Evaluation of Insulin and Glucagon-like peptide-1 Receptor Agonists Combination for Type 2 Diabetes Mellitus: An Updated Meta-analysis

Introduction

Type 2 diabetes mellitus (T2DM) is a chronic, progressive disorder that causes long-term vascular consequences and death globally. Per the International Diabetes Federation’s most recent estimates, 463 million individuals had diabetes in 2019, with the figure expected to climb to 700 million by 2045. 1–3

Because of the natural history of diabetes and the steady loss in β-cell activity, insulin often becomes necessary. Nevertheless, insulin therapy is hampered by challenging factors such as hypoglycemia risk, weight gain, and the complexities of injectable therapy. 4 Approximately 25% of T2DM patients are now on insulin. 5,6 However, about one-half of T2DM patients who take insulin achieve optimal control of diabetes, and the number of individuals with HbA1c of 9% or more is rapidly rising. 5,7 A recent consensus report documented that intensification approaches should be customized based on the patient factors (such as glycated haemoglobin (HbA1c) and fasting plasma glucose (FPG) levels). 8

Glucagon-like peptide-1 receptor agonists (GLP-1RA) boost glucose-stimulated insulin secretion, inhibit glucagon production, enhance satiety, reduce food intake, improve insulin sensitivity, and reduce deposition of visceral fat. 9 GLP1RA lowers HbA1c by up to 1.8% and has a minimal hypoglycemia risk while also lowering weight, blood pressure, and lipid profile. 10

Basal insulins combined with GLP-1RA are an efficient therapeutic choice for T2DM patients who require insulin therapy intensification. Insulin degludec (IDeg) combined with liraglutide [IDegLira], as well as insulin glargine (IGlar) combined with lixisenatide [iGlarLixi], are two combination medications (fixed-ratio combo) with set dosages of long-acting insulins and GLP-1RA, which are now authorized. 8

In the DUAL studies, IDegLira improved glycemic control alongside bodyweight benefits and equivalent or reduced rates of hypoglycemic episodes compared to basal insulin, as well as a decreased risk of gastrointestinal side effects compared to GLP-1RAs alone.^11–15 Previous literature has mentioned that iGlarLixi might offer reasonable glycemic control rather than administering the two medications separately. The fixed-ratio combination’s better efficacy is due to the complementary nature of the combined medications, the ease of administration and titration, and the decrease in adverse effects. 16,17

We conducted the current meta-analysis of randomized controlled trials (RCTs) published until December 2021 that compared combination therapy with other injectable therapies in T2DM patients.

Methods

This systematic review and meta-analysis has been conducted in accordance with the guidelines outlined in the "preferred reporting items for systematic review and meta-analysis (PRISMA) statement”. 18

Literature search strategy

We searched PubMed, Scopus, EBSCO, and Web of Science using a search strategy including the following search terms: “biphasic insulin regimen,” “premixed insulin,” “basal plus insulin regimen,” “basal-bolus insulin regimen,” “glargine,” “degludec,” “detemir,” “aspart,” “glulisine,” “lispro,” “glucagon-like peptide-1 receptor agonist”, “GLP-1 receptor agonist”, “GLP-1RA”, “exenatide,” “exenatide LAR,” “ liraglutide,” “ lixisenatide,” “ dulaglutide,” “ semaglutide,” “ albiglutide,” “ IDegLira,” and“ IGlarLixi” through December 2021.

Study eligibility

Inclusion criteria

We included the RCTs satisfying the following criteria:

Population: adults with type 2 diabetes mellitus

Intervention and comparison: a combination of GLP-1RA and insulin (whether fixed ratio or free combination) or GLP-1RA added to background insulin therapy compared with other injectable therapies, including placebo/insulin intensification (insulin up-titration)/GLP-1RA; or basal-plus/basal-bolus therapies.

Outcomes: HbA1c (%) change, the proportion of patients achieving HbA1c <7% at the study end, the incidence of blood glucose-confirmed symptomatic hypoglycemia, and weight change

Exclusion criteria

We excluded non-RCTs, reviews with no original data, studies with insufficient data, case reports, case series, letters to the editor, as well as studies on patients other than T2DM.

Study selection

Initially, the titles and abstracts of the retrieved records were assessed to determine whether they met the eligibility criteria, after which the full text of potentially relevant records was examined to further assess their eligibility. We searched for RCTs that looked at GLP-1RA and insulin combination compared with other injectable therapies in adults with T2DM in terms of the HbA1c (%) change, the proportion of patients achieving HbA1c <7% at the study end, the incidence of blood glucose-confirmed symptomatic hypoglycemia, and weight change.

