Direct Comparison Two Fixed-ratio Combination Glucagon-like Peptide Receptor Agonist and Basal Insulin on Glycemic and Non Glycemic Parameters in Type 2 Diabetes

doi:10.21203/rs.3.rs-1592081/v2

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Direct Comparison Two Fixed-ratio Combination Glucagon-like Peptide Receptor Agonist and Basal Insulin on Glycemic and Non Glycemic Parameters in Type 2 Diabetes

https://doi.org/10.21203/rs.3.rs-1592081/v2

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Journal Publication

published 01 Feb, 2023

Read the published version in BMC Endocrine Disorders →

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Background.

Two types of fixed-ratio combinations of basal insulin and a glucagon-like protein-1 receptor agonist (GLP-1RA) have been approved for use in type 2 diabetes. One is insulin degludec/liraglutide(iDergLira), and the other is insulin glargine/lixisenatide (iGlarLixi). Direct comparisons between these two combination is not available.

Methods.

The retrospective study included 186 patients with type 2 DM with inadequate glycemic control on metformin and basal insulin (degludec, glargin 100, glargin 300) who were switched fixed-ratio combination GLP-1 RA and basal insulin.Patients were divided into two groups based on the basal insulin before study: group I ( n = 86) treated with degludec were switched to iDegLira and patients group II ( n = 99), 48 treated with glargin were switched to iGlarLixi. The aim of this study was to direct compare the effect between two fixed – ratio combination on glycemic parameters and non glycemic parameters. Follow up was 6 months.

Results

. Mean HbA1c decreased similarly (-1.2% vs.-1.1%). Higher percentage patients in iDegLira group had reached the HbA1c < 7% after 6 months ( 22% vs. 18.2%, p < 0.05). The mean change in FPG was comparable for the two groups, while mean decrease PPG level were lower in iGlarLixi group (2 vs 1.8 mmol/l, p > 0.05). Change in body weight were significant difference in iDegLira group (1.8 kg vs. 0.7 kg, p < 0.001). At the end of the study patients showed decreased in total cholesterol and LDL for 0.2 mmol/L in iDegLira, 0.1 mmol/l in iGlarLixi, triglycerids for 0.3 mmol/l in both groups, increase HDL for 0.1 mm/l in iGlarLixi.

Conclusion

. Our results showed that more patients with iDegLira had HbA1c less than 7% and these combination had better effect on weight loss. There were no difference on FPG and PPG, lipid profile and rate of hypoglycemia.

fixed-ratio combination

type 2 diabetes

insulin degludec

insulin glargine

liraglutide

lixisenatide

Diabetes mellitus (DM) type 2 is a chronic, progressive disease, result of multiple pathophysiologic defects including insulin resistance, reduced beta cell function, increased hepatic glucose output, inappropriate glucagon secretion, and decreased incretin effect (1, 2). Achieving and maintaining glycemic control is essential for reducing the risk of diabetes associated microvascular complications (retinopathy, nephropathy, and neuropathy) and in many cases reducing the risk of macrovascular complications such as myocardial infarction (3).

The combination therapy with a long-acting basal insulin and a glucagon-like protein-1 receptor agonist (GLP-1RA) in patients with type 2 diabetes mellitus is based on the solid understanding of their complementary mechanisms of actions, which potentiate each other by acting through different mechanisms in different tissues (4). This approach is also supported by full clinical data. For patients already being treated with basal insulin, the addition of a GLP-1RA to their therapeutic regimen is an option when intensification therapy is needed (2, 4, 5). This combination therapy shows the same efficacy as the basal bolus treatment regimen with respect to glycemic control, but with a lower risk of hypoglycemia and weight gain, and is obtained with a lower dose of insulin (2, 5).

