Efficacy of Regimens in the Treatment of Latent Autoimmune Diabetes in Adults: A Network Meta-analysis

Abstract

Introduction: Latent autoimmune diabetes in adults (LADA) is a highly heterogeneous autoimmune condition with clinical and genetic characteristics that fall between those of type 1 diabetes mellitus and type 2 diabetes mellitus; therefore, there are no uniform criteria for the selection of therapeutic agents. We conducted a network meta-analysis to evaluate the efficacy of various therapeutic agents for LADA by comparing their effects on various indicators used to reflect LADA.

Methods: We searched the PubMed, Cochrane Library, Embase and Web of Science databases from their inception to March 2023 and collected data from 14 randomized controlled trials on glucose-lowering drugs for LADA, including 23 studies and 15 treatment regimens. The effectiveness of drugs was ranked and evaluated by combining surface under the cumulative ranking (SUCRA) plots and forest plots. Factors that may influence study heterogeneity were also searched and analyzed by combining subgroup analysis, publication bias, funnel plots and sensitivity analysis.

Results: The results of the network meta-analysis showed that insulin had the most significant effect on the control of change from baseline in glycosylated hemoglobin, type A1 (ΔHbA1c). Insulin combined with dipeptidyl peptidase-4 (DPP-4) inhibitors performed the best in reducing fasting blood glucose and body mass index. Treatment regimens involving thiazolidinediones were the most advantageous in HbA1c, fasting C-peptide and postprandial C-peptide control. Longer dosing may be more beneficial in maintaining islet β-cell function in the LADA population.

Conclusion: LADA is an immune condition with high heterogeneity, and treatment should be administered according to the C-peptide level of the LADA population. For this population with LADA with a certain level of β-cell function, combinations of insulin with DPP-4 inhibitors or thiazolidinediones probably can be more effective treatment options to maintain islet function and normal blood glucose.

Trial registration: PROSPERO CRD42023410795.

Keywords: C-peptide; Latent autoimmune diabetes in adults; Network meta-analysis; Randomized controlled trials.

Fig. 1

Flow diagram of the selection process. LADA Latent autoimmune diabetes in adults; RCT randomized controlled trial

Fig. 2

Network evidence for HbA1c and FCP of patients with LADA treated by different regimens. A HbA1c, B FCP. The size of each node is proportional to the number of participants assigned to the treatment. The thickness of the line is proportional to the number of trials between the corresponding drugs. HbA1c Glycosylated hemoglobin, FCP fasting C-peptide type A1c, LADA latent autoimmune diabetes in adults, VD 1-α-hydroxyvitamin D3 [1-α(OH)D3]

Fig. 3

Quality assessment. A, B Risk of bias graph (A) and of bias summary (B). Plus sign (+) denotes a low risk of bias, question mark (?) denotes a moderate risk of bias, minus sign (−) denotes a high risk of bias

Fig. 4

SUCRA curves of HbA1c, FCP, ΔHbA1c, PCP, FBG and BMI of patients with LADA treated by 15 different regimens. A HbA1c, B FCP, C ΔHbA1c, D PCP, E FBG, F BMI. SUCRA surface under the cumulative ranking, HbA1c glycosylated hemoglobin, type A1c, FCP fasting C-peptide, ΔHbA1c change from baseline in HbA1c, PCP postprandial C-peptide, FBG fasting blood glucose, BMI body mass index, LADA latent autoimmune diabetes in adults, VD 1-α-hydroxyvitamin D3 (1-α(OH)D3), DPP-4 dipeptidyl peptidase-4

Fig. 5

Funnel plots for HbA1c, FCP, PCP and BMI of patients with LADA treated by different regimens. A HbA1c, B FCP, C PCP, D BMI. HbA1c Glycosylated hemoglobin, type A1c, FCP fasting C-peptide, PCP postprandial C-peptide, BMI body mass index, LADA latent autoimmune diabetes in adults, VD 1-α-hydroxyvitamin D3 (1-α(OH)D3), se(WMD) standard error of the weighted mean difference