Data extraction

We extracted the following data for all of the included studies

1. Demographic data

Study ID with the year of publication, design of the study, duration of the study (weeks), studied arms, the total number of the included patients in each group, mean age (years), as well as baseline levels of HbA1c, and the primary outcome.

1. Study outcomes

For each study arm, we retrieved data about HbA1c, and weight change as well as the incidence of hypoglycemias (safety).

Risk of bias assessment

To assess the quality of the RCTs included in the study, the Cochrane risk of bias assessment tool was utilized. This tool evaluates various aspects of the RCTs, including sequence generation, allocation concealment, blinding of patients and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, and other factors that could potentially introduce bias into the study. There are three levels of potential bias assigned to the decision: low, high, and unclear.

Statistical analysis

Data analysis was performed using SPSS version 28.0 software for Windows. The effect size of continuous data was obtained according to Tierney et al. 19 and was pooled using weighted mean difference (WMD). Dichotomous data were pooled as a risk ratio (RR) using a random-effects model. According to Cochrane Handbook recommendations, heterogeneity was inspected visually and statistically through Chi-square and I^2 tests, and P<0.1 was designated as a level of significant heterogeneity. Upon detecting significant heterogeneity, we employed further sensitivity analyses to determine the source of heterogeneity by excluding one study at a time. Furthermore, we employed a comparison-adjusted funnel plot for each outcome, which displayed asymmetries for all interventions with a significant Egger’s test revealing a small-study effect. The funnel plot is a scatter diagram showing the distribution of studies, precision, and outcome measures. A single direct comparison is shown by each dot. Idealized dispersion owing to sample variance should resemble a pyramid or an inverted funnel on the plot. An asymmetrical funnel plot means publication/reporting bias, poor methodological design, or heterogeneity.

Results

The search strategy retrieved 3100 unique records; of them, 2995 records were excluded after title/abstract screening, while the remaining 105 records were sought for retrieval. Thus, 48 studies 11,12,14–17,20–61 were included in the present study, Supplementary Figure 1. The summary characteristics of the included studies are shown in Table 1 (a and b). Supplementary Table 1 displays the outcomes of the assessment of the risk of bias.