There are two new dual-agent products that are now available combining basal insulin with GLP-1 RA, insulin degludec/liraglutide (iDegLira) and insulin glargine/lixisenatide (iGlarLixi) (6). Both are indicated for treatment of type 2 diabetes in adjunct to lifestyle changes including diet and exercise, and are administered subcutaneously once daily. IDegLira is a fixed-ratio combination of a once-daily long-acting basal insulin degludec and a long acting, once-daily GLP-1 RA, liraglutide. IGlarLixi is a fixed-ratio combination of a once-daily long-acting basal insulin glargine and a short-acting, once-daily GLP-1 RA, lixisenatide. There are no trials directly comparing the two fixed ratio combination GLP-1RA and basal insulin products (6–10). The primary end point of this study was to compare the effect between two fixed – ratio combination (iDegLira and iGlarLixi) on glycated hemoglobin A1c (HbA1c). The secondary end points were change in 2 hours postprandial glucose (PPG), fasting plasma glucose (FPG)), proportion of patients achieving HbA1c < 7% and change in non glycemic parameters: body weight and lipid parameters.

Study design and subjects

A total of 186 patients with type 2 DM were included in this retrospective study at the University Clinical Centre of the Republic Srpska in Banja Luka. The inclusion criteria were inadequate glycemic control on metformin and basal insulin (degludec, glargin 100, glargin 300). Inadequate glycemic control was defined as HbA₁c ≥ 7.0%. Patients had to have been treated with a basal insulin for at least 6 months before study, with a stable regimen for at least 3 months. The permitted oral antihyperglycemic drugs at screening were metformin (≥ 1,500 mg/day or maximal tolerated dose). Patients were divided into two groups based on the basal insulin before study. Patient group I ( n = 86, 46 man and 50 women) treated with degludec as basal insulin before study, were switched to iDegLira. Patients group II ( n = 99, 48 man and 51 women) treated with glargin 100 or 300 < 30 units as basal insulin before study, were switched to iGlarLixi dose 20 units:10 µg. IDegLira was self –administrated once daily, at any time of the day but at approximately the same time every day. IGlarLixi was self –administrated once daily, during the half an hour before breakfast. The starting dose of fixed combination was determined from the last basal insulin dose received before study. Treatment was titrated once a week to reach and maintain a self-measured FPG 5–7 mmol/L while avoiding hypoglycemia, according to the following algorithm: +2 units (if FPG was 5–8 mmol/L]) or + 4 units (if FPG was > 8 mmol/l) or -2 units (if FPG was < 5 mmmol/L). Exclusion criteria were use of an oral agent other than the metformin and previous discontinuation of a GLP-1 RA due to safety, tolerability. All procedures were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964, as revised in 2013. The study protocol was approved by the Ethics Committee. All subjects gave written informed consent for participation.

Clinical and biochemical measurements

For each patient, the following demographic data were collected: gender, age, body height and weight. The following parameters were measured from baseline and after 6 months: FPG, 2 hours PPG, HbA1c, total cholesterol (TC), high density cholesterol (HDL), low density cholesterol (LDL), triglycerides. From self monitored glucose level we got data about hypoglycemia per week. Hypoglycemia defined as glycemia less than 3.9 mmol/l.

Statistical analysis

Central tendencies, mesures of variability and relative numbers were used for descriptive statistical methods. The normality of the distribution of continuous data was examined by graphical and mathematical methods. To compare means between continuous variables between two groups we used T test (or Mann Whitney test), depend of data distribution. To comapare change from baseline to 6 months we used T tets for continuos variables. Mc Nemar test was uses to comapare change from baseline to 6 months for nominal data. Correlation between the observed variables was assessed using the Spearman or Person correlation. A p-value < 0.05 was considered statistically significant. All analyses were performed using the SPSS Statistics.

There were no difference in baseline and demographic characteristics between the treatments groups, Table 1. Patients were mean age of 60 years, were generally obese and had a mean duration of diabetes 10 years, Table 1.

Table 1

Baseline, demographics and disease characteristics, baseline and the end of study
	IDegLira	IGlarLixi
	Baseline At the end	Baseline At the end
Age, years	58.6 ± 9.759.2 ± 3.5	60.2 ± 8.360.8 ± 7.4
Duration of DM, years	9.6 ± 3.6 10.2 ± 3.2	10.5 ± 3.9 11.1 ± 4.1
HbA1c, %	8.9 ± 1.1 7.7 ± 1	9 ± 1.4 7.9 ± 1.1
FPG, mmol/l	7.5 ± 1.5 6.0 ± 1.1	7.8 ± 1.7 6.4 ± 0.37
PPG, mmol/l	10.1 ± 2.5 8.3 ± 0.9	10.3 ± 1.8 8.3 ± 1.2
Weight, kg	87.1 ± 15.4 85.3 ± 14.5	89.4 ± 14.9 88.7 ± 14.5
BMI, kg/m²	30.2 ± 7.3 28.8 ± 3.2	30.8 ± 4.3 30.2 ± 4.1
Insulin dose, units	27 ± 5.5 26 ± 4	28 ± 5 26 ± 3.5

