The consensus reached in this Delphi study provides an overview of how diabetes specialists in Italy manage T2D patients whose BOT failed and gives a snapshot of issues that balance indications from guidelines and unmet needs from clinical practice. Consensus was reached on a variety of statements regarding treatment intensification after failure of BOT. Consensus was not reached on six of the 77 items, mainly due to heterogeneity in the management of patients at this disease stage in clinical practice.
DPP-4 inhibitors and SGLT2 inhibitors were the most widely used drugs associated with BI and metformin in clinical practice, while sulfonylureas were considered to be drugs that were no longer used or inappropriate in association with BI, which is in line with guidelines that recommend avoiding the use of sulfonylureas with BI and metformin due to the high risk of hypoglycaemia with this combination [3, 4]. However, data from the DARWIN T2D study documented that sulfonylureas were still a frequently adopted therapeutic option associated with BI .
There is a tendency to prefer newer second-generation insulin analogues since long and ultra-long BI analogues have a similar efficacy in terms of glycaemic control as the first-generation insulins, but with a lower risk of hypoglycaemia. The former have a more physiological pharmacokinetics profile that allows flexibility in the administration time .
The lack of agreement on the use of BOT in patients with CKD reflects different approaches in the treatment of this patient population, although recommendations do suggest using BI preferably in combination with a DPP-4 inhibitor in the presence of kidney impairment, especially in elderly patients . CKD affects up to 40% of people with T2D and represents a significant health challenge in terms of management because the majority of glucose-lowering agents must be downtitrated or withdrawn with declining estimated glomerular filtration rate . Therefore, BOT represents a rationale therapy when CKD is present. However, despite the current paucity of data on the use of long-acting BI in patients with T2D and CKD, observational studies have demonstrated that insulin glargine and insulin degludec are effective in reducing HbA1c with a low risk of hypoglycaemic events [23,24,25]. In a secondary analysis from the DEVOTE trial, a lower rate of severe hypoglycaemia was observed with degludec compared with insulin glargine, even in the presence of CKD . The lack of consensus in our study could also reflect a progressive change, that is still ongoing, in the management of patients with T2D and CKD.
Reaching an agreement on the definition of BOT failure is a prerequisite to identifying strategies for therapy intensification. The panellists reached consensus to consider BOT failure not only in relation to the inability of the therapy to control the traditional glycaemic indicators (HbA1c, FPG, PPG), but also to the presence of side effects, such as nocturnal hypoglycaemia or weight gain.
Fear of hypoglycaemia is one of the determinants of suboptimal glycaemic control. It can be overcome by using an ultra-long-acting insulin analogue, such as degludec, which has been shown to result in a lower incidence of hypoglycaemia, with a reduction in FPG levels [27, 28]. Despite this evidence, newer second-generation insulins are still not used in a large portion of patients treated with BI, and the risk of hypoglycaemia is still an issue.
The association of increase in body weight with BOT failure is still a debated issue. A meta-analysis of cardiovascular outcome trials on glucose-lowering drugs found that a decrease in bodyweight of 1 kg with glucose-lowering interventions led to a statistically significantly reduction of 5.9% in the relative risk of heart failure [29, 30]. Therefore, weight gain is considered to be a crucial aspect, representing an important challenge in the management of patients with T2D on insulin treatment .
The consensus that patients with T2D on BOT who experience hypoglycaemia or weight gain should require a change in therapy even if glycemic targets are met is revolutionary. At the present time, combination therapy with BI and GLP-1RA provides the possibility of reaching glycemic control with lower insulin doses, thereby dramatically limiting the risk of hypoglycaemia and without weight gain. This is one of the most important clinical messages from our survey.
Despite a consensus on the critical role of insulin titration in the BOT strategy, a modest titration of BI in the real-world setting has been observed, contributing to an inadequate glycaemic control [32, 33]. Data from Italian and international studies highlight that more than half of subjects with poorly controlled T2D receive low doses of insulin therapy, confirming a trend towards low insulin titration [6, 34, 37].
Combination therapies, such as BOT, often increase dosing frequency and the treatment burden in patients with T2D, leading to low adherence. In one study, the insulin adherence rate among people with T2D was found to be low, with one quarter of the patients initiating insulin therapy never refilling their prescription . In another study, one third of patients reported insulin omission/non-adherence at least 1 day in the last month, and the majority of physicians reported that their patients did not take their insulin as prescribed .
Although costs were not considered to be a critical issue of BOT, it should be noted that a recent study in Italian setting on the two fixed combinations of BI and GLP-1RA showed that IDegLira was associated with improved clinical outcomes at higher costs relative to iGlarLixi. The higher costs were due to higher acquisition costs although these were partially offset by reduced complication-related treatment costs .
The consensus on changing BI therapy is in line with existing evidence when the BI is not an ultra-long-acting insulin analogue. Experimental and observational studies have demonstrated that switching to insulin degludec from other BI improved glycaemic control with a low risk of overall hypoglycaemia, irrespective of previous BI therapy [38, 39]. Even in vulnerable older patients, glargine 300 U/ml has demonstrated comparable efficacy to glargine 100 U/ml in terms of HbA1c reduction, associated with fewer nocturnal hypoglycaemic events .
Adding GLP-1RA to ongoing BI therapy has several advantages in terms of synergy of action of the individual molecules: efficacy on metabolic parameters; cardiorenal protection; minimization of side effects; and body weight control. There are several well-documented clinical benefits associated with this combination and it is considered to be a safe and effective treatment intensification option [41,42,43]. In addition, this therapeutic strategy has been found to reduce the risk of major cardiovascular events, as well as all-cause mortality, hospital admission for heart failure and kidney outcomes .
