Weekly Fixed-Dose Insulin Efsitora in Type 2 Diabetes without Previous Insulin Therapy

Phase 3, open-label, treat-to-target, randomized, controlled trial

N= 795

Efsitora (n= 397)

Glargine (n= 398)

Participants were randomly assigned to receive once-weekly efsitora or once-daily glargine. Efsitora was initiated at 100 U weekly, with possible increases to 150, 250, or 400 U every 4 weeks based on fasting blood glucose levels. Glargine doses were adjusted weekly according to a standard algorithm. The primary endpoint was the change in glycated hemoglobin level at 52 weeks.

Primary: Change in glycated hemoglobin level from baseline to week 52

Secondary: Change in fasting blood glucose level, insulin dose at week 52, TRIM-D total score, incidence and rate of hypoglycemia

Once-weekly efsitora in a fixed-dose regimen was noninferior to once-daily glargine in reducing glycated hemoglobin levels in adults with type 2 diabetes who had not previously received insulin. The fixed-dose regimen may simplify treatment and reduce the injection burden.

The study's strengths include a large, multinational participant population and the inclusion of a range of noninsulin glucose-lowering agents, reflecting real-world practice. However, the open-label design could introduce bias, and the prohibition of dose reescalation after hypoglycemia does not reflect usual clinical practice. The lack of continuous glucose monitoring is another limitation.

Insulin Efsitora versus Degludec in Type 2 Diabetes without Previous Insulin Treatment

Phase 3, parallel-design, open-label, treat-to-target trial

N= 928

Efsitora (n= 466)

Degludec (n= 462)

Primary: Change in glycated hemoglobin level from baseline to week 52

Secondary: Change in glycated hemoglobin level in subgroups using and not using GLP-1 receptor agonists, percentage of time glucose level was in target range, hypoglycemic episodes

Once-weekly efsitora was noninferior to once-daily degludec in reducing glycated hemoglobin levels in adults with type 2 diabetes who had not previously received insulin. Efsitora may simplify insulin therapy initiation and improve adherence.

The study's strengths include a large, diverse international population and the use of continuous glucose monitoring. Limitations include the open-label design, which may introduce bias, and the inability to pool continuous glucose monitoring data from all countries due to device differences.

Once-Weekly Insulin Efsitora Alfa Versus Once-Daily Insulin Degludec in Adults with Type 2 Diabetes Currently Treated with Basal Insulin (QWINT-3): A Phase 3, Randomised, Non-Inferiority Trial

Randomised, 78-week, phase 3, parallel-design, open-label, treat-to-target, non-inferiority study

N= 986

Efsitora (n= 655)

Degludec (n= 331)

Primary: Change in least-squares mean HbA1c concentration from baseline to week 26

Secondary: Event rate of participant-reported combined clinically significant or severe nocturnal hypoglycaemia, time in glucose range measured by continuous glucose monitoring

Phase 3, randomised, parallel-design, open-label, non-inferiority trial

N= 730

Efsitora (n= 365)

Glargine U100 (n= 365)

Patients were randomly assigned 1:1 to receive either once-weekly efsitora or once-daily insulin glargine U100, administered subcutaneously using a multidose pen.

Efsitora was initiated with a one-time loading dose in eligible patients, followed by weekly dosing based on the participant’s pre-study basal insulin dose; glargine U100 was initiated at an equivalent dose to the pre-study basal insulin, with dose reductions for certain prior insulin regimens.

Basal insulin doses were titrated weekly through week 12 and monthly thereafter based on fasting blood glucose and hypoglycemia. All participants also received mealtime insulin lispro, which was titrated based on glucose levels, hypoglycemia, and clinical factors.

Blood glucose was monitored using a blood glucose meter and an intermittently worn continuous glucose monitoring (CGM) device throughout the study.

Primary: Change in HbA1c from baseline to week 26 (non-inferiority)

Secondary:  Change in HbA1c from baseline to week 26 (superiority), proportion of participants achieving HbA1c <7% at week 26 without nocturnal level 2 or 3 hypoglycaemia, event rate of participant-reported combined clinically significant or severe nocturnal hypoglycaemia, change in fasting blood glucose, time in, below, and above glucose range during 4-week CGM session, glycaemic variability during the CGM session before week 26, insulin doses at week 26, hypoglycaemia incidence, other adverse events

Race

American Indian or Alaska native

Asian

Black or African American

White

46 (13%)

54 (15%)

20 (5%)

245 (67%)

45 (12%)

51 (14%)

11 (3%)

258 (71%)

Ethnicity

Hispanic or Latin American

Not Hispanic or Latin American

201 (55%)

163 (45%)

203 (56%)

161 (44%)

Fasting serum glucose, mg/dL

eGFR, mL/min/1.73 m²

<60

≥60 to <90

≥90

48 (13%)

122 (33%)

195 (53%)

61 (17%)

117 (32%)

187 (51%)

