A Randomized Controlled Trial Comparing the Efficacy and Safety of IDegLira Versus Basal-Bolus in Patients With Poorly Controlled Type 2 Diabetes and Very High HbA_1c ≥9–15%: DUAL HIGH Trial

Abstract

OBJECTIVE

In participants with type 2 diabetes (T2D) and HbA_1c >9.0–10.0%, guidelines recommend treatment with basal-bolus insulin.

RESEARCH DESIGN AND METHODS

This randomized trial compared the efficacy and safety of insulin degludec and liraglutide (IDegLira) and basal-bolus among participants with high HbA_1c ≥9.0–15.0%, previously treated with 2 or 3 oral agents and/or basal insulin, allocated (1:1) to basal-bolus (n = 73) or IDegLira (n = 72). The primary end point was noninferiority (0.4%) in HbA_1c reduction between groups.

RESULTS

Among 145 participants (HbA_1c 10.8% ± 1.3), there was no statistically significant difference in HbA_1c reduction (3.18% ± 2.29 vs. 3.00% ± 1.79, P = 0.65; estimated treatment difference (ETD) 0.18%, 95% CI −0.59, 0.94) between the IDegLira and basal-bolus groups. IDegLira resulted in significantly lower rates of hypoglycemia <70 mg/dL (26% vs. 48%, P = 0.008; odds ratio 0.39, 95% CI 0.19, 0.78), and less weight gain (1.24 ± 8.33 vs. 5.84 ± 6.18 kg, P = 0.001; ETD −4.60, 95% CI −7.33, −1.87).

CONCLUSIONS

In participants with T2D and HbA_1c ≥9.0–15.0%, IDegLira resulted in similar HbA_1c reduction, less hypoglycemia, and less weight gain compared with the basal-bolus regimen.

Graphical Abstract

Introduction

Landmark studies have shown that persistent hyperglycemia in participants with type 2 diabetes (T2D) is associated with short- and long-term complications (1–4). Participants with severe hyperglycemia usually respond poorly to oral antidiabetes agents and frequently require insulin therapy (4,5). Guidelines recommend initiating basal insulin and progressively step-up to basal-bolus insulin in participants with high HbA_1c >10% (86 mmol/mol), particularly if symptomatic or with catabolic symptoms (6). The basal-bolus insulin regimen increases hypoglycemia risk and weight gain (7,8), is labor intensive, and requires multiple daily injections (MDI), which may decrease treatment adherence (9–12). However, simplified regimens may improve adherence and glycemic control (10,11,13).

Prior studies demonstrated the efficacy and safety of fixed-ratio combination (FRC) of basal insulin and glucagon-like peptide 1 receptor agonists (GLP1-RA) (14–18) but excluded participants with very high HbA_1c (≥9.0–15.0%, 75–140.4 mmol/mol). Accordingly, this randomized controlled trial (RCT) compared the efficacy and safety of insulin degludec and liraglutide (IDegLira) and a basal-bolus insulin regimen in glycemic control (efficacy end point), hypoglycemia, and weight gain (safety end points) in participants with T2D and HbA_1c ≥9.0–15.0% (75–140.4 mmol/mol).

Research Design and Methods

This prospective RCT was conducted at two academic clinics in Atlanta, GA. This trial was approved by Emory University’s Institutional Review Board and was registered with clinicaltrials.gov (NCT03737240). We screened male and female participants between 18 and 80 years of age, HbA_1c between 9.0 and 15.0% (75–140.4 mmol/mol), history of T2D for at least 6 months, treated with two or more oral antidiabetic agents and/or with basal insulin (total daily dose ≤50 units/day). Exclusion criteria are listed in the Supplementary Materials (Supplementary Tables 1 and 3 and pages 3–10). After randomization, the insulin regimen was adjusted by the study team following a validated titration algorithm (14,15) (Supplementary Table 2).

Statistical Analysis

Our hypothesis was that participants randomized to IDegLira would experience similar HbA_1c reduction from baseline to end-of-study compared with the basal-bolus group. To test the noninferiority of IDegLira, we assumed a noninferiority margin of 0.4% for HbA_1c reduction, and the corresponding SD bounded above by 0.85%. Based on a one-sided, two-sample t test, we assumed that 57 participants per group (total 114), with an attrition rate of 15% and total of 134 (67 per group) randomized, would provide a power of 80%, with α (type 1 error) set as 0.05 to detect noninferiority (Supplementary Material, Statistical Considerations).

