A phase 3b trial examined patients with uncontrolled type 2 diabetes mellitus (T2DM) on insulin glargine (IGlar U100) 20–50 units/day and metformin, randomised to IDegLira or IGlar U100 and insulin aspart (IAsp) four or fewer times per day. 

66% of patients on IDegLira vs 67% on basal-bolus achieved HbA1c <7%

In patients with uncontrolled type 2 diabetes on basal insulin, prandial insulin may be initiated. Billings et al (2021) assessed the efficacy and safety of initiating insulin degludec/liraglutide fixed-ratio combination (IDegLira) vs basal-bolus insulin. 

Results 

Glycated haemoglobin (HbA1c) decreased from 8.2% to 6.7% with IDegLira, and from 8.2% to 6.7% with basal-bolus (estimated treatment difference 20%), confirming IDegLira noninferiority vs basal-bolus. The number of severe or blood glucose-confirmed symptomatic hypoglycaemia events was lower with IDegLira versus basal-bolus. Body weight decreased with IDegLira and increased with basal-bolus (estimated treatment difference 23.6kg). Fasting plasma glucose reductions were similar. Lunch, dinner and bedtime self-monitored plasma glucose measurements were significantly lower with basal-bolus. Sixty-six per cent of patients on IDegLira vs 67% on basal-bolus achieved HbA1c <7% (53mmol/mol). Total daily insulin dose was lower with IDegLira (40 units) than basal bolus (84 units total; 52 units basal). 

Background 

In the disease progression of T2DM, adequate blood glucose (BG) control with basal insulin may deteriorate over time. By the time basal insulin is initiated, patients, on average, have had a T2DM diagnosis for 9.2 years and a HbA1c level of 9.5% (80mmol/mol). In one study, only 29% of patients could maintain HbA1c <7% (53mmol/mol) three years after basal insulin initiation.  

Current guidelines recommend therapy intensification if HbA1c targets are not reached after three-six months of basal insulin. However, many patients remain without therapy intensification due to concerns such as potential increased hypoglycaemia risk, weight gain and treatment complexity. 

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are incretin mimetics that lower fasting plasma glucose (FPG) and postprandial glucose via stimulation of endogenous insulin and inhibition of glucagon secretion, with weight-reducing effects through appetite suppression. 

Using basal insulin with GLP-1RAs is a recognised therapeutic option after failure to achieve glycaemic control with basal insulin. Comparison of basal insulin and GLP-1RA given in separate injections vs basal insulin alone showed a significantly greater HbA1c reduction and weight loss with the combination therapy, with significantly more hypoglycaemic events. Comparison with basal-bolus showed noninferior HbA1c reduction with basal insulin and GLP-1RA loose combination, and more desirable hypoglycaemia rates and weight management. This evidence supports combination therapies such as IDegLira, a fixed-ratio combination of insulin degludec (degludec) and liraglutide. 

IDegLira efficacy and safety were established in the DUAL clinical trial programme in patients with uncontrolled T2DM on oral antidiabetic drugs (DUAL I, IV, and VI trials, GLP-1RAs (DUAL III trial, and basal insulin (DUAL II and V trial). This, the DUAL VII trial, then assessed IDegLira efficacy and safety vs basal-bolus. 

Primary endpoint  

After 26 weeks of treatment, mean HbA1c decreased from 8.2% (66mmol/mol) at baseline to 6.7% (50mmol/mol) at end of trial with IDegLira, and from 8.2% (67mmol/mol) to 6.7% (50mmol/mol) with basal bolus. The estimated treatment difference was 20.02% (95% CI 20.16, 0.12) (20.2mmol/mol [95% CI 21.7, 1.3]), confirming noninferiority of IDegLira vs basal-bolus. 

In total, 489 patients (244 and 245 in the IDegLira and basal-bolus arms, respectively) contributed to the primary analysis. 

Conclusion 

This unique trial compares a fixed-ratio combination of basal insulin and GLP-1RA with basal-bolus. With once-daily vs multiple daily injections, IDegLira was noninferior to basal-bolus in terms of HbA1c reduction and was statistically superior in a lower hypoglycaemia rate and change in bodyweight in patients on IGlar U100 and metformin with uncontrolled BG. 

Other trials have investigated combinations of insulin and GLP-1RA given separately. 

In the BEGIN: VICTOZA ADD-ON trial, addition of liraglutide to degludec in separate injections resulted in a significantly greater reduction in HbA1c vs addition of IAsp at one meal to degludec, with weight loss and a reduced risk of hypoglycaemia. The addition of once weekly albiglutide to IGlar U100 resulted in similar HbA1c reductions vs IGlar U100 and prandial insulin lispro, with weight loss and a reduced risk of hypoglycaemia.  

These results are mirrored in this trial. Furthermore, the fixed combination achieved these outcomes with only one injection per day (vs five or fewer in the basal-bolus arm) and lower rates of nausea, likely attributable to the ability to slowly titrate the IDegLira dose in contrast to the separate injections. 

An insulin-sparing effect was demonstrated with IDegLira vs basal-bolus. Patients achieved similar HbA1c reductions with a mean daily dose of 13 units of basal insulin less with IDegLira and nearly 45 units of total daily insulin less. 

Despite being an efficacious glucose-lowering therapy, basal-bolus treatment is associated with a higher rate of hypoglycaemia vs other diabetes therapies. Although resulting in similar HbA1c reductions, IDegLira was confirmed to be statistically superior to basal-bolus, with an 89% lower rate of severe or BG-confirmed symptomatic hypoglycaemic episodes and 92% lower rate in nocturnal hypoglycaemia. The striking difference in the cumulative incidence of hypoglycaemia.  

In patients with uncontrolled T2DM on IGlar U100 and metformin, IDegLira treatment elicited HbA1c reductions comparable to basal-bolus, with statistically superior lower hypoglycaemia rates and weight loss vs weight gain.  

REFERENCES:  

Billings LK, Agner BFR, Altuntas Y, et al. The Benefit of Insulin Degludec/Liraglutide (IDegLira) Compared with Basal-Bolus Insulin Therapy is Consistent Across Participant Subgroups with Type 2 Diabetes in the DUAL VII Randomized Trial. Journal of Diabetes Science and Technology. 2021;15(3):636-645. doi:10.1177/1932296820906888