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Efficacy of sitagliptin for the hospital management of general medicine and surgery patients with type 2 diabetes (Sita-Hospital): a multicentre, prospective, open-label, non-inferiority randomised trial

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Summary

Background

The role of incretin-based drugs in the treatment of patients with type 2 diabetes admitted to hospital has not been extensively assessed. In this study, we compared the safety and efficacy of a dipeptidyl peptidase-4 inhibitor (sitagliptin) plus basal insulin with a basal–bolus insulin regimen for the management of patients with type 2 diabetes in general medicine and surgery in hospitals.

Methods

We did a multicentre, prospective, open-label, non-inferiority randomised clinical trial (Sita-Hospital) in five hospitals in the USA, enrolling patients aged 18–80 years with type 2 diabetes and a random blood glucose concentration of 7·8–22·2 mmol/L who were being treated with diet or oral antidiabetic drugs or had a total daily insulin dose of 0·6 units per kg or less, admitted to general medicine and surgery services. We randomly assigned patients (1:1) to receive either sitagliptin plus basal glargine once daily (the sitagliptin–basal group) or a basal–bolus regimen with glargine once daily and rapid-acting insulin lispro or aspart before meals (the basal–bolus group) during the hospital stay. All other antidiabetic drugs were discontinued on admission. The randomisation was achieved by computer-generated tables with block stratification according to randomisation blood glucose concentrations (ie, higher or lower than 11·1 mmol/L). The primary endpoint of the trial was non-inferiority in mean differences between groups in their daily blood glucose concentrations measured during the duration of the hospital stay, up to 10 days (point-of-care measurements; non-inferiority was deemed a difference <1 mmol/L). The safety endpoints included hypoglycaemia, and uncontrolled hyperglycaemia leading to treatment failure was defined as a post-hoc endpoint. All participants who received at least one dose of study drug were included in the analysis. This study is registered with ClinicalTrials.gov, number NCT01845831.

Findings

Between Aug 23, 2013, and July 27, 2015, we recruited 279 patients, and randomly assigned 277 to treatment; 138 to sitagliptin–basal and 139 to basal–bolus. The length of stay in hospital was similar for both groups (median 4 days [IQR 3–8] vs 4 [3–8] days, p=0·54). The mean daily blood glucose concentration in the sitagliptin–basal group (9·5 mmol/L [SD 2·7]) was not inferior to that in the basal–bolus group 9·4 mmol/L [2·7]) with a mean blood glucose difference of 0·1 mmol/L (95% CI −0·6 to 0·7). No deaths occurred in this trial. Treatment failure occurred in 22 patients (16%) in the sitagliptin–basal group versus 26 (19%) in the basal–bolus group (p=0·54). Hypoglycaemia occurred in 13 patients (9%) in the sitagliptin–basal group and in 17 (12%) in the basal–bolus group (p=0·45). No differences in hospital complications were noted between groups. Seven patients (5%) developed acute kidney injury in the sitagliptin–basal group and six (4%) in the basal–bolus group. One patient (0·7%) developed acute pancreatitis (in the basal–bolus group).

Interpretation

The trial met the non-inferiority threshold for the primary endpoint, because there was no significant difference between groups in mean daily blood glucose concentrations. Treatment with sitagliptin plus basal insulin is as effective and safe as, and a convenient alternative to, the labour-intensive basal–bolus insulin regimen for the management of hyperglycaemia in patients with type 2 diabetes admitted to general medicine and surgery services in hospital in the non-intensive-care setting.

Funding

Merck.

Introduction

Hyperglycaemia is a common and serious health-care problem in hospitals, reported in approximately 30% of patients in general medicine and surgery with and without a history of previous diabetes mellitus.1, 2 Extensive evidence from observational and randomised clinical studies in patients admitted to hospital indicates that hyperglycaemia, in patients both with and without diabetes, is a predictor of poor outcome.3, 4 In such patients, hyperglycaemia is associated with prolonged hospital stay, increased incidence of infections, hospital complications, and death.4 Improvement in glycaemic control with insulin therapy has been shown to reduce the risk of infection and complications in patients in hospital critical-care units and in patients admitted to general surgical and medical services.1, 5, 6, 7, 8

Research in context

Evidence before this study

We systematically searched the PubMed, EMBASE, and Web of Science electronic databases for articles published between January, 2000, and July, 2016, using a combination of search terms including “inpatient” OR “hospital”, “diabetes/exp” OR “diabetes”, and “clinical trial/de” OR “randomized controlled trial/de”. We excluded reviews and observational studies. Additionally, we reviewed current clinical trial registrations on ClinicalTrials.gov and EudraCT. We supplemented the search by reviewing the reference lists of relevant publications.

