7,053 patients with T2D were included. Compared with basal insulin ± RAI, reduction in glycated hemoglobin (HbA1c) from baseline (difference in means: -0.48% [95% confidence interval (CI), -0.67 to -0.30]; p < 0.0001) and weight loss ...

Diabetes, obesity & metabolism, Jan 7, 2017

To simplify administration of aqueous exenatide once weekly, which requires reconstitution, the e... more To simplify administration of aqueous exenatide once weekly, which requires reconstitution, the exenatide microspheres have been reformulated in a ready-to-use autoinjector with a Miglyol® diluent (exenatide QWS-AI). This study compared the efficacy and safety of exenatide QWS-AI with the first-in-class glucagon-like peptide-1 receptor agonist exenatide twice daily (BID). This randomized, open-label, controlled study in patients with type 2 diabetes on diet and exercise or stable oral glucose-lowering medication randomized patients 3:2 to either exenatide QWS-AI (2 mg) or exenatide BID (10 μg) for 28 weeks. The primary outcome was the 28-week change in glycated hemoglobin (HbA1c). A subset of patients completed a standardized meal test for postprandial and pharmacokinetic assessments. A total of 375 patients (mean HbA1c: 8.5% [69 mmol/mol]; body mass index: 33.2 kg/m(2) ; diabetes duration: 8.5 years) received either exenatide QWS-AI (n=229) or exenatide BID (n=146); HbA1c was reduc...

Diabetes, obesity & metabolism, Jan 6, 2017

To assess the impact of baseline characteristics on clinical outcomes in the LixiLan-L trial, a r... more To assess the impact of baseline characteristics on clinical outcomes in the LixiLan-L trial, a randomized open-label trial designed to evaluate the efficacy and safety of iGlarLixi, a novel fixed-ratio combination of insulin glargine 100 U (iGlar) plus lixisenatide, in comparison with iGlar over 30 weeks in a population of patients with type 2 diabetes mellitus (T2DM) inadequately controlled on a previous regimen of basal insulin alone or in combination with 1 or 2 oral glucose-lowering drugs. In this exploratory analysis of LixiLan-L (N = 736), efficacy outcomes were assessed within population subgroups derived from the following baseline characteristics: glycated haemoglobin [HbA1c; <8%, ≥8% (<64, ≥64 mmol/mol)]; duration of T2DM (<10, ≥10 years); body mass index (<30, ≥30 kg/m(2) ). Furthermore, the incidence of symptomatic hypoglycaemia with plasma glucose ≤3.9 mmol/L (≤70 mg/dL) was also analysed according to the same subgroups. Compared with the iGlar treatment gr...

Diabetes care, Sep 1, 2016

This study assessed the efficacy and safety of LixiLan, a fixed-ratio, titratable, combination of... more This study assessed the efficacy and safety of LixiLan, a fixed-ratio, titratable, combination of 2 units insulin glargine (Gla-100) and 1 μg lixisenatide administered once daily via a single pen, versus Gla-100 in insulin-naïve type 2 diabetes on metformin. Participants were randomized to once-daily LixiLan (n = 161) or Gla-100 (n = 162) for 24 weeks, while continuing metformin. LixiLan and Gla-100 were started at 10 units/5 μg and 10 units, respectively, and titrated based on the Gla-100 requirement according to fasting plasma glucose levels. The primary objective was to test noninferiority (upper bound of the 95% CI ≤0.4%) of LixiLan in reducing HbA1c; if met, statistical superiority was tested. Secondary objectives included body weight changes, hypoglycemia, and safety. Baseline characteristics (mean age 57 years, diabetes duration 6-7 years, BMI 32 kg/m(2)) were similar between groups. At week 24, mean HbA1c was reduced from 8.0% (64 mmol/mol) at baseline to 6.3% (45 mmol/mol) ...

Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists, Jan 26, 2015

To compare efficacy and safety of 2 dosing regimens for human regular U-500 insulin (U-500R, 500 ... more To compare efficacy and safety of 2 dosing regimens for human regular U-500 insulin (U-500R, 500 units/mL) replacing high-dose U-100 insulins with or without oral antihyperglycemic drugs in patients with inadequately controlled type 2 diabetes (T2D). We conducted a 24-week, open-label, parallel trial in 325 patients (demographics [means]: age, 55.4 years; diabetes duration, 15.2 years; body mass index, 41.9 kg/m2; glycated hemoglobin [HbA1c], 8.7%; U-100 insulin dose, 287.5 units administered in 5 injections/day [median; range, 2 to 10]). Patients were randomized to thrice-daily (TID, n = 162) or twice-daily (BID, n = 163) U-500R after a 4-week lead-in period. The primary outcome was HbA1c change from baseline. After 24 weeks, both treatments demonstrated significant HbA1c reductions (TID, -1.12%; BID, -1.22%; both, P < .001) and clinical equivalence (difference, -0.10%; 95% CI, -0.33% to 0.12%; noninferiority margin, 0.4%). Comparable increases in total daily U-500R dose (TID, 2...

Endocrine Practice, 2012

The clinical management of hyperglycemia in patients with type 2 diabetes mellitus (T2DM) is guid... more The clinical management of hyperglycemia in patients with type 2 diabetes mellitus (T2DM) is guided not only by published treatment algorithms, but also by consideration of recent evidence and through consultation with colleagues and experts. Recent studies have dramatically increased the amount of information regarding the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs). Topics that may be of particular interest to clinicians who treat T2DM patients include relative glycemic control efficacy of GLP-1 RAs, use of GLP-1 RAs across T2DM progression and in combination with insulin, recent data regarding GLP-1 RA safety, nonglycemic actions of GLP-1 RAs, including weight effects, and impact of GLP-1 RAs on patient quality of life and treatment satisfaction. The following review includes expert consideration of these topics with emphasis on recent, relevant reports to illustrate current perspectives.

Clinical diabetes : a publication of the American Diabetes Association, 2018

Novel co-formulations of basal insulin analogs and glucagon-like peptide-1 (GLP-1) receptor agoni... more Novel co-formulations of basal insulin analogs and glucagon-like peptide-1 (GLP-1) receptor agonists have provided new options for patients with type 2 diabetes who are not reaching recommended glycemic targets. The components of currently available co-formulations (insulin degludec/ liraglutide [IDegLira,] and insulin glargine U100/lixisenatide [iGlarLixi]) act synergistically to address multiple pathophysiologic defects while minimizing the side effects associated with either component when used alone. In Europe, these products are approved for use in patients on regimens of one or more oral antidiabetic drugs; in the United States, they are indicated for use as an adjunct to diet and exercise in patients with type 2 diabetes inadequately controlled with either basal insulin or their respective GLP-1 receptor agonist component. This article reviews key clinical trials in which these products were initiated in insulin-naive patients and describes how they can be safely and effectiv...