DISCUSSION
hypoglycaemia, type 2 diabetes, weight loss, gastrointestinal, transient, HbA1c ≤
ADVERSE EVENTS, ADVERSE EFFECTS, TYPE 2 DIABETES, INSULIN SENSITIVITY, HYPOGLYCAEMIA
MDI‐treated patients who present with low HbA1c values < 7.5% and report frequent hypoglycaemia may be overtreated and similar patients without frequent hypoglycaemia may also be overtreated if they are using unnecessarily complex treatment instead of simpler options which could ensure the same efficacy with less risk and burden. It is clear that overtreated patients are among those who can benefit the most from treatment simplification. We examined prospectively the safety and efficacy of switching from MDI to once daily IDegLira in subjects with type 2 diabetes using low TDD who were considered to be overtreated (either overcontrolled or well‐controlled). Our preliminary 3‐month follow‐up data were promising but we wanted to confirm our results in a larger group of patients with a longer follow‐up.We used IDegLira for de‐escalation because beside its marked effect on fasting glucose it also has a clinically relevant impact on postprandial glucose. Moreover, the GLP‐1RA component of the drug has an insulin‐sparing effect as it enhances endogenous insulin secretion in a glucose‐dependent way. It also generates weight loss which is associated with improved insulin sensitivity and lower insulin requirement. Furthermore, the LEADER and DEVOTE trials proved the cardiovascular benefits and safety of liraglutide and degludec.Endogenous insulin secretion is a major criterion for the glucose‐lowering effect of liraglutide and supplements the effects of IDegLira on postprandial glucose control; therefore, we enrolled only adults who had at least partially preserved beta‐cell function. Average daily insulin production in healthy men is about 0.7–0.8 IU/kg, and the mean TDD in Caucasian men and women with type 2 diabetes treated with MDI is usually between 0.9 and 1.4 IU/kg.Our objective was to assess the sustained efficacy and safety of the simplified treatment during a 12‐month follow‐up in a larger group of overtreated patients. Our results clearly confirmed that the glycaemic control achieved with the previously used complex insulin regimes can be maintained in the longer term with IDegLira, since mean HbA1c actually remained unchanged during the follow‐up.In the subgroup of overtreated subjects who had an HbA1c < 6.5% (48 mmol/mol) at baseline, mean HbA1c did not change significantly during the trial, but the risk of hypoglycaemia decreased markedly. In the subgroup of relatively well‐controlled patients with a baseline HbA1c ≥ 6.5% to ≤7.5% (48 and 58 mmol/mol), replacing MDI with IDegLira resulted in clinically significant decrease in mean HbA1c without increasing hypoglycaemia risk. Actually in this subgroup, the percentage of patients experiencing hypoglycaemia was substantially lower during the last 3 months of the follow‐up than during the month before BV.Besides the beneficial glycaemic effects, insulin treatment simplification with IDegLira resulted in clinically meaningful weight loss, a reduction of insulin requirement of nearly 50% and a decrease of treatment burden. In addition, there are data which support that among older patients with type 2 diabetes taking multiple glucose‐lowering agents deprescribing with IDegLira may also improve quality of life.According to our observations, IDegLira + metformin combination therapy was safe and generally well tolerated. The most frequent adverse events were gastrointestinal, transient and non‐serious, and the incidence and severity of these digestive symptoms were similar to those described in the literature.In our trial, we focused on overtreated patients with HbA1c ≤ 7.5% (58 mmol/mol), but insulin treatment simplification with the fixed combination of basal insulin and a GLP‐1RA may be applicable for people with suboptimal glycaemic control as well.The post hoc analysis of the DUAL VII Japan study found that switching from low‐dose premixed insulin to IDegLira in patients with uncontrolled type 2 diabetes (The BEYOND trial demonstrated that in patients with type 2 diabetes and inadequate glycaemic control (baseline HbA1c > 7.5% (58 mmol/mol), mean HbA1c 8.6% [70 mmol/mol] at baseline) it was safe to switch from a basal‐bolus regimen to either a once‐daily FRC (IDegLira or iGlarLixi) or once‐daily gliflozin added to basal insulin, with similar glucose control, fewer insulin doses and less hypoglycaemia.Our work in line with the above‐mentioned trials draws attention to the fact that in a significant proportion of subjects with type 2 diabetes complex insulin regimens can be successfully simplified. Since clinical inertia to insulin treatment simplification has an unfavourable effect on patients, efforts should be made to avoid it.We demonstrated that simplification of basal‐bolus or premixed insulin regimens can be performed with an FRC successfully in adults with type 2 diabetes who have an HbA1c ≤ 7.5% (58 mmol/mol), are treated with relatively low insulin doses (TDD ≤ 0.6 IU/kg and TDD ≤ 70 IU/day) and have a detectable (≥1.1 ng/ml) random, non‐fasting serum C‐peptide level indicating some degree of preserved beta‐cell function. We also showed that IDegLira added to metformin to simplify treatment maintains appropriate glycaemic control at least for 12 months with less hypoglycaemia and weight loss compared to the previous insulin regimens.Our real‐world setting, prospective, before‐after study has several limitations. It was a non‐randomized, non‐blinded, uncontrolled, one‐centred study and only Caucasian subjects were enrolled. Besides the initiation of IDegLira the initiation and/or the titration of metformin also affected the observed effects on glycaemic status, body weight and the incidence of adverse effects, but we could not estimate the strength of that effect. Our aim was to examine an IDegLira‐based strategy and not a certain medicine.These 12‐month data confirm that in everyday clinical practice switching from low‐dose MDI to IDegLira in overtreated (well‐controlled or overcontrolled) patients with type 2 diabetes is safe, may induce weight loss, results in similar or better glycaemic control and substantially reduces insulin requirement on longer term.