Table 1 (a) presents the summary characteristics of the included double-blind randomized clinical trials.
Author, year (trial name)	Study duration (week)	Study arms	Number of patients	Mean age (SD) (year)	Baseline HbA1c (SD) (%)	Primary outcome
Pei et al. 2021 (DUAL II China) 21	26	IDegLira	302	54.5 (9.8)	8.93 (1.20)	HbA1c change from baseline after 26 weeks of treatment
Degludec	151	55.3 (10.0)	8.96 (1.17)
Watada et al. 2019 25	26	Insulin degludec/liraglutide (IDegLira)	105	56.6 (10.4)	8.61 (0.88)	Change from baseline in HbA1c after 26 weeks of treatment
Insulin degludec (degludec)	105	55.5 (10.0)	8.56 (0.80)
Buse et al, 2011 26	30	Exenatide 10 μg BID	138	59 (9)	8.3 (0.8)	HbA1c levels at week 30
Placebo	123	59 (10)	8.5 (0.9)
Seino et al, 2012 (Get-Goal-L-Asia) 29	24	Lixisenatide 20 μg	154	58.7 (10.2)	8.5 (0.7)	Change in HbA1c to week 24
Placebo	157	58.0 (10.1)	8.5 (0.8)
Riddle et al, 2013 (Get-Goal-L) 30	24	Lixisenatide 20 μg	328	57 (10)	8.4 (0.9)	Change in HbA1c to week 24
Placebo	167	57 (10)	8.4 (0.8)
Riddle et al, 2013 (GetGoal-Duo 1) 31	24	Lixisenatide 20 μg	223	56 (10)	7.6 (0.5)	Change in HbA1c to week 24
Placebo	223	56 (10)	7.6 (0.5)
Buse et al, 2014 (DUAL II) 12	26	IDegLira + Metformin	207	57 (9)	8.7 (0.7)	Change in HbA1c to week 26
Degludec + Metformin titration	206	58 (11)	8.8 (0.7)
Ahmann et al, 2015 (LIRA-ADD2BASAL) 34	26	Liraglutide 1.8 mg	226	59.3 (9.2)	8.2 (0.8)	Change in HbA1c to week 26
Placebo	225	57.5 (11.1)	8.3 (0.9)
Lind et al, 2015 (MDI Liraglutide trial) 35	24	Liraglutide 1.8 mg	64	63.8 (8.2)	9.0 (1.0)	Change in HbA1c to week 24
Placebo	60	63.5 (7.7)	9.0 (1.1)
Aroda et al, 2016 (BEGIN:ADD TO GLP-1 Study) 36	26	Degludec	174	57 (10)	7.6 (0.6)	Change in HbA1c to week 26
Placebo	172	57.3 (9.4)	7.6 (0.6)
Seino et al, 2016 38	36	Liraglutide 0.9 mg	127	61.3 (11)	8.8 (0.9)	Change in HbA1c to week 16
Placebo	130	59.8 (11.3)	8.8 (0.9)
Vanderheiden et al, 2016 39	24	Liraglutide 1.8 mg	35	52.8 (8.1)	9.0 (1.2)	Change in HbA1c to week 24
Placebo	36	55.5 (6.6)	8.9 (1.0)
Pozzilli et al, 2017 (AWARD-9) 41	28	Dulaglutide 1.5 mg	150	60.2 (9.5)	8.4 (0.9)	Change in HbA1c to week 28
Placebo	150	60.6 (10.1)	8.3 (0.8)
Guja et al, 2018 (DURATION-7) 42	28	Exenatide LAR 2 mg	231	57.8 (9)	8.5 (0.9)	Change in HbA1c to week 28
Placebo	230	57.6 (10.3)	8.5 (0.9)
Rodbard et al, 2018 (SUSTAIN-5) 43	30	Semaglutide 0.5 mg	132	59.1	8.4	Change in HbA1c to week 30
Semaglutide 1 mg	131	58.5	8.3
Placebo	133	58.8	8.4
Yang et al, 2018 (GetGoal-L-C) 44	24	Lixisenatide 20 μg	224	53.9 (9.9)	7.9 (0.6)	Change in HbA1c to week 24
Placebo	224	56.2 (9.1)	7.9 (0.7)