Data are presented as % or mean± SD. HbA1c-glycated hemoglobin A1c, FPG-fasting plasma glucose, PPG- postprandial glucose, DM-diabetes mellitus, BMI-body mass index

Mean HbA1c decreased similarly in two treatments groups (-1.2% vs.-1.1%), Figure 1. There were statistical differency for the change in HbA1c from baseline to 6 months in both groups, Table 1. Higher percentage patients in iDegLira group had reached the HBA1c<7% after 6 months ( 22% vs. 18.2%, p<0.05), Figure 1. The mean change in FPG was comparable for the two groups, while mean decrease PPG level was lower in iGlarLixi group, but these difference no significance (2 vs 1.8 mmol/l, p>0.05), Figure 1.

Figure 1. Mean change glycemic parameters

HbA1c – glycated haemoglobin A1c, FPG: fasting plasma glucose, PPG: postprandial glucose

At the end of the study patients showed decreased in total cholesterol and LDL for 0.2 mmol/L in iDeg Lira and 0.1 mmol/l in iGlar Lixi, triglycerids for 0.3 mmol/l in both groups, increase HDL for 0.1 mm/l in iGlarLixi, Fig. 2.

Figure 2. The mean lipid parameters, baseline and at the end of study

TC: total cholesterol, HDL: high density cholesterol, LDL: low density cholesterol,Tg: triglycerides.

Change in body weight were significant difference of 1.8 kg from baseline in iDegLira group, than 0.7 kg in iGlarLixi group ( p < 0.001), Table 1. After 6 month in both groups were significant less hypoglycemia episodes per week. In iDegLira group without hypoglycemia were 97.7%, in iGlarLixi 96%, with 1–2 hypoglycemia per week in iDegLira 2.3% and in iGlarLixi 3%. In both groups at the end of study there were no more than 2 hypoglycemia episodes per week. There were not any participant drop outs during the study.

Diabetes impacts multiple systems within the body, and achievement and maintenance of glycemic goals are important in preventing or at least delaying the development and progression of diabetes-associated complications (11). To effectively treat type 2 diabetes, treatment intesification is often required using combinations of medications that address one or the more of the many pathologic processes associated with the disease (4, 5, 12). The fixed-ratio combination therapy is appropriate for patients who are already taking either a basal insulin or a GLP-1 RA but still show insufficient glycemic control (13). Specific patients who may particularly benefit from such a therapy include those who want to avoid the multiple injections required with prandial insulin in an insulin intensification regimen, as well as the frequent blood glucose testing needed to adjust prandial doses and lessen the risk of hyper/hypoglycemia (4, 5, 12, 13). Combination therapy using the complementary mechanisms of action of basal insulin and GLP-1 RA targets seven of the many pathophysiologic defects in type 2 diabetes, adressing both FPG and PPG (5, 8, 12). No head-to-head comparison has been done with fixed-ratio combination and therefore it is not possible to make recommendations between the two for glycemic control alone (13–15).

With a mean diabetes duration od 10 years, mean BMI of 30 kg/m² and already on two glucose lowering agens, population of this study represents a group of patients that is challenging to treat successfully in the clinical setting. These patients need more than one glucose-lowering drugs to maintain glycemic control.

