SGLT2 inhibitor monotherapy alleviates hyperglycemia in heredity severe insulin resistance syndrome

To the Editor: Hereditary severe insulin resistance syndrome (H-SIRS) shows a wide and variable clinical spectrum and results in severe complications in the endocrinological and cardiovascular systems. Multiple treatments are recommended to control hyperglycemia in H-SIRS, including dietary intervention, insulin therapy, insulin sensitization, and recombinant human insulin-like growth factor-1 (rhIGF-1) administration.[1] However, the heterogeneous etiology of H-SIRS leads to poor glycemic control in patients with different mutations, requiring multiple antihyperglycemic medications. Therefore, this study described two cases diagnosed with H-SIRS and the treatment effect of multi-drug therapy and sodium-glucose cotransporter 2 inhibitor (SGLT2i) monotherapy. The probands were recruited from the Chinese Multicenter Heredity Endocrinological Diseases Cohort (CMHEDC), established in 2018, and approved by the Ethics Committee of the National Clinical Research Center for Metabolic Diseases, the Second Xiangya Hospital of Central South University (No. 2018-03). The trial registration number was ChiCTR1800019030 at http://www.chictr.org.cn. Clinical data and family history were collected by professional physicians. Written informed consent was obtained from all subjects involved in the study. Whole exome sequencing (WES) was performed and the pathogenicity of variant was evaluated according to the American College of Medical Genetics and Genomics (ACMG) guidelines for variant interpretation.[2] The target variants were verified by Sanger sequencing. The primers are listed in Supplementary Table 1, https://links.lww.com/CM9/B981. We assessed clinical features, including anthropometric indexes, physical signs, glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), 2-hour postprandial plasma glucose (2h-PG), and fasting and 2-hour postprandial C peptide/insulin (FCP/FIns and 2h-PCP/2h-Ins) to a mixed meal tolerance as well as follow-up data before and after the dapagliflozin and/or multitherapy treatment in the probands. To compare the hypoglycemic effect and safety of different remedies in H-SIRS. Published studies were considered eligible if they met all of the following inclusion criteria: (1) Genetic diagnosis of H-SIRS, the candidate genes are listed in Supplementary Table 2, https://links.lww.com/CM9/B981;[1] (2) Clinical diagnosis of diabetes; (3) With the description of remedies and follow-up. The primary outcomes were mean differences in HbA1c and FPG levels. The differences in biochemical parameters at first evaluation were calculated with the values collected at the first follow-up subtracting the values at baseline, which indicated the instant response of treatments. And the differences in biochemical parameters at the second evaluation were calculated with the values collected at the second follow-up subtracted from those collected at the first follow-up, indicating the persistent efficacy. The safety was evaluated by the incidence of hypoglycemia, urogenital infection, and diabetic ketoacidosis. The first case was a 16-year-old female who was admitted to the hospital because of hyperglycemia and skin change. She mainly manifested canthosis nigricans and lipoatrophy, and her HbA1c was up to 9.9% with severe insulin resistance [Supplementary Table 3, https://links.lww.com/CM9/B981]. Her grandmother (I-2), father (II-2), and consanguineous sister (III-2) were also diagnosed with diabetes and two of them died of it [Figure 1A]. We performed WES on the proband and found the candidate LMNA gene c.1456A>G, p.Lys486Glu mutation. And tested the LMNA gene mutation in her grandfather (I-2), mother (II-3), and her consanguineous sister (III-2). Unfortunately, her other consanguineous sister (III-4), consanguineous brothers (III-1, III5, III-6), stepmother (II-1), and stepfather (II-4) were not willing to do genetic testing. But the special pattern in the reunited family indicated that the LMNA gene c.1456A>G, p.Lys486Glu mutation was inherited from the proband's father (II-2) and grandmother (I-2). The mutation was reported as pathogenic before.