Table 1 (b) presents the summary characteristics of the included open-label trials.
Author, year (trial name)	Study duration (week)	Study arms	Number of patients	Mean age (SD) (year)	Baseline HbA1c (SD) (%)	Primary outcome
Abrue et al. 2019 (SIMPLE Study) 57	24	Basal Insulin + GLP1RA Group	59	46.7 (9.0)	12.1 (1.4)	Change in HbA1c; changes in weight, insulin dose, hypoglycemia
Basal-Bolus Insulin Group	61	48.1 (10.0)	12.0 (1.5)
Aroda et al. 2019 (DUAL VIII) 58	104	Insulin degludec plus liraglutide (IDegLira)	506	56.8 (10.0)	8.4% (1.0)	Time from randomization to need for treatment intensification
Insulin glargine 100 units/Ml (IGlar U100)	506	56.4 (10.1)	8.6% (1.0)
Aso et al. 2020 59	52	Insulin degludec/insulin aspart (IDegAsp)	28	68.8 (8.9)	8.2 (0.9)	HbA1c changes over 52 weeks of treatment, and the percentage of participants achieving HbA1c<7.0% at week 52
Basal insulin degludec and liraglutide (IDeg+Lira)	24	6 8.0 (10.4)	7.9 (0.6)
Billings et al. 2020 (DUAL VII) 60	26	Insulin Degludec/Liraglutide (IDegLira)	238	<65= 170 of 238 & ≥65= 68 of 238	Change in HbA1c from baseline to week 26
Basal-Bolus Insulin Group	233	<65= 184 of 233 & ≥65= 48 of 233
Giugliano et al. 2021 (BEYOND) 61	24	Intensification of the basal-bolus insulin (BBI) regimen	101	62.1 ± 10.2	8.5 (1.1)	Change from baseline in HbA1c at 6 months
A fixed ratio of basal insulin plus GLP-1RA (fixed-combo group)	102	62.6 ± 9.6	8.5 (1.0)
Kaku et al. 2019 20	52	Insulin degludec/liraglutide (IDegLira)	275	56.9 (10.2)	8.5 (1.1)	Change from baseline in HbA1c after 52 weeks of treatment
Degludec	271	57.8 (9.9)	8.5 (1.1)
Liraglutide 1.8	273	56.8 (10.1)	8.3 (1.0)
Philis-Tsimikas 2019 (DUAL IX) 15	26	Insulin Degludec/Liraglutide (IDegLira)	210	56.1 (10.4)	8.2 (0.9)	Change in HbA1c from baseline to week 26
Insulin Glargine U100	210	57.2 (10.2)	8.4 (1.1)
Rosenstock et al. 2020 22	26	Albiglutide + glargine	402	58.0 (9.4)	7.7 (0.6)	Change from baseline in HbA1c at 26 weeks
Lispro + glargine	412	58.1 (9.5)	7.7 (0.6)
Terauchi et al. 2020 23	26	Insulin glargine/lixisenatide fixed-ratio combination (iGlarLixi)	260	59.2 (11.0)	8.08 (0.50)	Change in HbA1c from baseline to week 26.
Insulin glargine U100 (iGlar)	261	60.2 (10.3)	8.01 (0.45)
Wang et al. 2020 24	24	Exenatide twice daily plus insulin glargine (intervention group)	46	55.9 (8.9)	9.1 (1.4)	Urinary albumin excretion rate percentage change from the baseline after 24 weeks of intervention
Insulin lispro plus glargine (control group)	46	55.9 (8.9)	9.0 (1.3)
DeVries et al, 2012 27	26	Detemir	162	56.8 (9.4)	7.6 (0.6)	Change in HbA1c to week 26
Continuing metformin + liraglutide 1.8 mg	161	57.3 (9.8)	7.6 (0.7)
Li et al, 2012 28	12	Liraglutide 1.2 mg	42	51.2 (10.5)	8.8 (0.8)	HbA1c levels at week 12
Insulin up-titration	42	52.7 (10.8)	8.7 (0.9)
de Wit et al, 2014 (ELEGANT) 32	26	Liraglutide 1.8 mg	26	57 (10)	7.2 (0.6)	Change in body weight to week 26
Intensification of insulin therapy	24	59 (8)	7.5 (0.7)
Gough et, al 2014 (DUAL-I) 11	26	IDegLira	834	55.1 (9.9)	8.3 (0.9)	Change in HbA1c to week 26
Degludec Titration	414	54.9 (9.7)	8.3 (1.0)
Liraglutide 1.8 mg	415	55.0 (10.2)	8.3 (0.9)
Lane et al, 2014 33	24	Liraglutide 1.8 mg	21	59 (11.8)	7.8 (0.6)	HbA1c at week 24
Insulin up-titration	16	60.8 (9.7)	7.8 (0.7)
Aroda et al, 2016 (LixiLan-L) 16	30	IGlarLixi	367	59.6 (9.4)	8.1 (0.7)	Change in HbA1c to week 30
Glargine titration	369	60.3 (8.7)	8.1 (0.7)
Lingvay et al, 2016 (DUAL V) 14	26	IDegLira	278	58.4 (9.8)	8.4 (0.9)	Change in HbA1c to week 26
Glargine titration	279	59.1 (9.3)	8.2 (0.9)
Rosenstock et al, 2016 (Lixilan PoC) 37	24	IGlarLixi	161	56.9 (9.5)	8.1 (0.8)	Change in HbA1c to week 24
Glargine titration	162	56.6 (9.4)	8.0 (0.8)
Rosenstock et al, 2016 (LixiLan-O) 17	30	IGlarLixi	469	58.2 (9.5)	8.1 (0.7)	Change in HbA1c to week 30
Glargine titration	467	58.3 (9.4)	8.1 (0.7)
Lixisenatide 20 μg	234	58.7 (8.7)	8.1 (0.7)
Linjawi et al, 2017 (DUAL III) 40	26	IDegLira	292	58.3 (9.9)	7.8 (0.6)	Change in HbA1c to week 26
Liraglutide or Exenatide at their pre-trial dose	146	58.4 (8.8)	7.7 (0.6)
Diamant et al, 2014 (4B Study) 45	30	Exenatide 10 μg BID	315	59.8 (9.5)	8.3 (1.0)	Change in HbA1c to week 30
Lispro thrice daily	312	57.4 (8.9)	8.2 (0.9)
Mathieau et al, 2014 (BEGIN: VICTOZA ADD-ON) 46	26	Liraglutide 1.8 mg	88	61.1 (9.5)	7.7 (0.6)	Change in HbA1c to week 26
Aspart at largest meal	89	60.9 (8.8)	7.7 (0.8)
Rosenstock et al, 2014 (Harmony 6) 47	26	Albiglutide 30 mg	282	54.8 (9.1)	8.5 (0.9)	Change in HbA1c to week 26
Lispro thrice daily	281	56.3 (8.9)	8.4 (0.9)
Shao et al, 2014 48	12	Exenatide 10 μg BID	30	43 (4.1)	7.6 (0.6)	HbA1c at week 12
Aspart thrice daily	30	42 (3.2)	7.7 (0.6)
Blonde et al, 2015 (AWARD-4) 49	52	Dulaglutide 1.5 mg	295	58.9 (9.6)	8.5 (1.1)	Change in HbA1c to week 26
Dulaglutide 0.75 mg	293	59.3 (9.0)	8.4 (1.0)
Glargine titration	296	59.9 (9.1)	8.5 (1.0)
FLAT-SUGAR investigators, 2016 50	26	Exenatide 5-10 μg	52	62	7.9 (0.3)	Change in glucose coefficients of variation to week 26
Short-acting insulin analogs thrice daily	50	62	7.9 (0.3)
Rosenstock et al, 2016 (GetGoal Duo-2) 51	26	Lixisenatide 20 μg	298	59.8 (8.6)	7.8 (0.6)	Change in HbA1c to week 26
Glulisine once daily	298	60.2 (8.6)	7.7 (0.6)
Glulisine thrice daily	298	59.4 (9.5)	7.8 (0.6)
Tonneijck et al, 2017 52	8	Lixisenatide 20 μg	17	62 (7)	8.3 (0.2)	Change in Glomerular filtration rate and effective renal plasma flow to week 8
Glulisine once daily	18	61 (7)	7.8 (0.2)
Billings et al, 2018 (DUAL VII) 53	32	IDegLira	25,2	58.6 (9.0)	8.2 (0.8)	Change in HbA1c to week 26
Glargine and Insulin Aspart four or fewer times daily	254	58.0 (8.6)	8.2 (0.8)
Miya et al, 2018 54	12	Lixisenatide 20 μg plus insulin glargine	11	66 (8.4)	7.1 (0.5)	Change in the Diabetes Treatment Satisfaction Questionnaire scores to week 12
Continuing Multiple daily injections of insulin	15	59.6 (12.8)	7.2 (0.9)
Tuttle et al, 2018 (AWARD-7) 55	52	Dulaglutide 1.5 mg	192	64.7 (8.8)	8.6 (0.9)	HbA1c at 26 weeks
Dulaglutide 0.75 mg	190	64.7 (8.6)	8.6 (1.1)
Glargine titration	194	64.3 (8.4)	8.6 (1.0)
Yamamoto et al, 2018 56	24	Liraglutide 0.9 mg and basal insulin	13	60.0 (7.8)	7.3 (1.2)	Change in HbA1c to week 24
Continuing basal bolus insulin therapy	12	61.5 (10.6)	6.9 (0.8)