Our results had showed higher proportions of patients with iDegLira reaching the HbA1c < 7% and greater reductions in HbA1c. Other studies had showed higher reduction HbA1c than our results (15, 16). A systematic review and meta-analysis of trials indirectly compared iGlarLixi and iDegLira and showed the mean change in HbA1c was 1.50% after iGlarLixi treatment and 1.89% after iDegLira treatment. Evans et al showed in indirect comparison the mean reduction in HbA_1c was 0.44% greater with IDegLira compared to iGlarLixi, and a greater proportion of patients reached HbA_1c < 7.0%. The results of this indirect treatment comparison demonstrate that, among patients with type 2 diabetes uncontrolled on basal insulin, treatment with IDegLira resulted in a greater reduction of HbA1c and higher odds of reaching HbA1c < 7% compared with iGlarLixi (14). Other meta analises showed similar results (11, 15, 16). We didn't find difference between iDegLira and iGlarLixi for change in FPG. Groups with iGlarLixi had more decrease PPG. Other meta analyses had showed favour od iDegLira for change in FPG, but iGlarLixi for PPG. IGlarLixi contain short acting GLP-1 RA with a predominant PPG lowering effect (5, 6, 16–18).

These better glycemic control did not associated with higher rate of hypoglycemia. We did not found significant difference in hypoglycemic episodes between groups. Hypoglycemia episode were reduced in both groups at the end of study. A lower incidence of hypoglycemia indicating that the fixed ratio combination may mitigate the increased risk of hypoglycemia often seen in long-standing DM. Other studies also showed good safety profile of fixed ratio combination therapy (12, 13).

Obesity in one of the main risk factors for type 2 diabetes. Modest weight loss can minimize and reduce diabetes-associated complications (19). Fixed combination iDegLira was superior in reduction body weight and BMI than iGlarLixi in our study. Different GLP 1 RA have different effect on weight change. Differences in uptake across the blood–brain barrier (or in brain access through subfornical organs) have been postulated as an explanation (20–23). Clinical trial data from patients receiving fixed-ratio combination showed a weight change of -0,3 to -0,7 kg for iGlarLixi and − 2 to -2,7 kg for iDeg Lira (12, 13, 16, 17, 24).

Our results had showed improvements in lipid levels. Both preparation had showed the most effect on triglycerids level. Although, iDegLira more decrease total cholesterol and LDL, but these differences were not significant. Other studies showed better lipid profil with fixed ratio combination (25–30). Unlike other results which had not showed diffrence in HDL level, our results also had showed increase in HDL level in iGlarLixi groups.

Our results had showed that more patients with iDegLira had HbA1c less than 7% and these combination had better effect on weight loss. Both preparation had similar effect on FPG and PPG, benefit on lipid profile and similar rate of hypoglycemia.

Diabetes mellitus

GLP-1RA

glucagon-like protein-1 receptor agonist

iDegLira

insulin degludec/liraglutide, iGlarLixi:insulin glargine/lixisenatide

BMI

Body mass index

HbA1c

glycated haemoglobin A1c

FPG

fasting plasma glucose

PPG

postprandial glucose

total cholesterol

HDL

high density cholesterol

LDL

low density cholesterol.

Acknowledgements

We acknowledge and thank all participants for their cooperation and sample contributions.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author contributions IR, MB, MSD and DD were drafted this manuscript and collected the sample. IR, DD and MDD analyzed the data. IR and MDD are responsible for the integrity of the work as a whole. All authors read and approved the final manuscript.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Availability of data and materials

original data sets and materials are not publicly available because of patient privacy protection but are available from the corresponding author upon reasonable request.

Ethics approval and consent to participate

The study was reviewed and approved by the ethics committee of the University Clinical Center of the Republic of Srpska. The number of ethics committee approval is 01-19-123-2/21.

Consent for publication Not applicable.

Competing interests The authors declare that they have no competing interests.

Author details

¹ Faculty of Medicine, University of Banja Luka, Bosnia and Herzegovina

² University Clinical Center of the Republic of Srpska, Department of Endocrinology, Banja Luka, Bosnia and Herzegovina

³ School of Medicine, University of Belgrade, Clinic for Endocrinology, Diabetes and Diseases of Metabolism, Belgrade, Serbia

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No competing interests reported.

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You are reading this latest preprint version

Direct Comparison Two Fixed-ratio Combination Glucagon-like Peptide Receptor Agonist and Basal Insulin on Glycemic and Non Glycemic Parameters in Type 2 Diabetes

Status:

Journal Publication

Version 2

Abstract

Background.

Methods.

Results

Conclusion

Figures

Background

Methods

Statistical analysis

Results

Discussion

Conclusion

Abbreviations

Declarations

References

Additional Declarations

Status:

Journal Publication

Version 2