DIABETICMedicine DOI: 10.1111/dme.13041
Research: Treatment Efficacy and safety of linagliptin as add-on therapy to basal insulin and metformin in people with Type 2 diabetes S. Duran-Garcia1, J. Lee2, H. Yki-J€ arvinen3, J. Rosenstock4, U. Hehnke2, S. Thiemann2, S. Patel5 2 and H.-J. Woerle 1 Valme University Hospital Medical School, Seville, Spain, 2Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany, 3Department of Medicine, University of Helsinki, Helsinki, Finland, 4Dallas Diabetes and Endocrine Center at Medical City, Dallas, TX, USA and 5Boehringer Ingelheim Ltd, Bracknell, UK
Accepted 18 November 2015
Abstract Aim To evaluate the efficacy and safety of linagliptin in people with Type 2 diabetes inadequately controlled on basal insulin and metformin. Methods This was a post hoc subanalysis of participants who received basal insulin and metformin in a global phase III study that randomized participants (1:1) to receive linagliptin 5 mg once daily or placebo for ≥52 weeks as add-on therapy to basal insulin alone or in combination with metformin and/or pioglitazone. During the first 24 weeks, the background dose of basal insulin remained stable; thereafter, adjustments based on glucose concentrations were recommended. The primary endpoint of the subanalysis was the change from baseline in HbA1c after 24 weeks. The safety analysis incorporated data up to a maximum of 110 weeks.
A total of 950 participants receiving background insulin and metformin were included in this subanalysis (linagliptin and placebo, both n = 475). At week 24, the placebo-corrected adjusted mean (SE) change from baseline in HbA1c with linagliptin was –7 (1) mmol/mol [–0.7 (0.1) %; 95% CI –0.8, –0.6; P < 0.0001]. The overall frequency of drug-related adverse events (linagliptin, 18.9%; placebo, 21.9%) and investigator-reported hypoglycaemia (linagliptin, 30.7%; placebo, 31.6%) were similar in both groups at the end of treatment. The frequency of severe hypoglycaemia was low (linagliptin, 1.7%; placebo, 0.8%). No meaningful changes in mean (SD) body weight were noted in either group [week 52: linagliptin, –0.5 (3.2) kg; placebo, 0.0 (3.1) kg]. Results
Conclusions Linagliptin added to basal insulin and metformin improved glycaemic control, without increasing the risk of hypoglycaemia or body weight gain.
Diabet. Med. 33, 926–933 (2016)
Introduction Guidelines for the treatment of Type 2 diabetes mellitus collectively recommend metformin as initial therapy [1–3]; however, because of the progressive decline in pancreatic bcell function in Type 2 diabetes, many patients will eventually fail to maintain glycaemic control with metformin alone . Failure of monotherapy alone is also attributed to the inability to act on the multiple pathophysiological mechanisms involved in the deterioration in glucose control ; therefore, most patients will eventually require the addition of one or more oral antidiabetic drugs or insulin replacement therapy to help achieve and maintain treatment glycaemic targets. Correspondence to: S. Duran-Garcia. E-mail: [email protected]
Although patients and physicians are often reluctant to initiate insulin therapy, patients with worsening or very high levels of hyperglycaemia may need daily subcutaneous insulin to achieve glycaemic targets. When insulin is initiated, metformin is typically continued—the rationale being that combining insulin with an insulin-sensitizing drug will reduce the need for high daily doses of insulin, thereby minimizing the risk of hypoglycaemia and body weight gain . Compared with insulin alone, this combination has been shown to provide better glycaemic control with less risk of hypoglycaemia and minimal increase in body weight [7–10]. As a consequence, combining basal insulin with metformin represents a common treatment option for patients with Type 2 diabetes in clinical practice .
ª 2015 Diabetes UK
What’s new? • In people with Type 2 diabetes who are receiving metformin and are required to transition to basal insulin therapy, metformin is often continued as an effective adjunct therapy to mitigate the need for high doses of insulin, and thereby minimize the risk of hypoglycaemia and body weight gain. • In those who fail to achieve or maintain glycaemic targets with this combination, the addition of a dipeptidyl peptidase-4 inhibitor may further improve glycaemic control. • The results of the present analysis suggest that the addition of linagliptin to a background of basal insulin and metformin improves glycaemic control, with low additional risk of hypoglycaemia or body weight gain.
As a result of disease progression, the combination of basal insulin and metformin may also eventually be insufficient to achieve glycaemic targets; however, patients and physicians are often reluctant to further titrate the dose of basal insulin or add prandial insulin because of concerns about the increased risk of hypoglycaemia and body weight gain, as well as the complexity of insulin therapy. The addition of a dipeptidyl peptidase (DPP)-4 inhibitor to a regimen of insulin and metformin could be a simple option to improve glucose control without the deleterious effects associated with insulin uptitration. Furthermore, the combination of a DPP-4 inhibitor and basal insulin provides complementary mechanisms of action because DPP-4 inhibitors lower postprandial glucose and basal insulin reduces fasting plasma glucose (FPG). Linagliptin is an oral DPP-4 inhibitor which is available for the treatment of Type 2 diabetes in a 5-mg once-daily dose as monotherapy or in combination with various oral antidiabetic drugs and also insulin . A phase III study evaluated the efficacy and long-term safety of linagliptin added to basal insulin, alone or in combination with metformin and/or pioglitazone . The addition of linagliptin significantly improved glycaemic control compared with placebo without increasing hypoglycaemia or body weight. In the present subanalysis we investigated the efficacy and safety of linagliptin in combination with basal insulin and specifically in participants also on metformin, the most common background treatment in the aforementioned phase III study .
Participants and methods
Type 2 diabetes (NCT00954447). The design and methodology of this trial have been described previously in detail . Briefly, eligible study participants were aged ≥18 years with a diagnosis of Type 2 diabetes and inadequate glycaemic control [glycated haemoglobin (HbA1c) ≥53 to ≤86 mmol/mol (≥7.0 to ≤10.0%)], had a body mass index (BMI) of ≤45 kg/m2, and were being treated with basal insulin alone or in combination with metformin and/or pioglitazone for ≥12 weeks. The main exclusion criteria were: uncontrolled fasting hyperglycaemia (glucose >13.3 mmol/l); myocardial infarction, stroke or transient ischaemic attack < 6 months before informed consent; impaired hepatic function; previous gastric bypass surgery; or any medical history of cancer in the 5 years before screening . The protocol of the original study  was reviewed and approved by the independent ethics committees or institutional review boards of each participating site. The study was conducted in compliance with the principles of the Declaration of Helsinki (1996), and in accordance with Good Clinical Practice guidelines as defined by the International Conference on Harmonisation. All participants gave written informed consent before participation. Eligible participants were randomized (1:1) to receive double-blind treatment with linagliptin 5 mg or placebo for ≥52 weeks as add-on therapy to basal insulin, alone or in combination with metformin and/or pioglitazone. The background basal insulin dose was kept stable for the first 24 weeks (within 10% of baseline dose), but could then be titrated according to the clinical judgement of the investigator with a FPG target of 6.1 mmol/l. The dose of metformin was to remain stable throughout the study. This subanalysis included data from all participants who were receiving basal insulin in combination with metformin in the original parent trial . The primary endpoint was the change from baseline in HbA1c after 24 weeks of treatment. Secondary endpoints were the change from baseline in HbA1c over time, the proportion of participants achieving HbA1c