Results

The intention-to-treat analysis included 145 participants, with 72 participants allocated to IDegLira and 73 to the basal-bolus group, of which 56 (78%) and 58 (79%) completed the intervention up to 26 weeks, respectively (Fig. 1). Baseline demographic and clinical characteristics are shown in Table 1.

Figure 1.

Participant flow diagram.

Table 1.

Baseline demographic and clinical characteristics of study participants

	IDegLira	Basal-bolus
	n = 72	n = 73
Age, years	54.5 ± 10.1	53.8 ± 9.7
Sex
Male	28 (39)	35 (48)
Female	44 (61)	38 (52)
Race/ethnicity
Black	63 (88)	61 (84)
White	3 (4.2)	7 (9.6)
Hispanic	6 (8.3)	5 (6.8)
Weight, kg	93.1 ± 20.5	91.9 ± 19.5
BMI, kg/m2	32.4 ± 6.5	31.5 ± 6.2
Waist circumference, cm	108.7 ± 14.3	106.8 ± 14.9
Blood pressure, mmHg
Systolic	134.2 ± 18.5	134.3 ± 17.4
Diastolic	75.4 ± 11.2	78.6 ± 10.8
Diabetes duration
<20 years	62 (86.2)	64 (87.7)
>20 years	10 (13.8)	9 (12.3)
Oral antidiabetes therapy	22 (30.6)	25 (34.3)
Insulin only	10 (13.8)	12 (16.4)
Oral and insulin therapy	40 (55.6)	36 (49.3)
Insulin dose, units/kg/day	0.31 ± 0.17	0.31 ± 0.13
Laboratory testing
HbA1c, %	10.8 ± 1.4	10.7 ± 1.3
HbA1c, mmol/mol	95.0 ± 15.3	93.0 ± 14.2
Fasting blood glucose, mg/dL	234.3 ± 82.3	238.1 ± 90.6
Fasting blood glucose, mmol/L	13.0 ± 4.6	13.2 ± 5.0
Creatinine, mg/dL	0.9 ± 0.4	0.9 ± 0.3
GFR >30–60, mL/min/1.73 m2	23 (32)	26 (36)
GFR >60, mL/min/1.73 m2	49 (68)	47 (64)
Total cholesterol, mg/dL	176.0 ± 52.6	172.9 ± 47.4
Triglycerides, mg/dL	150.2 ± 85.5	150.2 ± 85.5
LDL, mg/dL	102.1 ± 43.9	94.9 ± 41.7
HDL, mg/dL	44.4 ± 9.2	46.1 ± 17.5

Data are reported as means ± SD or n (%).

GFR, glomerular filtration rate.

There was no statistically significant difference on the primary end point of HbA_1c reduction between the IDegLira and basal-bolus groups (3.18% ± 2.29 vs. 3.00% ± 1.79, P = 0.65; estimated treatment difference [ETD] 0.18%, 95% CI −0.59, 0.94) after 26 weeks (Fig. 2A).

Figure 2.

Efficacy and composite outcomes. A: HbA_1c change from baseline (week 12, and week 26). B: Change in body weight from baseline to week 26. C: Participants achieving composite outcomes: efficacy (HbA_1c) targets and safety (hypoglycemia and/or weight) targets, from baseline to week 26. *P < 0.05. Data are presented as mean ± SD, except where otherwise noted.

The IDegLira group met the prespecified safety outcome of resulting in a significantly lower hypoglycemia rate <70 mg/dL (26% vs. 48%, P = 0.008; odds ratio 0.39, 95% CI 0.19, 0.78) and decreased number of episodes (0.9 vs. 2.9 episodes, P = 0.002). Clinically significant hypoglycemia rate (<54 mg/dL) was numerically lower in IDegLira group compared with basal-bolus groups (9.7% vs. 19%, P = 0.2; odds ratio 0.45, 95% CI 0.17, 1.20) (Table 2).

Table 2.