Meta-analysis characteristics

Different intervention groups were analyzed as follows: the combination between basal insulin and GLP-1RA (fixed-ratio or free combination), basal-plus/basal-bolus, and placebo/insulin intensification (insulin up-titration)/GLP-1RA.

The Change in HbA1c (%)

Thirty-three studies reported reliable data for the comparison of the change in HbA1c level between combination therapy and placebo/insulin intensification (insulin up-titration)/GLP-1RA. The mean change from baseline in the HbA1c was significantly higher in the combination arm than in the control arm (WMD -0.693, 95% CI -0.818 to -0.567; p <0.001). The pooled analysis was substantially heterogeneous (I2 =93%; Figure 1A). Heterogeneity was not resolved after further sensitivity analysis. The trim-and-fill analysis of publication bias imputed 33 missing studies for this comparison, donating significant publication bias (p <0.001), confirmed by an asymmetrical funnel plot (Supp. Figure 2A).

On the other hand, 20 studies compared the change in HbA1c level between combination therapy and basal-plus/basal-bolus. Again, the pooled analysis favoured the combination regimen (WMD -0.105, 95% CI -0.199 to -0.012; p =0.027), with substantial heterogeneity (I2 =79%; Figure 1B) that could not be resolved by further sensitivity analysis. The trim-and-fill analysis of publication bias imputed 20 missing studies for this comparison, donating significant publication bias, confirmed by an asymmetrical funnel plot (Supp. Figure 2B).

