Composite endpoints in trials of type‐2 diabetes

Abstract

Composite endpoints (CEPs) are being used more frequently as outcomes for trials of drugs in type-2 diabetes. We reviewed the literature to determine how CEPs have been used to date in trials of drugs for type-2 diabetes. A systematic search was undertaken on Medline, Embase and Cochrane databases and Clinicaltrials.gov for randomized controlled trials of currently marketed agents including SGLT-2 inhibitors (dapagliflozin), GLP-1 agonists (exenatide, liraglutide) and DPP-4 inhibitors (linagliptin, saxagliptin, sitagliptin and vildagliptin). CEPs used were identified as well as numbers and percentages of patients achieving each. Thirty-six studies were identified that reported results on ≥1 CEP; 15 different CEPs were reported (7 with 2 components, 8 with 3 components). All CEPs addressed goals recommended by the American Diabetes Association (ADA). All included HbA1c<7%; other endpoints measured weight, blood pressure and hypoglycaemic events. Results were obtained for CEPs from 6 months to 2 years. Rates of achieving CEPs decreased with increasing numbers of components and outcomes assessed. CEPs are becoming used as indicators of clinical outcomes in type-2 diabetes trials, but are still not common. More research is required to identify optimal CEPs. Standardization of outcomes and their reporting is needed. Keywords: clinical trials, composite endpoints, HbA1c, type-2 diabetes Date submitted 19 August 2013; date of first decision 2 October 2013; date of final acceptance 15 October 2013 IntroductionType-2 diabetes mellitus is a disease that affects multiple organ systems, especially over time and when control of symptoms is lost. The result is serious end organ damage, especially to the kidneys and heart. Intermediate factors in the processes leading to organ damage include hyperglycaemia, hypertension and obesity, among others. The American Diabetes Association (ADA) has made recommendations which incorporate specific targets for a number of physiological parameters in type-2 diabetes [1]. Targets include maintaining HbA1c levels <7%, blood pressure <130/80, avoiding hypoglycaemia events and maintaining weight, or losing weight, if obese.To address multiple desired outcomes, composite endpoints (CEPs) are increasingly being used in clinical trials as primary or secondary outcomes [2][3][4]. They have been adopted in a wide variety of clinical areas, such as urology [5], anaesthesia [6], migraines [7], infectious diseases [8] and especially cardiovascular disease (CVD) [3,9]. Their use continues to grow.Chi defines a CEP as 'an endpoint defined at the patient level, in terms of multiple clinically relevant endpoints ' [2]. The appropriate representation of patient outcomes requires that all of the endpoints incorporated into the composite be clinically meaningful on their own and also related to ultimate outcomes [3]. In fact, Chi recommends including as many clinically relevant endpoints as possible [2]. In all cases, these relationships must be validated [2][3][4].There are several advantages to a CEP, with...

Achieving the composite end‐point of glycated hemoglobin <7.0% without weight gain or hypoglycemia with once‐weekly dulaglutide in Chinese patients with type 2 diabetes: A post‐hoc analysis

“…The International Association of Diabetes (the USA and Europe) recommend glucose‐dropping agents based on the efficacy (HbA1c reduction) and safety (lower risk of weight gain and hypoglycemia). The efficacy and safety of treatment modalities can be defined more systematically using the clinically important CE, especially when more than one desired therapeutic response of treatment is essential. The present post‐hoc analysis is the first analysis to compare the effect of DU (1.5/0.75 mg) with GLIM or GLAR on the CE of HbA1c <7.0%, without WG and hypoglycemia in Chinese type 2 diabetes patients.…”

CANadian CAnagliflozin REgistry: Effectiveness and safety of canagliflozin in the treatment of type 2 diabetes mellitus in Canadian clinical practice

“…Findings from the STENO‐2 study emphasized the importance of focusing on multifactorial risk reduction in T2DM management, on reduction of CV disease and renal impairment, as well as on improvement in treatment compliance in T2DM patients . Glycaemic control, weight loss and SBP reduction are known to markedly lower modifiable metabolic and CV‐related risk factors, and are recognized as valid composite endpoints in assessing T2DM management . In addition, changes in anthropometric measures are important and relevant to patients, and they have been associated with improvements in patient adherence to medication .…”

“…28,29 Glycaemic control, weight loss and SBP reduction are known to markedly lower modifiable metabolic and CV-related risk factors, and are recognized as valid composite endpoints in assessing T2DM management. [30][31][32] In addition, changes in anthropometric measures are important and relevant to patients, and they have been associated with improvements in patient adherence to medication. 33,34 Over the 12-month study period, 40% of patients achieved the double composite endpoint and approximately 25% of patients achieved triple target control (Figure 3 Consistent with the safety findings observed in CANA clinical trials, [12][13][14][15][16][17][18] the overall incidence of AEs was low, with most being either mild or moderate in severity.…”

Sex and age discrepancy of HbA1c and fetal hemoglobin determined by HPLC in a large Chinese Han population

“…In current clinical practice, dose adjustments of insulin injections or oral hypoglycemic drugs are usually made on the basis of HbA1c concentrations, and HbA1c is now recommended as an established parameter reflecting average blood glucose control over 2-3 months. 7,8 Accurate detection of HbA1c can be made using most methods if the fetal hemoglobin (HbF) value is <10%. 9 It is widely regarded that HPLC analysis is the gold standard method for HbA1c.…”