[3] According to the ACMG guidelines,[2] the pathogenic pieces of evidence of LMNA c.1456A>G, p. Lys486Glu included strong evidence of pathogenicity (PS1), PS4, supporting evidence of pathogenicity (PP1), and PP4.The second case, a 16-year-old female, was admitted to the hospital because of growth retardation, facial dysmorphia, and hyperglycemia. The WES showed that she carried a de novo mutation of PIK3R1 gene c.1945C>T, p. Arg649Trp [Figure 1B], which was reported pathogenic before.[4] The blood assays indicated severe insulin resistance [Supplementary Table 3, https://links.lww.com/CM9/B981]. She also was diagnosed with H-SIRS with the pathogenic pieces of evidence, including PS1, PS2, PS4, PP3, and PP4.Figure 1: Diagnosis and the efficacy of SGLT2i in LMNA- and PIK3R1-SIRS. (A) Pedigree and Sanger sequence of the family carried LMNA c.1456A >G, p. Lys486Glu mutation with early onset diabetes. (B) Pedigree and Sanger sequence of the family carried PIK3R1 c.1945C >T, p. Arg649Trp mutation with early onset diabetes. (C) Composite line graphs described the mono- or multi-antidiabetic treatment, dosage, duration, and results of the blood glucose, HbA1c, and HOMA-IR in LMNA-SIRS. (D) The Acanthosis nigricans before and after the monotherapy of SGLT2i in LMNA-SIRS. (E) Composite line graphs described the multi-antidiabetic drug, dosage, duration, and the effect of SGLT2i withdrawal in PIK3R1-SIRS. (F) HbA1c changes in treatment and withdrawal of SGLT2i in H-SIRS. Squares and circles indicate males and females; Roman numerals indicate generations; Filled symbols indicate patients with early onset diabetes; Black arrows indicate the proband. H-SIRS: Hereditary severe insulin resistance syndrome; HbA1c: Glycosylated hemoglobin; N/M: Heterozygous mutation; N/N: Non-mutation; PIK3R1: Phosphoinositide-3-kinase regulatory subunit 1; SGLT2i: Sodium-glucose cotransporter 2 inhibitor.The first proband was diagnosed with LMNA-SIRS and received continuous subcutaneous insulin infusion (CSII) at the onset stage. Afterward, pioglitazone, thiazolidinedione (TZD), metformin, saxagliptin, and dipeptidyl peptidase 4 inhibitor (DPP4i), were used as multi-drug therapy for 2 months. But the hyperglycemia was still not improved. The addition of dapagliflozin in multi-drug therapy for one month significantly improved hyperglycemia at first evaluation. HbA1c decreased from 9.9% to 8.0%. The level of FPG and 2h-PG significantly decreased to 6.7 mmol/L at fasting and 7.4 mmol/L at postprandial. Afterward, SGLT2i monotherapy was used for four months. The HbA1c and HOMA-IR reduced gradually, and the levels of glucose were stable within the range of 6.0–8.0 mmol/L. Moreover, the Acanthosis nigricans alleviated [Figure 1C, D]. The second proband was diagnosed with PIK3R1-SIRS and received CSII, pioglitazone, metformin, and dapagliflozin at the onset stage. HbA1c decreased from 12.7% to 9.1%. The level of plasma glucose decreased to 5.9 mmol/L in fasting and 11.4 mmol/L in postprandial. Out of ignorance, dapagliflozin was stopped for 1 year by the patient. Once withdrawing SGLT2i, the level of HbA1c rebounded and was even worse than the initial value (14.3%) [Figure 1E]. Although there was no direct evidence about SGLT2i monotherapy in this patient, once SGLT2i was withdrawn, the glycemic control deteriorated rapidly and was even worse than the onset stage. During the administration of SGLT2i, no event of hypoglycemia and or urogenital infection was reported. β-hydroxybutyric acid levels were within the normal range. Of 45 clinical case reports assessed for eligibility with a total number of 57 H-SIRS patients (2 cases from our study) were included in analysis from 2003 to 2023, including AGPAT2-, BSCL2-, INSR-, LMNA-, PPARG-, or