Primary and secondary efficacy and safety outcomes

	IDegLira	Basal-bolus
Variables	n = 72	n = 73	P value
Efficacy outcomes
HbA1c change from baseline
HbA1c change at 12 weeks, %	−3.07 ± 2.17	−2.92 ± 1.58	0.66
HbA1c change at 12 weeks, mmol/mol	−33.55 ± 23.71	−31.91 ± 17.26
HbA1c change at 26 weeks, %	−3.18 ± 2.29	−3.00 ± 1.79	0.65
HbA1c change at 12 weeks, mmol/mol	−34.75 ± 25.02	−32.79 ± 19.56
Weight change from baseline, kg
Body weight change at 4 weeks	0.47 ± 7.29	1.70 ± 3.30	0.23
Body weight change at 8 weeks	0.71 ± 8.07	2.78 ± 4.23	0.10
Body weight change at 12 weeks	0.71 ± 7.50	3.76 ± 4.14	0.007
Body weight change at 20 weeks	1.13 ± 8.80	5.23 ± 5.67	0.008
Body weight change at 26 weeks	1.24 ± 8.33	5.84 ± 6.18	0.001
Safety outcomes
Hypoglycemia
Blood glucose <70 mg/dL (3.9 mmol/mol)	19 (26)	35 (48)	0.008
Blood glucose <54 mg/dL (3.0 mmol/mol)	7 (9.7)	14 (19)	0.16
Composite outcomes
HbA1c <7% without hypoglycemia at
12 weeks	21 (34)	8 (13)	0.005
26 weeks	19 (34)	6 (10)	0.003
HbA1c <7% without weight gain at	12 (20)	2 (3.2)	0.004
12 weeks
26 weeks	13 (23)	3 (5.3)	0.007
HbA1c <7% without hypoglycemia or weight gain at	10 (17)	2 (3.2)	0.015
12 weeks
26 weeks	8 (14)	1 (1.7)	0.016
Common adverse events
Nausea, weeks 1–12	26 (36)	3 (4.1)	<0.001
Nausea, weeks 1–26	27 (38)	3 (4.1)	<0.001
Vomiting, weeks 1–12	8 (11)	1 (1.4)	0.017
Vomiting, weeks 1–26	9 (13)	1 (1.4)	0.009
Abdominal pain, weeks 1–12	11 (15)	4 (5.5)	0.06
Abdominal pain, weeks 1–26	13 (18)	6 (8.2)	0.09
Diarrhea, weeks 1–12	6 (8.3)	4 (5.5)	0.53
Diarrhea, weeks 1–26	8 (11)	6 (8.2)	0.59

Data are presented as mean ± SD or cumulative n (%) of participants with one or more events during the study duration. In the basal-bolus group, the sample size for HbA_1c at 12 weeks was n = 63 and at 26 weeks was n = 58. In the IDegLira group, the sample size for HbA_1c at 12 weeks was n = 61 and at 26 weeks was n = 56. P values were obtained from the Wilcoxon test, χ² test, or Fisher exact test, when appropriate.

After 26 weeks of treatment, the basal-bolus intervention resulted in greater weight gain (5.84 ± 6.18 kg vs. 1.24 ± 8.33 kg; ETD +4.60 kg, 95% CI 1.87, 7.33, P = 0.001) compared with IDegLira. Body weight increased progressively in the basal-bolus group, while IDegLira resulted in less weight gain over the study period (Fig. 2B).

Compared with basal-bolus, IDegLira treatment was associated with greater proportion of participants achieving the prespecified composite outcome of a target HbA_1c of <7.0% (53 mmol/mol) with no hypoglycemia <70 mg/dL after 12 weeks (34% vs. 13%, P = 0.005) and after 26 weeks (34% vs. 10%, P = 0.003). IDegLira treatment was associated with greater proportion of participants achieving a target HbA_1c of <7.0% (53 mmol/mol) with no weight gain after 12 weeks (20% vs. 3.2%, P = 0.004) and after 26 weeks (23% vs. 5.3%, P = 0.007). In addition, IDegLira treatment was associated with greater proportion of participants achieving a target HbA_1c of <7.0% (53 mmol/mol) without hypoglycemia <70 mg/dL and without weight gain after 12 weeks (17% vs. 3.2%, P = 0.015) and after 26 weeks (14% vs. 1.7%, P = 0.016) (Fig. 2C and Table 2). Nine participants (12.5%) in the IDegLira group met the prespecified “treatment failure” definition, requiring an additional injection of basal insulin.

A higher proportion of participants in the IDegLira group reported nausea (38.0% vs. 4.1%, P < 0.001), vomiting (13% vs. 1.4%, P = 0.009), and abdominal pain (18% vs. 8.2%, P = 0.009) over the study duration (Table 2). Most of the gastrointestinal adverse effects were reported early in the titration period (Supplementary Fig. 3). One participant had nonproliferative retinopathy before randomization to the IDegLira group that progressed and was withdrawn from the study. Additional secondary outcomes are reported in the Supplementary Material (Supplementary Figs. 2 and 3).