Duration of diabetes, years

Non-insulin glucose-lowering agents at screening

Biguanides (metformin)

SGLT2 inhibitors

DPP-4 inhibitors

GLP-1 receptor agonists 

Combination oral non-insulin glucose-lowering agents

245 (67%)

115 (32%)

62 (17%) 

63 (17%)

13 (4%) 

249 (68%)

97 (27%)

54 (15%)

68 (19%)

10 (3%)

Baseline total insulin dose, units/day 

53.6 (37.9–77.9)

56.0 (38.8–82.5)

Time below range

<54 mg/dL

54 mg/dL to 69 mg/dL

0.4%

1.2%

0.4%

1.1%

0.23

0.27

Insulin doses at week 26, units/day

Total

Basal

Prandial

84.7

55.9

27.0

95.2

61.0

34.6

<0.001

0.0008

<0.001

Within-day glycaemic variability was similar during the 24 h period, significantly lower during the night-time period, and significantly higher during the daytime period for efsitora compared with glargine U100. Between-day glycaemic variability was similar during the daytime, night-time, and 24 h periods with efsitora versus glargine U100.

There was no difference in the rate of patient-reported composite level 2 and 3 hypoglycaemia over 24 hours.

Treatment-emergent adverse events: 196 (54%) in the efsitora group vs 189 (52%) in the glargine U100 group. The most frequently reported in both groups were nasopharyngitis and urinary tract infection.

Serious adverse events: 25 (7%) in the efsitora group vs 23 (6%) in the glargine U100 group.

Deaths: 1 reported in each group (unrelated to treatment).

Once-Weekly Insulin Efsitora Alfa Versus Once-Daily Insulin Degludec in Adults with Type 1 Diabetes (QWINT-5): A Phase 3 Randomised Non-Inferiority Trial

Phase 3, randomised, open-label, parallel-design, treat-to-target non-inferiority study

N= 692

To assess the efficacy and safety of once-weekly insulin efsitora alfa compared with once-daily insulin degludec in adults with type 1 diabetes

Efsitora (n=343)

Degludec (n=349)

Adults aged ≥18 years with type 1 diabetes, HbA1c 7.0-10.0%, previously treated with basal and bolus insulin analogue multiple daily injection therapy for at least 90 days before screening

History of more than one episode of severe hypoglycaemia within 6 months before screening or hypoglycaemia unawareness

Participants at 82 centers in Argentina, Japan, Poland, Slovakia, Taiwan, and the USA were randomized 1:1, stratified by country, screening HbA1c, previous continuous glucose monitoring (CGM) use, and carbohydrate counting. Efsitora’s weekly dose was calculated from the previous daily basal insulin dose ×7, rounded to the nearest 10 units; the first injection was three times this weekly dose. Protocol-directed adjustments applied for elevated baseline fasting glucose and conversion from insulin glargine U300. Degludec generally began at the previous daily basal dose. Basal doses were assessed weekly through week 12 and at least every 4 weeks thereafter, targeting fasting self-monitored glucose of 80–120 mg/dL. All participants transitioned to insulin lispro and used unmasked Dexcom G6 CGM throughout the study. The primary analysis used a treatment-regimen estimand, regardless of adherence or rescue therapy, with a noninferiority margin of 0.4 percentage points; an efficacy estimand assessed outcomes during treatment adherence without rescue therapy. Secondary superiority objectives were multiplicity-adjusted.

52-week treatment period with a 5-week safety follow-up

Primary: Change in HbA1c from baseline to week 26

Secondary: Event rate of clinically significant nocturnal hypoglycemia, time in target glucose range, change in self-monitored blood glucose fasting levels, insulin doses, treatment satisfaction score

Female

Male

Age, years

Weight, kg

White

Not Hispanic or Latin

Screening HbA1c

Baseline fasting serum glucose, mg/dL (IQR)

Duration of diabetes, years (IQR)

Pre-study basal insulin - Insulin degludec

Abbreviations: IQR, interquartile range

Change in HbA1c from baseline to week 26

Combined level 2 or level 3 hypoglycemia (events per patient-year)

Severe hypoglycemia incidence

Higher rates of combined level 2 or level 3 hypoglycaemia with efsitora compared to degludec (14.03 vs 11.59 events per patient-year; p= 0.016). Severe hypoglycaemia incidence was higher with efsitora (10% vs 3%; p= 0.0011).

In adults with type 1 diabetes, once-weekly efsitora showed non-inferior HbA1c reduction compared with daily insulin degludec. Higher rates of combined level 2 or level 3 hypoglycaemia and greater incidence of severe hypoglycaemia in participants treated with efsitora compared with participants treated with degludec might suggest the need for additional evaluation of efsitora dose initiation and optimisation in people with type 1 diabetes.