The proportion of patients achieving the targeted HbA1c (%)

The pooled analysis of the 33 studies reported comparing the proportion of patients achieving the targeted HbA1c between combination therapy and placebo/insulin intensification (insulin up-titration)/GLP-1RA showed that patients on combination therapy had a higher chance of achieving the HbA1c target (RR 1.964, 95% CI 1.708 to 2.22; p <0.001). The pooled analysis was substantially heterogeneous (I2 =93%; Figure 2A). Heterogeneity was not resolved after further sensitivity analysis. The trim-and-fill analysis of publication bias imputed 43 missing studies for this comparison donating significant publication bias (p <0.001), confirmed by an asymmetrical funnel plot (Supp. Figure 3A)

On the contrary, the 15 studies comparing combination therapy and basal-plus/basal-bolus showed no significant difference (RR 1.037, 95% CI 0.971 to 1.103), with no significant heterogeneity (I2 =12%; Figure 2B) that could not be resolved by further sensitivity analysis. The trim-and-fill analysis of publication bias imputed 21 missing studies for this comparison, donating significant publication bias, confirmed by an asymmetrical funnel plot (Supp. Figure 3B).

The change in body weight (Kg)

Thirty-one compared the change in body weight between combination therapy and placebo/insulin intensification (insulin up-titration)/GLP-1RA. The mean reduction from baseline in body weight was significantly higher in the combination arm than in the control arm (WMD -1.894, 95% CI -2.697 to -1.091; p <0.001). The pooled analysis was substantially heterogeneous (I2 =98%; Figure 3A). Heterogeneity was not resolved after further sensitivity analysis. The trim-and-fill analysis of publication bias imputed 31 missing studies for this comparison, donating significant publication bias (p <0.001), confirmed by an asymmetrical funnel plot (Supp. Figure 4A).

On the other hand, 20 studies compared the change in body weight between combination therapy and basal-plus/basal-bolus. Again, the pooled analysis favoured the combination regimen (WMD -3.6, 95% CI -4.435 to -2.766; p =0.001), with substantial heterogeneity (I2 =94%; Figure 3B) that could not be resolved by further sensitivity analysis. The trim-and-fill analysis of publication bias imputed 20 missing studies for this comparison, donating significant publication bias, confirmed by an asymmetrical funnel plot (Supp. Figure 4B).

The incidence of hypoglycemia

The pooled analysis of the 32 studies comparing the proportion of patients with confirmed hypoglycemia between combination therapy and placebo/insulin intensification (insulin up-titration)/GLP-1RA showed comparable rates (RR 0.94, 95% 0.84 - 1.04). The pooled analysis was substantially heterogeneous (I2 =75%; Figure 4A). Heterogeneity was not resolved after further sensitivity analysis. The trim-and-fill analysis of publication bias imputed eight missing studies for this comparison, donating significant publication bias (p <0.001), confirmed by an asymmetrical funnel plot (Supp. Figure 5A).

On the contrary, the 13 studies comparing combination therapy and basal-plus/basal-bolus showed a statistically significant difference (RR 0.63, 95% CI 0.51 - 0.74; p <0.001), with no significant heterogeneity (I2 =76%; Figure 4B) that could not be resolved by further sensitivity analysis. The trim-and-fill analysis of publication bias no imputed missing studies for this comparison donating no significant publication bias, confirmed by a symmetrical funnel plot (Supp. Figure 5B).

Discussion

Given the progressive nature of T2DM, many patients require insulin to attain their desired glycemia. Since 2019, when injectable therapy is necessary, the American Diabetes Association has advised GLP-1RA before basal insulin. 62 A basal insulin single injection is a standard way to begin insulin therapy, gradually increasing to maximize therapy. Adding premeal rapid-acting insulin analogues to the continuing dose of basal insulin or switching to a premixed insulin regimen with a predetermined dosage of “intermediate-acting: and “short- or rapid-acting” insulin are two ways to increase insulin therapy to reach glycaemic goals. Even though these regimens of intensified insulin results in the same drop in HbA1c, 63,64 people are often reluctant to intensify insulin therapy because of possible side effects like the risk of hypoglycemia and gaining weight, as well as practical issues such as patients’ anxiety regarding insulin and difficulties in teaching patients of injections. Thus, combining GLP-1RA with insulin may give a unique and effective treatment alternative for improving glycemic control while reducing the risks of insulin intensification.

