Elsevier

The Lancet

Volume 382, Issue 9902, 26 October–1 November 2013, Pages 1413-1423
The Lancet

Articles
Linagliptin for patients aged 70 years or older with type 2 diabetes inadequately controlled with common antidiabetes treatments: a randomised, double-blind, placebo-controlled trial

https://doi.org/10.1016/S0140-6736(13)61500-7Get rights and content

Summary

Background

A substantial proportion of patients with type 2 diabetes are elderly (≥65 years) but this group has been largely excluded from clinical studies of glucose-lowering drugs. We aimed to assess the effectiveness of linagliptin, a dipeptidyl peptidase-4 inhibitor, in elderly patients with type 2 diabetes.

Methods

In this randomised, double-blind, parallel-group, multinational phase 3 study, patients aged 70 years or older with type 2 diabetes, glycated haemoglobin A1c (HbA1c) of 7·0% or more, receiving metformin, sulfonylureas, or basal insulin, or combinations of these drugs, were randomised (by computer-generated randomisation sequence, concealed with a voice–response system, stratified by HbA1c level [<8·5% vs ≥8·5%] and insulin use [yes vs no], block size four) in a 2:1 ratio to once-daily oral treatment with linagliptin 5 mg or matching placebo for 24 weeks. Investigators and participants were masked to assignment throughout the study. The primary endpoint was change in HbA1c from baseline to week 24. This trial is registered with ClinicalTrials.gov, number NCT01084005.

Findings

241 community-living outpatients were randomised (162 linagliptin, 79 placebo). Mean age was 74·9 years (SD 4·3). Mean HbA1c was 7·8% (SD 0·8). At week 24, placebo-adjusted mean change in HbA1c with linagliptin was −0·64% (95% CI −0·81 to −0·48, p<0·0001). Overall safety and tolerability were much the same between the linagliptin and placebo groups; 75·9% of patients in both groups had an adverse event (linagliptin n=123, placebo n=60). No deaths occurred. Serious adverse events occurred in 8·6% (14) of patients in the linagliptin group and 6·3% (five) patients in the placebo group; none were deemed related to study drug. Hypoglycaemia was the most common adverse event in both groups, but did not differ between groups (24·1% [39] in the linagliptin group, 16·5% [13] in the placebo group; odds ratio 1·58, 95% CI 0·78–3·78, p=0·2083).

Interpretation

In elderly patients with type 2 diabetes linagliptin was efficacious in lowering glucose with a safety profile similar to placebo. These findings could inform treatment decisions for achieving individualised glycaemic goals with minimal risk in this important population of patients.

Funding

Boehringer Ingelheim.

Introduction

Elderly people (≥65 years) are the main users of medications but have been substantially under-represented in clinical trials.1, 2 About a quarter of people aged 65 years or older have diabetes mellitus,3 nearly all of whom have type 2 disease.4 However, an analysis5 showed that only 0·6% of interventional trials in diabetes specifically targeted this age group, 31% excluded patients older than 65 years, and almost all excluded those older than 75 years. Glucose-lowering treatment of elderly patients with type 2 diabetes is generally deemed necessary to alleviate symptoms associated with hyperglycaemia, improve general wellbeing, and, in some cases, to reduce the risk of long-term complications;4 untreated hyperglycaemia is also frequently associated with cognitive impairment.6 Randomised clinical trials of glucose-lowering treatments in elderly patients with type 2 diabetes are particularly rare in those whose hyperglycaemia is uncontrolled by common antidiabetes treatments.4 This evidence gap hinders clinical decision making for elderly patients, because the risks and benefits of treatment are unclear.4, 7, 8

Treatment of elderly patients with type 2 diabetes is challenging because of the high prevalence of comorbidities, use of polypharmacy, frailty, and age-related reduction in pancreatic islet function.9 Safety is therefore an important consideration for treatment, especially avoidance of iatrogenic hypoglycaemia, which occurs frequently in elderly patients and can have severe consequences.4, 7 Renal impairment is also very common in elderly patients with type 2 diabetes, increasing their risk for hypoglycaemia and complicating treatment strategies.10 Consequently, although the general goal for patients with type 2 diabetes of a glycated haemoglobin A1c (HbA1c) level of less than 7% might still be reasonable for some elderly patients, it is judged important to individualise this target to balance potential benefits and risks of treatment.4, 9, 10 For some patients, a more appropriate treatment goal might be, for example, HbA1c of 7·5% or higher, depending on individual circumstances.

Many glucose-lowering drugs have potential disadvantages for elderly patients, particularly a risk for hypoglycaemia (sulfonylureas, insulin) or fractures (thiazolidinediones, of which pioglitazone is the only agent remaining widely available), or contraindication or dose adjustments for renal impairment (most oral and injectable agents).4 Additionally, efficacy of glucose-lowering drugs can be affected by disease duration, because of deterioration over time in pancreatic β-cell function. Dipeptidyl peptidase-4 (DPP4) inhibitors are oral agents with little risk for hypoglycaemia and are generally well tolerated.11 Unlike other DPP4 inhibitors, linagliptin, given in a once-daily, single-dose 5 mg regimen, is excreted mainly by non-renal pathways and dose adjustment is not needed for renal impairment or any other factor.12 Linagliptin also has minimal drug interactions.12 In phase 3 studies in patients with type 2 diabetes aged up to 80 years, linagliptin elicited meaningful glucose-lowering effects and was well tolerated with little intrinsic risk for hypoglycaemia.13, 14, 15, 16, 17 This pharmacological profile suggests that linagliptin might be particularly useful for treatment of elderly patients with type 2 diabetes.

The aim of this study was to investigate the glucose-lowering efficacy, safety, and tolerability of linagliptin in patients aged 70 years and older with type 2 diabetes with inadequate glycaemic control on other common glucose-lowering drugs.

Section snippets

Study design and patients

This randomised, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial was done at 33 clinics in five countries (Australia, Canada, Denmark, the Netherlands, and Sweden). The first patient was enrolled on March 10, 2010, and the last patient visit occurred on June 22, 2011.

Men and women with type 2 diabetes were eligible to participate if they were aged 70 years or older, had insufficient glycaemic control (HbA1c ≥7·0%), and had been receiving stable doses of metformin,

Results

241 community-living outpatients (the treated set) were randomised to linagliptin 5 mg (n=162) or placebo (n=79), of whom 220 (91·3%) completed 24 weeks of treatment (figure 1). The full analysis set consisted of 238 patients (160 linagliptin, 78 placebo). The mean age of patients at baseline was 74·9 years (range 70–91), with 44·4% aged 75 years or older, and nearly all were white (table 1). Overall, patients had mean baseline HbA1c of 7·8% (SD 0·8), FPG of 8·3 mmol/L (1·6), bodyweight of 85·7

Discussion

In this randomised clinical trial, linagliptin improved glycaemia and was well tolerated in elderly patients with type 2 diabetes with inadequate glycaemic control from other glucose-lowering drugs, a group generally excluded from clinical trials despite being a large and growing proportion of the population of patients with type 2 diabetes.

There was a high prevalence of long-standing diabetes (>10 years in more than half the patients) and comorbidities—particularly cardiovascular disease (87%)

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