Randomization, multinational enrollment, 52-week treatment, and continuous CGM strengthen the comparison, but HbA1c noninferiority was accompanied by significantly higher clinically significant and severe hypoglycemia rates with efsitora. The open-label design and exclusion of patients with recurrent severe hypoglycemia or hypoglycemia unawareness limit generalizability, particularly to higher-risk patients with type 1 diabetes.

Multicenter, phase 2 randomized, parallel, open-label, comparator-controlled trial

N= 278

BIF (n= 129)

Degludec (n= 135)

Primary: HbA1c change from baseline to week 26

Secondary: Fasting blood glucose, six-point self-monitoring of blood glucose (SMBG) profiles, rate of hypoglycemia

Oral T2D medications

Metformin alone

Metformin, DPP-4 inhibitors 

Metformin, SGLT2 inhibitors 

Metformin, SGLT2, DPP-4 inhibitors

74 (54.8%)

18 (13.3%) 

29 (21.5%) 

14 (10.4%)

76 (58.9%)

17 (13.2%) 

25 (19.4%)

11 (8.5%) 

Fasting blood glucose at week 26 for BIF was 4.7 mg/dL higher than degludec (p= 0.09).

The six-point SMBG profiles were similar between treatments for all time points and showed improvement from baseline assessments.

Occurrence of treatment-emergent adverse events was similar between BIF and degludec.

No severe hypoglycemia was reported. Hypersensitivity reactions were more frequent with BIF (6 vs 0 patients for degludec).

Deaths: 1 in the degludec group (unrelated to study treatment).

Safety and efficacy of once-weekly basal insulin Fc in people with type 2 diabetes previously treated with basal insulin: a multicentre, open-label, randomised, phase 2 study

Multicenter, open-label, randomized, phase 2 study

N=399

To explore the safety and efficacy of once-weekly basal insulin Fc (BIF) in people with type 2 diabetes who had been previously treated with basal insulin

BIF-A1 (n=135)

BIF-A2 (n=132)

Insulin degludec (n=132)

Adults aged ≥18 years with type 2 diabetes, body mass index (BMI) between 20 and 45 kg/m², HbA1c between 6.5% and 10.0%, treated with at least 10 units per day and less than 1.5 units/kg per day of basal insulin, with or without up to three oral antidiabetic medications

Not specified in the provided text

Participants at 44 sites in the USA, Puerto Rico, and Mexico were randomized 1:1:1, stratified by country, baseline HbA1c, sulfonylurea use, and BMI. Previous basal insulin was stopped the day before treatment; oral antidiabetic medications were continued. BIF (insulin efsitora alfa) was administered subcutaneously once weekly after a one-time loading dose of 1.5–3 times the calculated weekly dose, determined by previous insulin dose and baseline HbA1c; the first maintenance dose followed 1 week later. BIF was dosed in mg using a study conversion of 1 mg=49 IU. Unblinded Dexcom G6 continuous glucose monitoring (CGM) guided titration: BIF-A1 targeted fasting glucose ≤140 mg/dL with adjustments every 2 weeks; BIF-A2 targeted ≤120 mg/dL every 4 weeks; daily degludec targeted ≤100 mg/dL with weekly adjustments. HbA1c, glucose, weight, participant-reported hypoglycemia, and adverse events were assessed. The efficacy and safety populations included 398 treated participants; primary-outcome analyses included 379. Efficacy analyses excluded observations after rescue medication or treatment discontinuation and used mixed-model repeated measures. Noninferiority versus degludec used a 0.40-percentage-point HbA1c margin and 90% CIs; no multiplicity adjustment was performed.

32-week treatment period with a 5-week safety follow-up

Primary: Change in HbA1c from baseline to week 32

Secondary: Fasting serum glucose change, incidence and rate of hypoglycemia, bodyweight change, time in target glucose range

Age, years 

Female

White

Weight, kg

BMI, kg/m² 

HbA1c

Fasting serum glucose, mg/dL

HbA1c change from baseline

Fasting plasma glucose change, mg/dL

Bodyweight change, kg

CGM time in range, 71–180 mg/dL

BIF was well tolerated with no clinically significant changes in clinical laboratory evaluations, vital signs, or electrocardiograms. The most frequently reported treatment-emergent adverse events were upper respiratory tract infections (7%) and diarrhoea (5%). Two severe hypoglycaemic events were reported in the BIF-A2 group.

Weekly BIF achieved similar efficacy compared with degludec despite higher fasting glucose targets in the BIF groups. Higher fasting glucose targets and lower glucose variability might have contributed to lower hypoglycaemia rates for BIF compared with degludec. These findings support continued development of BIF as a once-weekly insulin treatment for people with diabetes.

Randomization, an active comparator, and continuous CGM assessment strengthen the evaluation of switching from daily basal insulin to weekly BIF. However, unequal glucose targets and titration schedules confound comparisons of hypoglycemia and weight gain, while the open-label, 32-week design and absence of multiplicity adjustment limit interpretation of secondary outcomes and long-term safety.