Conclusions

This prospective RCT demonstrated the similar efficacy in HbA_1c reduction of IDegLira and resulted in significantly lower hypoglycemia and less weight gain compared with basal-bolus insulin therapy in patients with T2D and high HbA_1c ≥9.0–15.0% (75–140.4 mmol/mol).

Despite recent advances in pharmacology, only 60–70% of participants with T2D met personalized HbA_1c targets from 1999 to 2018 in the U.S. (16), with 13.2% having HbA_1c values >9.0% (75 mmol/mol) (17). Participants with severe hyperglycemia frequently respond poorly to oral antidiabetes agents and require insulin therapy for at least a period of time (5). As expected, we observed that insulin requirements were high during the titration phase (first 3 of months of the study) given the elevated baseline glucose value. However, IDegLira treatment resulted in a significantly higher proportion of participants achieving a target HbA_1c of <7.0% (53 mmol/mol) during the 12-week titration period. There was significantly higher weight gain with basal-bolus treatment compared with IDegLira, particularly during the first 12 weeks of insulin titration, and less weight gain with IDegLira at the end of the study (26 weeks). These findings are of contemporary interest given a recent paradigm change in the management of participants with T2D to a more patient-centered approach, favoring therapeutic options associated with weight neutral or weight loss effect (18).

Our study challenges the current widespread practice of basal-bolus insulin therapy as the most effective option for glycemic control in participants with T2D and severe hyperglycemia (i.e., HbA_1c >10%, 86 mmol/mol), who are usually excluded from clinical trials, and suggests that combination therapy with basal insulin and GLP1-RA, in an FRC daily injection, results in better patient-centered outcomes. Previous studies have demonstrated that a combination of basal insulin and GLP1-RA have similar efficacy in lowering HbA_1c, with benefits on hypoglycemia and weight gain (15), but excluded this population with severe hyperglycemia and HbA_1c ≥9.0–15.0% (75–140.4 mmol/mol) (19,20). Ongoing st-udies assessing the efficacy and safety of the combination of weekly insulin and GLP1-RA, in FRC or alone, or more potent weekly GLP1-RA or dual/triple agonists alone, may provide another alternative for patients with poorly controlled T2D. However, these studies usually do not include patients with very high HbA_1c and will take years to be completed. Our study was designed to clarify the clinical need for better therapeutic strategies that will allow glycemic targets to improve and also patient-centered outcomes in participants with severe hyperglycemia and HbA_1c >9.0–15.0% (75–140.4 mmol/mol), despite the failure of oral antidiabetes agents and/or basal insulin. Our approach in a real-word diabetes clinic and serving underserved populations demonstrated the benefits of a simpler treatment (daily FRC injection) and underscores the complexity and burden of the basal-bolus regimen. Notably, our participants are highly representative of racial minorities who are usually disproportionally affected by higher rates of complications.

Despite being efficacious and widely implemented, basal-bolus insulin therapy is a complex and burdensome regimen for participants, requiring insulin multiple daily injections, multiple glucose checks per day, and ongoing diabetes education. Furthermore, it is associated with increased risk of hypoglycemia, poor adherence, and weight gain (15). Our study demonstrated similar efficacy on glycemic improvement, but lower hypoglycemia rates and less weight gain, with more participants achieving glycemic targets (e.g., HbA_1c <7%, 53 mmol/mol) without hypoglycemia and without weight gain. In accordance with prior studies (15,19), a higher proportion of participants in the IDegLira group reported gastrointestinal adverse events. We acknowledge that ∼20% of participants did not finish all visits, mostly occurring during the coronavirus disease 2019 pandemic and in concordance with prior studies (19).

In conclusion, we demonstrated that a simpler and more physiologic treatment approach, with a single daily injection of basal insulin and liraglutide, compared with the traditional approach of basal-bolus insulin, was not inferior in achieving glycemic control in participants with T2D and severe hyperglycemia (HbA_1c >9.0–15.0%, 75–140.4 mmol/mol). This simpler regimen resulted in less hypoglycemia and less weight gain. Our study supports a paradigm change from the widely use basal-bolus approach to a simpler regimen with basal insulin and GLP1-RA as a more patient-centered option for participants with severe hyperglycemia and HbA_1c >9.0–10.0% (75–86 mmol/mol).