Compared with increasing the insulin dose therapy, the present study demonstrated the beneficial effects of adding the long-acting GLP-1 analog liraglutide to established insulin therapy, which resulted in a significant improvement in glycemic control, reduction in insulin requirement, lower incidence of hypoglycemia events and weight loss in the Chinese patients with poorly controlled T2D and abdominal obesity. Although beneficial effects of combination use of GLP-1 receptor agonists (liraglutide or exenatide) and insulin were observed in previous small studies [17–19], most of these are retrospective studies. This study is the first designed study using the insulin dose-increasing approach as an active comparator.
The data from all six LEAD trials have been analysed in pooled meta-analysis which has shown that addition of liraglutide to existing OAD therapy resulted in mean HbA1c reductions of approximately 1.4% and mean HbA1c level of 7.1%, and the proportion of subjects with HbA1c <7% was 59% at the end of trial . In the present study, addition of liraglutide to the established insulin therapy resulted in a significant 1.9% decrease in HbA1c and mean HbA1c level of 6.88%, and 76.2% of patients treated with addition liraglutide achieved an HbA1c ≤ 7.0% level at the end of study. Patients in the insulin-increasing group experienced similar glucose control compared with that in the liraglutide-added group, but when compared with the composite endpoint including HbA1c ≤ 7.0% with no weight gain and no hypoglycemia, there is a significant difference between two groups. The composite endpoint goal was achieved by 67% of patients in the liraglutide-added group which was significantly higher than that 19% of patients in the insulin-increasing group. In this study, we also found that liraglutide-added treatment improved postprandial glucose control better than insulin-uptitration. One possible explanation for this beneficial effect is that liraglutide can suppress glucagon secretion in addition to increasing the physiological insulin secretion [7, 8]. Furthermore, add-on liraglutide treated patients had lower rate of hypoglycemic events and greater insulin and OAD discontinuation than did patients treated with increased insulin doses. This suggests that the addition of liraglutide to insulin therapy might be a good practice to attain glucose control.
In the Diabetes Control and Complications Trial, subjects assigned to intensive therapy experienced a three-fold increased risk of severe hypoglycemic events . A similar finding was also obtained in the UK Prospective Diabetes Study . In the present study, no severe hypoglycemia events were reported in liraglutide-added group, while two patients in the insulin-increasing group reported severe hypoglycemia. In addition, the percentage of patients reporting minor hypoglycemic episodes during the 12-week treatment period was significantly lower in the liraglutide-added group than in the insulin-increasing group. The finding is consistent with the previous studies [3, 10–13] and highlights a second advantage to the liraglutide adding strategy. The lower risk of hypoglycemia with liraglutide administration may be explained by its stimulation of insulin release and glucagon suppression in a glucose-dependent manner . Obese patients with T2D are at high risk for CVD . Given that recent studies have shown an association between hypoglycemic events and risk cardiovascular events , our study may suggest that adding liraglutide to insulin is advantageous from a cardiovascular standpoint owing to its reduced frequency of hypoglycemia compared to treatment with insulin only. In addition to a lower risk of hypoglycemia, liraglutide may favorably affect several CV risk factors, such as blood pressure, lipid profiles, and body weight [11–17, 25]. A recent meta-analysis of cardiovascular safety by exenatide showed that patients treated with exenatide twice daily were less likely to have a CVD event than were treated with other glucose-lowering therapies . The direct cardiovascular benefits of adding liraglutide should be verified in prospective clinical trials.
Insulin, the most effective therapeutic agent for lowering the blood glucose, is particularly associated with weight gain [27, 28] and especially causes undesirable weight gain in an already obese population. Therefore it increases physicians’ reluctance to intensify treatment and decreases patient adherence. All OADs for the treatment of T2D are associated with either weight gain or weight neutrality, except for GLP-1 receptor agonist class which resulted in weight loss through central appetite suppression, leading to reduced energy intake. Therefore, the third advantage to the liraglutide adding strategy was the reduction of body weight. In the present study, a mean weight reduction of 5.62 kg was observed in the liraglutide-added group at the end of the study. It is greater than that observed in any of the preclinical trials of liraglutide as monotherapy or as add-on therapy to oral agents [10–13] and the trial performed in Asian countries [3, 29]. As seen in a recent observational study which combined liraglutide and insulin therapy, the weight loss seen in our study may be explained by a combination of reduced caloric intake caused by the appetite-suppressing effect of liraglutide coupled to reduced lipogenesis achieved by insulin reduction . Moreover, the mean waist circumference reduction of 5.7 cm was most impressive in the liraglutide-added group. Visceral fat in particular increases the risk of CVD, with a recent meta-regresion analysis reporting a 2% increase in the relative of a CVD event for 1-cm increase in waist circumference . Therefore, mean 5.7 cm reduction of waist circumference in the liraglutide-added group was sufficient to reduce the risk of cardiovascular events.
Participants who are T2D and abdominal obesity are likely to develop hypertension, hypercholesterolaemia, liver disease and eventually CVD. Accordingly these participants have a considerably elevated risk of morbidity and mortality. Unfortunately, traditional treatments for these patients are associated with weight gain and hypoglycemia that limit the number of patients reaching acceptable therapeutic goals. The present study provides evidence that liraglutide, when given to insulin-treated obese patients with T2D, results in clinically relevant beneficial effects on body weight and waist circumference reduction, lower risk of hypoglycemia and insulin dose reduction in addition to improved glycemic control.