PIK3R1-SIRS. Approximately 85% of participants were Asian and White. Among them, 10 patients were treated with SGLT2i and 47 patients without SGLT2i. The SGLT2i group showed better glycemic control than the no-SGLT2i group (mean differences of HbA1c at first evaluation, −2.2% vs. −1.1%, P = 0.02) [Supplementary Table 4, https://links.lww.com/CM9/B981]. In the subgroups of H-SIRS, including INSR-, PIK3R1-, and LMNA-SIRS, SGLT2i also manifested better efficacy of glycemic control [Supplementary Table 5, https://links.lww.com/CM9/B981]. The level of HbA1c in SGLT2i group decreased 2.3% at the first evaluation. Monotherapy of dapagliflozin resulted in a 1.9% reduction in HbA1c, and the discontinuation of SGLT2i led to a 5.2% rebound [Figure 1F]. We also did the monotherapy comparison. In all, 26 H-SIRS cases were treated with monotherapy, and only one of them was treated with SGLT2i monotherapy. Insulin, metreleptin, rhIGF-1, and SGLT2i had good efficacy in glycemic control at the first evaluation. Taking the second evaluation into analysis, SGLT2i was the reliable and stable choice to control hyperglycemia in H-SIRS [Supplementary Figure 1, https://links.lww.com/CM9/B981]. PIK3R1-SIRS patients were not reported to be treated with monotherapy. Hence, we only did the LMNA-SIRS monotherapy comparison. TZD played an uncertain role in glycemic control in LMNA-SIRS. Metreleptin, metformin, and SGLT2i monotherapy had good efficacy in glycemic control [Supplementary Figure 1, https://links.lww.com/CM9/B981]. Although metreleptin had the best hypoglycemic efficacy, it costs a lot. For safety evaluation, 8/10 patients in SGLT2i group reported no adverse effect. But hypoglycemia, adenoid hypertrophy, and tumor occurred in the no-SGLT2i group [Supplementary Table 4, https://links.lww.com/CM9/B981]. Hypoglycemia happened in the patients treated with rhIGF-1 and glimepiride monotherapy. Adenoid hypertrophy and tumor were reported in the patients treated with rhIGF-1. SGLT2i is a new class of anti-diabetic agents which increases urinary glucose excretion through SGLT2 inhibition on the luminal surface of proximal convoluted tubules of the kidney and intestine. Most pathogenic genes in H-SIRS cluster in insulin and post-insulin receptor-dependent pathways.[1] Therefore, the potential hypoglycemic mechanism might be that SGLT2i acts in an insulin- and post-insulin receptor-independent manner. The disposal of glucose from the kidney and intestine effectively decreases glucose toxicity and also reduces the dosage of exogenous insulin as well as the level of serum insulin, which might prevent the development of hypertrophic cardiomyopathy and nephropathy. However, SGLT2i might not solve the problems of growth retardation. Paradoxically, SGLT2i could increase lipid oxidation and fat loss,[5] which might deteriorate the phenotype of lipoatrophy, although no evidence has been proven in H-SIRS patients so far. We still need a longer treatment duration to identify the effects of lipoatrophy in these patients. In summary, monotherapy of SGLT2i could alleviate hyperglycemia in H-SIRS patients caused by the heterozygous mutations in LMNA and P1K3R1 genes. Administration of SGLT2i could serve as a potential precise and safe hypoglycemic treatment for different subtypes of H-SIRS. Funding This work was supported by grants from the National Natural Science Foundation of China (Nos. 8217033609, 81770880, and 81970762), the Science & Technology Department of Hunan Province (Nos. 2020SK2080 and 2015JC3012), and the Science & Technology Department of Changsha City (Nos. k1906019 and kq190111). Conflicts of interest None. Data sharing statement The basic data of clinical research were available in the main text or the supplementary materials, https://links.lww.com/CM9/B981. The privacy and sequencing data are supposed to be acquired with the agreement from the corresponding author in accordance with the domestic laws and regulations.