The search yielded 212 results from PubMed (68), Embase (70), and Web of Science (74). There were 155 results after removal of duplicates, and we identified 41 interventions to improve glycaemic control in patients admitted to hospital. We previously reported a small feasibility study (n=90) of a dipeptidyl peptidase-4 (DPP-4) inhibitor in patients with type 2 diabetes admitted to hospital who were treated with oral drugs and a low dose of insulin (<0·4 U/kg per day). In this pilot study we reported that treatment with sitagliptin plus correction doses of rapid-acting insulin before meals was effective in improving glycaemic control in patients with mild hyperglycaemia (blood glucose concentration <10 mmol/L); however, it was not as effective in patients whose blood glucose concentrations were higher than 10 mmol/L.

Added value of this study

Our study is the first large randomised trial investigating whether the use of a non-insulin drug (a DPP-4 inhibitor) in combination with basal insulin is a safe and effective alternative to the more labour-intensive basal–bolus insulin regimen.

Implications of all the available evidence

Guidelines from professional organisations for the management of non-critically ill patients with type 2 diabetes admitted to hospital recommend the use of basal–bolus insulin regimens, which are labour-intensive and associated with a risk of hypoglycaemia. The results of our clinical trial show that treatment with the DPP-4 inhibitor sitagliptin and basal insulin once daily is similarly efficacious and safe compared to multidose regimens with basal insulin once daily and rapid-acting insulin before meals in patients in hospital with uncontrolled glucose concentrations. Moreover, treatment with sitagliptin plus basal insulin was associated with lower daily insulin requirements and fewer insulin injections.

Clinical guidelines from professional organisations3, 4, 9, 10 have recommended the use of multidose insulin regimens as the preferred therapy for glycaemic control in patients admitted to hospital in a non-intensive-care-unit setting. The use of a basal–bolus regimen with a once daily basal insulin and rapid-acting insulin analogs before meals has been shown to improve glycaemic control and to reduce the rate of hospital complications in general medical and surgical patients with type 2 diabetes.11, 12, 13 The basal–bolus regimen however is labour-intensive, requiring several insulin injections, and is associated with a high risk of hypoglycaemia. Hypoglycaemia has been reported in 12% to 32% of patients in general medicine and surgery with type 2 diabetes treated with basal–bolus insulin regimens.12, 13, 14, 15, 16 Because of these limitations, alternative treatment regimens are needed that could improve glycaemic control and clinical outcomes, while facilitating care and minimising the risk of hypoglycaemia in patients with diabetes.4, 17

We assessed the feasibility of the use of the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin for the management of hyperglycaemia in the hospital in a small pilot study18 in patients with type 2 diabetes treated at home with diet, oral antidiabetic drugs, or a low dose insulin given daily (≤0·4 units/kg per day). Patients were randomly assigned to sitagliptin alone, sitagliptin plus low-dose glargine insulin, or to a basal–bolus regimen with glargine once daily and rapid-acting insulin before each meal. The results of this study suggested that sitagliptin resulted in similar improvement in glycaemic control in patients with mild hyperglycaemia (blood glucose concentration <10 mmol/L). However, patients with an admission glucose concentration greater than 10 mmol/L who were treated with sitagliptin alone had a higher mean daily blood glucose concentration compared with patients treated with sitagliptin plus basal insulin or with a basal–bolus insulin regimen. To validate the results of our feasibility study, and to expand their applicability to patients given higher doses of insulin, we did a multicentre clinical trial to compare the safety and efficacy of sitagliptin plus glargine once daily to basal–bolus insulin regimens (standard of care) for the inpatient management of patients in general medicine and surgery with type 2 diabetes.

Section snippets

Study design and participants

We did a multicentre, prospective, open-label, non-inferiority randomised study (Sita-Hospital) in five hospitals in the USA (Grady Memorial Hospital and Emory University Hospital [Atlanta, GA], University of Michigan Health System [Ann Arbor, MI], Temple University Hospital [Philadelphia, PA], and Ohio State University Wexner Medical Center [Columbus, OH]). The study protocol and consent form were approved by the institutional review board at each participating institution.

We enrolled patients

Results

Between Aug 23, 2013, and July 27, 2015, we recruited 279 eligible patients who were admitted to general medicine and surgery services (figure 1). Of these, we randomly assigned 140 patients to sitagliptin–basal and 139 to basal–bolus. Two patients were excluded from the analysis because they withdrew consent and did not receive study drug; therefore 138 patients in the sitagliptin–basal group and 139 in the basal–bolus group were included in the analysis. 233 patients (84%) were admitted to

Discussion

The trial met the non-inferiority threshold for the primary endpoint of differences between the sitagliptin–basal and basal–bolus groups for mean daily blood glucose concentrations. Of patients with type 2 diabetes admitted to general medicine and surgery services in hospital, treatment with a daily dose of sitagliptin and basal insulin or with a basal bolus regimen resulted in similar glycaemic control and frequency of complications. We noted a rapid improvement in glycaemic control in both

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