Fig. 6

Forest plots of HbA1c, FCP, ΔHbA1c, PCP, FBG and BMI of patients with LADA treated by different regimens. A HbA1c, B FCP, C ΔHbA1c, D PCP, E FBG, F BMI. The treatment regimens for the experimental groups in the forest plot of HbA1c (A) for each study were, from top to bottom, sulfonylureas, sitagliptin, glibenclamide, insulin + sitagliptin, sulfonylureas, rosiglitazone, insulin + rosiglitazone, insulin + sitagliptin and insulin + rosiglitazone. The treatment regimens for the experimental groups in the forest plot of FCP (B) for each study were, from top to bottom, insulin + glibenclamide, sitagliptin, insulin + 1-α-hydroxyvitamin D3, insulin + sitagliptin, sulfonylureas, rosiglitazone, insulin + rosiglitazone, insulin + sitagliptin and insulin + rosiglitazone. The treatment regimens for the experimental groups in the forest plot of ΔHbA1c (C) for each study were, from top to bottom, glimepiride, placebo, dulaglutide + insulin glargine. The treatment regimens for the control groups in the forest plot of ΔHbA1c (C) for each study were, from top to bottom, linagliptin, saxagliptin, sitagliptin and sitagliptin. The treatment regimens for the experimental groups in the forest plot of PCP (D) for each study were, from top to bottom, insulin + 1-α-hydroxyvitamin D3, insulin + sitagliptin, sulfonylureas, rosiglitazone, insulin + rosiglitazone, insulin + sitagliptin and insulin + rosiglitazone. The treatment regimens for the experimental groups in the forest plot of FBG (E) for each study were, from top to bottom, insulin + glibenclamide, sitagliptin, glibenclamide + insulin and sitagliptin. The treatment regimens for the experimental groups in the forest plot of BMI (F) for each study were, from top to bottom, insulin + glibenclamide, glibenclamide, insulin + sitagliptin, sulfonylureas, rosiglitazone, insulin + rosiglitazone and insulin + sitagliptin. The treatment regimen for the control group in the forest plots of HbA1c (A), FCP (B), PCP (D), FBG (E) and BMI (F) for each literature was insulin. HbA1c Glycosylated hemoglobin, type A1c, FCP fasting C-peptide, ΔHbA1c change from baseline in HbA1c, PCP postprandial C-peptide, FBG fasting blood glucose, BMI body mass index, LADA latent autoimmune diabetes in adults, CI confidence interval, VD 1-α-hydroxyvitamin D3 (1-α(OH)D3), DPP-4 dipeptidyl peptidase-4.

Fig. 7

Subgroup analysis of HbA1c, FCP, PCP, FBG and BMI of patients with LADA treated by different regimens. A Subgroup analysis conducted at baseline FCP levels (stratified according to the international expert consensus), B subgroup analysis by class of drug regimens, C subgroup analyses conducted by whether insulin was chosen, D subgroup analyses conducted by duration of medication, E subgroup analysis of FCP conducted at baseline FCP levels (stratified according to the tertiles of baseline C-peptide index of the included literature). Aa HbA1c, Ab FCP, Ac PCP, A FBGd, Ae BMI; Ba HbA1c, Bb FCP, Bc PCP, Bd FBG, Be BMI; Ca HbA1c, Cb FCP, Cc PCP, Cd FBG, Ce BMI; Da FCP, Db PCP, Dc FBG, Dd BMI. The treatment regimens for the experimental groups are detailed in the Electronic Supplementary Material. The treatment regimen for the control group was insulin. HbA1c Glycosylated hemoglobin, type A1c, FCP fasting C-peptide, PCP postprandial C-peptide, FBG fasting blood glucose, BMI body mass index, LADA latent autoimmune diabetes in adults, VD 1-α-hydroxyvitamin D3 (1-α(OH)D3), DPP-4 Dipeptidyl peptidase-4, CI confidence interval