Summary of main findings

The current updated systematic review and meta-analysis of RCTs aimed to compare the combination therapy with other injectable therapies in T2DM patients. Compared to placebo/insulin intensification (insulin up-titration)/GLP-1RA alone, the combination resulted in a higher decline in HbA1c levels, with more patients reaching the HbA1c target of 7%, weight loss, and a comparable risk of hypoglycemia. Moreover, the combination led to a higher decline in HbA1c, weight loss, lower risk of hypoglycemia, and a comparable proportion of patients reaching the HbA1c target of 7%. A previous meta-analysis published in 2019 showed that compared to placebo, insulin up-titration, or GLP-RA alone, the combination resulted in a larger HbA1c reduction, with more patients reaching the HbA1c goal of 7%, a higher risk of hypoglycemia, and weight loss, and was as effective as insulin regimens, with less hypoglycemia and weight loss. 65

In the currently updated meta-analysis, in terms of change in HbA1c (%), the combination therapy of insulin and GLP-1RA significantly reduced HbA1c (%) than the placebo/insulin intensification (insulin up-titration)/GLP-1RA arm (WMD -0.693, p <0.001) and basal-plus/basal-bolus arm (WMD -0.105, p =0.027). The combination therapy of insulin and GLP-1RA significantly reduced body weight than the placebo/insulin intensification (insulin up-titration)/GLP-1RA arm (WMD -1.894, p <0.001) and basal-plus/basal-bolus arm (WMD -3.6, p =0.001). Patients on combination therapy of insulin and GLP-1RA had a higher chance of achieving the HbA1c target than placebo/insulin intensification (insulin up-titration)/GLP1 RA arm (RR 1.964, p <0.001), but not than basal-plus/basal-bolus arm (RR 1.037, 95% CI 0.971 to 1.103). Regarding the proportion of patients with confirmed hypoglycemia, comparable rates were observed when compared between combination therapy and placebo/insulin intensification (insulin up-titration)/GLP-1RA (RR 0.94, 95% 0.84 - 1.04); however, it was statistically significant when compared combination therapy and basal-plus/basal-bolus (RR 0.63, p <0.001).

Comparison with previous studies and the significance of the study findings

HbA1c and body weight decreased by 0.44% and 3.22 kg in a meta-analysis of 15 RCTs that compared GLP-1RA plus basal insulin with other antidiabetic drugs without increasing hypoglycemia risk. 66 GLP-1RA and basal insulin, when used together, had comparable effects on decreasing HbA1c as the basal-bolus insulin regimen, with a 33% reduced risk of hypoglycemia and 5.66 kg less weight gain. 66 Based on data from 26 RCTs, Maiorino and colleagues found that basal insulin combined with GLP-1RA was more effective than other injectable antidiabetics in treating T2DM. Compared to other injectable treatments, GLP-1RA with basal insulin reduced HbA1c by 0.47% greater, resulting in 1.65-fold higher proportions of patients meeting the 7.0% HbA1c criteria. While HbA1c reduction was not more remarkable with the combination treatment than basal-bolus insulin regimens, it showed a 34% reduced risk of hypoglycemia and 4.7 kg more weight loss. 67

The short-acting GLP-1RA agents primarily affect postprandial glucose due to their capacity to decrease stomach emptying, which is closely associated with the activation of the GLP-1 receptor. Long-acting GLP-1RA agents, on the other hand, have a more prominent insulinotropic action, providing glycemic control by lowering fasting glucose and, as a result, hyperglycemia throughout the day. 68 The most common combination treatment regimen consists of basal insulin combined with a short-acting GLP-1RA or once-daily liraglutide, either as a separate ingredient preparation or a fixed ratio combination. Other new treatment plans include using a GLP-1RA injection once a week in addition to a single injection of a long-acting insulin analogue or numerous injections of a short-acting insulin analogue prior to meals. 49,52 When basal insulin fails to meet the fasting glucose goal, and improvements in fasting and postprandial glucose are needed, long-acting GLP1 RAs may be especially beneficial. One of the benefits of using GLP-1RAs once weekly is that additional daily injections beyond basal insulin are avoided. Type 2 diabetics who need to increase their insulin doses but do not want to increase their daily injections might benefit from adding a once-weekly GLP-1RA to meal-time insulin.^49,55