Finally, panellists agreed that the association of insulin and GLP-1RA can improve patient adherence. This aspect is fundamental to successful therapy as adherence is a predictor of metabolic control and diabetes complications .
As far as BOT intensification is concerned, it is not surprising that consensus was reached on the switch to multi-injection insulin. This consensus reflects physicians’ persistent attitude to initiate multi-injection insulin more often than the combination of BI and GLP-1RA. A meta-analysis evaluating the efficacy of GLP-1RA as add-on to insulin in comparison with basal-plus/basal-bolus insulin regimens showed that insulin intensification with GLP-1RA is as effective as multi-injection insulin therapy on achieving the HbA1c target, with the added advantages of significant weight loss, reduced risk of hypoglycaemia and sparing of insulin dose . Furthermore, the association has been demonstrated to be less expensive than multi-injection insulin therapy when direct and indirect costs are considered [46, 47].
The lack of agreement for the items on whether fixed-dose combinations preclude optimization of the dosages of the individual components or whether they always have an advantage may depend on the personal clinical experience of the respondent with fixed-dose combinations. The latter do have some advantages, but sometimes lack flexibility in how dosages of the individual components are combined.
A loose-dose combination of BI and GLP-1RA could be chosen if the need for full-dose GLP-1RA is prioritized over intensification of the BI dose. It has been demonstrated that, although the loose- and the fixed-dose combinations similarly improved glycaemic control, the loose-dose combination significantly induced a greater body weight reduction than the fixed-dose combination, providing the possibility to use higher GLP-1RA doses. However, despite lower GLP-1RA doses, similar metabolic control was obtained due to the titration of insulin doses . Furthermore, the slower titration of GLP-1RA in the fixed-dose combinations, which follows the titration schedule for the BI component, was found to result in less nausea compared with independent titration of GLP-1RA . The advantages of the fixed-dose combination come from the synergy of the separate mechanisms of action of BI and GLP-1RA, resulting in improved glycaemic control compared with its mono-components given separately, thereby also improving patient compliance. An observational real-life data study reported that patients previously treated with a loose-dose combination of BI and GLP-1RA who switched to a fixed-dose combination showed increased adherence with a subsequent improvement in glycaemic control .
Results with liraglutide and insulin degludec in the respective cardiovascular outcome trials [51, 52] reflect the panellists’ opinion: there was, in fact, a strong consensus on the potential effectiveness of IDegLira against cardiovascular events. Despite the lack of direct evidence on the safety and efficacy of IDegLira in the prevention of major cardiovascular events, data on the improvement in cardiovascular risk factors in patients treated with IDegLira compared to BI or basal-bolus are available . The advantageous effects of IDegLira on cardiovascular risk factors are consistent with the results from the LEADER trial, even if the dose of liraglutide administered in the co-formulation IDegLira was lower than the dose of 1.8 mg used in the LEADER trial.
The lack of consensus reached on the cardiovascular protection of iGlarLixi probably resulted from a balance between the attitude of some respondents to consider the beneficial effects of GLP-1RA as a class effect and the findings of the ELIXA trial showing that treatment with lixisenatide, compared to placebo, did not provide protection from major adverse cardiovascular events in patients with T2D and recent acute coronary syndrome . These results could be misleading as they might be largely influenced by the literature on the individual components rather than the actual experience of the respondents.
Of note, in the light of the different results from cardiovascular outcomes trials with various GLP-1RA, guidelines underline the importance to use, in the intensification algorithm, GLP-1RA with proven cardiovascular benefit .
The technical limitation in optimizing the dose of GLP-1RA with the fixed BI/GLP-1RA combination is overcome by the perception of the clinical benefits of the co-formulation; consequently, the unlikelihood of reaching the maximum GLP-1RA dose is not perceived as a limitation. In a European retrospective real-world study, after 6 months of treatment with IDegLira, HbA1c was significantly reduced by 0.9% in the subgroup of patients on BOT at baseline, with no increase in body weight, and a mean daily dose of IDegLira of 28.5 dose steps (corresponding to 1.03 mg of liraglutide) .
No consensus was reached among the Expert Panel on the same item referring to iGlarLixi. The panellists, in fact, believed that the limitations of GLP-1RA titration are not completely overcome by the clinical benefits or by manageability of iGlarLixi. This association offers reduced flexibility in terms of time of administration in comparison with IDegLira since the daily dose should be administered within 1 h before a meal of the day due to the shorter half-life and duration of lixisenatide as compared to liraglutide. Furthermore, the clinical trial programme DUAL, which evaluated the efficacy and safety of IDegLira, is broader than the LIXILAN trials programme developed for the evaluation of iGlarLixi, and investigated multiple clinical situations, including comparisons of IDegLira with different comparators.
To date, no head-to-head studies with the two fixed-dose combinations are available. Indirect comparisons suggest that the efficacy of both co-formulations in terms of reduction of HbA1c is comparable, although iGlarLixi reduces PPG slightly more than IDegLira due to the action of the short-acting GLP-1RA lixisenatide on slowing gastric emptying. On the other hand, IDegLira has a greater effect on the reduction of FPG due to action of the long-acting GLP-1RA liraglutide .
There are some limitations to our study. Even when consensus is reached, there is no guarantee it is generalizable; results are dependent on the limited number and the composition of the respondents. However, to minimize the potential for selection bias, panellists were selected based on their experience in the field of diabetes and their distribution thoughout all regions of Italy. Furthermore, the attrition rates over the two rounds were extremely low, ensuring that the range of expert opinion was adequately represented, and the level of consensus was clearly specified a priori.