Fig. 7

Subgroup analysis of HbA1c, FCP, PCP, FBG and BMI of patients with LADA treated by different regimens. A Subgroup analysis conducted at baseline FCP levels (stratified according to the international expert consensus), B subgroup analysis by class of drug regimens, C subgroup analyses conducted by whether insulin was chosen, D subgroup analyses conducted by duration of medication, E subgroup analysis of FCP conducted at baseline FCP levels (stratified according to the tertiles of baseline C-peptide index of the included literature). Aa HbA1c, Ab FCP, Ac PCP, A FBGd, Ae BMI; Ba HbA1c, Bb FCP, Bc PCP, Bd FBG, Be BMI; Ca HbA1c, Cb FCP, Cc PCP, Cd FBG, Ce BMI; Da FCP, Db PCP, Dc FBG, Dd BMI. The treatment regimens for the experimental groups are detailed in the Electronic Supplementary Material. The treatment regimen for the control group was insulin. HbA1c Glycosylated hemoglobin, type A1c, FCP fasting C-peptide, PCP postprandial C-peptide, FBG fasting blood glucose, BMI body mass index, LADA latent autoimmune diabetes in adults, VD 1-α-hydroxyvitamin D3 (1-α(OH)D3), DPP-4 Dipeptidyl peptidase-4, CI confidence interval

Fig. 7

Subgroup analysis of HbA1c, FCP, PCP, FBG and BMI of patients with LADA treated by different regimens. A Subgroup analysis conducted at baseline FCP levels (stratified according to the international expert consensus), B subgroup analysis by class of drug regimens, C subgroup analyses conducted by whether insulin was chosen, D subgroup analyses conducted by duration of medication, E subgroup analysis of FCP conducted at baseline FCP levels (stratified according to the tertiles of baseline C-peptide index of the included literature). Aa HbA1c, Ab FCP, Ac PCP, A FBGd, Ae BMI; Ba HbA1c, Bb FCP, Bc PCP, Bd FBG, Be BMI; Ca HbA1c, Cb FCP, Cc PCP, Cd FBG, Ce BMI; Da FCP, Db PCP, Dc FBG, Dd BMI. The treatment regimens for the experimental groups are detailed in the Electronic Supplementary Material. The treatment regimen for the control group was insulin. HbA1c Glycosylated hemoglobin, type A1c, FCP fasting C-peptide, PCP postprandial C-peptide, FBG fasting blood glucose, BMI body mass index, LADA latent autoimmune diabetes in adults, VD 1-α-hydroxyvitamin D3 (1-α(OH)D3), DPP-4 Dipeptidyl peptidase-4, CI confidence interval

Fig. 7

Subgroup analysis of HbA1c, FCP, PCP, FBG and BMI of patients with LADA treated by different regimens. A Subgroup analysis conducted at baseline FCP levels (stratified according to the international expert consensus), B subgroup analysis by class of drug regimens, C subgroup analyses conducted by whether insulin was chosen, D subgroup analyses conducted by duration of medication, E subgroup analysis of FCP conducted at baseline FCP levels (stratified according to the tertiles of baseline C-peptide index of the included literature). Aa HbA1c, Ab FCP, Ac PCP, A FBGd, Ae BMI; Ba HbA1c, Bb FCP, Bc PCP, Bd FBG, Be BMI; Ca HbA1c, Cb FCP, Cc PCP, Cd FBG, Ce BMI; Da FCP, Db PCP, Dc FBG, Dd BMI. The treatment regimens for the experimental groups are detailed in the Electronic Supplementary Material. The treatment regimen for the control group was insulin. HbA1c Glycosylated hemoglobin, type A1c, FCP fasting C-peptide, PCP postprandial C-peptide, FBG fasting blood glucose, BMI body mass index, LADA latent autoimmune diabetes in adults, VD 1-α-hydroxyvitamin D3 (1-α(OH)D3), DPP-4 Dipeptidyl peptidase-4, CI confidence interval

Fig. 8

Sensitivity analysis of HbA1c, FCP, ΔHbA1c, PCP, FBG and BMI of patients with LADA treated by different regimens. A HbA1c, B FCP, C ΔHbA1c, D PCP, E FBG, F BMI. HbA1c Glycosylated hemoglobin, type A1c, FCP fasting C-peptide, ΔHbA1c change from baseline in HbA1c, PCP postprandial C-peptide, FBG fasting blood glucose, BMI body mass index, LADA latent autoimmune diabetes in adults, CI confidence interval