A meta-analysis showed no significant differences in HbA1c change, the achievement of goal HbA1c, hypoglycemia risk, or bodyweight change when comparing each combination treatment method with the up-titration of basal insulin. 69 Moreover, in a real-world study, the decrease in HbA1c levels between free up-titration and the fixed-ratio combination was about the same. The free-up-titration group, on the other hand, used fewer insulin doses at the end of the study and lost more weight. In this investigation, the risk of hypoglycemia was not assessed. 70 A recently published article 71 showed that the efficiency of glycemic control was equivalent between free up-titration and fixed-ratio combination, which supports prior research that compared the two approaches. 69,70

Strength points and limitations

This updated meta-analysis has many strength points. We conducted this meta-analysis in strict adherence to the PRISMA checklist, and we only included RCTs. We compared the combination therapy with (a) placebo/insulin intensification (insulin up-titration)/GLP-1RA and (b) basal-plus/basal-bolus. We included a considerable number of the included studies through the end of 2021.

However, A few caveats must be taken into account, as well. The findings’ generalizability may be limited due to the heterogeneity among the included studies and evidence of publication bias. Inherent characteristics of the studies included in this meta-analysis, such as patient characteristics, comparator medications, GLP-1RA doses, background treatment, and trial design, may explain the significant degree of heterogeneity. In addition, most studies were funded by industry, had short durations, and employed open-label designs to evaluate the long-term effects of the combination. To further understand the long-term effects, tolerance, and development of diabetic complications, more research is warranted.

Conclusion

Overall, our findings support the use of GLP-1RA in combination with insulin as a useful intensification approach for producing therapeutic improvement in type 2 diabetes therapy for individuals who have not reached their HbA1c goal. Compared to placebo insulin intensification (insulin up-titration)/GLP-1RA alone, the combination resulted in a higher decline in HbA1c levels, with more patients reaching the HbA1c target of 7%, weight loss, and a comparable risk of hypoglycemia. Moreover, the combination led to a higher decline in HbA1c, weight loss, lower risk of hypoglycemia, and a comparable proportion of patients reaching the HbA1c target of 7%.

Acknowledgement

Not applicable

Author’s contributions

Dr. RA. was involved in study conceptualization, design, developing search strategy, data extraction, data analysis, and manuscript writing.

Dr. KKA is involved in data extraction and manuscript writing.

Dr. ASH is involved in manuscript writing and editorial support.

PROSPERO registry number

NA

Key PointsGLP-1RA has multiple benefits in patients with T2DM, including improved insulin secretion, reduced food intake, and weight loss.This study aimed to compare the efficacy of GLP-1RA with other injectable therapies in patients with T2DM.Insulin and GLP-1RA combination therapy was found to be more effective in reducing HbA1c and body weight compared to placebo/insulin intensification (insulin up-titration)/GLP-1RA and basal-plus/basal-bolus therapies.Patients on insulin and GLP-1RA combination therapy had a higher chance of achieving the HbA1c target than those on placebo/insulin intensification (insulin up-titration)/GLP-1RA therapy.GLP-1RA in combination with insulin is a useful intensification approach for therapeutic improvement in T2DM therapy.

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FIGURES’ Legends

Figure 1: (a) forest plot of the pooled estimate for the comparison of the change in HbA1c level (%) between combination therapy and placebo/insulin intensification (insulin up-titration)/GLP-1RA, (b) forest plot of the pooled estimate for the comparison of the change in HbA1c level (%) between combination therapy and basal-plus/basal-bolus.

Figure 2: (a) forest plot of the proportion of patients achieving the targeted HbA1c between combination therapy and placebo/insulin intensification (insulin up-titration)/GLP-1RA, (b) forest plot of the proportion of patients achieving the targeted HbA1c between combination therapy and basal-plus/basal-bolus.

Figure 3: (a) forest plot of the pooled estimate for the change in body weight between combination therapy and placebo/insulin intensification (insulin up-titration)/GLP-1RA, (b) forest plot of the pooled estimate for the change in body weight between combination therapy and basal-plus/basal-bolus.

Figure 4: (a) forest plot of the pooled estimate for the incidence of hypoglycaemia between combination therapy and placebo/insulin intensification (insulin up-titration)/GLP-1RA, (b) forest plot of the pooled estimate for the incidence of hypoglycaemia between combination therapy and basal-plus/basal-bolus.