Clinical effects of SGLT2 inhibitors in seven persons with HNF1A-MODY (MODY3)

Abstract

Maturity-onset diabetes of the young (MODY) is a heterogeneous subset of monogenic diabetes characterized by early onset of diabetes, typically between the second and fifth decade of life. Pathogenic variants in HNF1A cause one of the most prevalent MODY types named HNF1A-MODY (or MODY3).¹ Sulfonylureas (SU) are typically used as the primary treatment,² while incretin-based treatments have also been shown to lower glucose levels.^{3, 4} In type 2 diabetes, sodium-glucose cotransporter 2 (SGLT2) inhibitors are effective glucose-lowering agents. However, the utility and safety of SGLT2 inhibitors in HNF1A-MODY are scarcely described.^5-7 Here, we describe seven individuals with HNF1A-MODY treated with SGLT2 inhibitors as add-ons to SU, insulin and incretin-based therapies.

At initiation of SGLT2 inhibitor, all persons (n = 7) were treated with SU (glimepiride) and incretin-based therapy, four persons were treated with insulin and one with metformin (Table 1). Estimated glomerular filtration rate (eGFR) was >90 mL/min/1.73 m² for all but one individual with eGFR in the range of 45–60 mL/min/1.73 m². The persons carried the following HNF1A variants: c.956-2A>G (n = 2), p.Glu332Ter, p.Leu12Phe, p.Pro379Ala, p.Pro379fs, p.Tyr218Cys (RefSeq NM_000545.5). All individuals started the SGLT2 inhibitor empagliflozin at a dose of 10 mg once daily. After 4 months, HbA1c had decreased in six individuals, BMI decreased in all participants, and three of four insulin-treated persons had discontinued insulin therapy (Table 1). After 1 year, the daily insulin dose was reduced from 15 units/day (four injections daily) to 2 units/day (one injection daily) in the remaining insulin-treated individual. After 1 year, HbA1c was markedly lower in three individuals (range −2.6%; −0.8% [−28; −9 mmol/mol]), including one person discontinuing insulin therapy), remained at baseline level (within 0.3% [3 mmol/mol]) in three participants (including two persons discontinuing insulin therapy) and was increased (1.1% [12 mmol/mol]) in the person with impaired kidney function in whom insulin dose was lowered.

During the follow-up period (14 person-years), 11 adverse events were identified of which none were considered serious (death, life-threatening or leading to hospitalization) or led to permanent discontinuation of the SGLT2 inhibitor. Five adverse events were considered related to empagliflozin: balanitis (n = 1, single occasion), cystitis (three instances in two males, symptoms confirmed by either dipstick or urine culture) and mild polyuria (n = 1). Other adverse events considered not to be related to empagliflozin included non-specific dizziness (n = 2, single occasions, hypoglycaemia and volume-depletion were excluded as the cause), gastroenteritis (n = 2, no signs of volume depletion, not hospitalized) and flank/stomach pain (two instances in one individual, both leading to emergency department visit without hospitalization, considered urolithiasis).

In conclusion, the use of an SGLT2 inhibitor was associated with glycaemic control that improved or remained stable despite discontinuation or reduction of insulin and decreased BMI. Further, no unexpected side effects were observed during the treatment with SGLT2 inhibitor. Data on the effects and use of SGLT2 inhibitor therapy in HNF1A-MODY are scarce. The cases presented here provide, to our knowledge, the largest data set on the efficacy and safety of long-term SGLT2 inhibitor therapy in HNF1A-MODY.

HNF1A encodes the transcription factor hepatocyte nuclear factor 1-alpha (HNF1A), which is involved in the expression of glycolytic and mitochondrial enzymes in the β-cell.⁸ Pathogenic variants of HNF1A result in insulin secretion defects.⁸ HNF1A also regulates the expression of SGLT2 which encodes a glucose transporter that is responsible for the majority of glucose reuptake from the proximal tubules in the kidney.⁹ Individuals with HNF1A-MODY have a lower threshold for glucose excretion compared to individuals with type 1 diabetes and type 2 diabetes,^{9, 10} supporting the notion that SGLT2 expression is lower in individuals with HNF1A-MODY. Hypothetically, a reduced expression of SGLT2 in HNF1A-MODY may compromise the efficacy of SGLT2 inhibition in these individuals. However, a single dose of the SGLT2 inhibitor dapagliflozin has previously been shown to increase glucose excretion in persons with HNF1A-MODY⁵; supporting that SGLT2 inhibitors may induce glucosuria in HNF1A-MODY.

HNF1A-MODY is characterised by insulin deficiency rather than insulin resistance,⁸ and (euglycemic) diabetic ketoacidosis, as observed in SGLT2 inhibitor-treated persons with type 1 diabetes, is a potential concern. Indeed, ketonemia has been associated with SGLT2-inhibitor monotherapy as reported in a woman with HNF1A-MODY.⁶ In the present cases, the SGLT2 inhibitor was used as adjunctive therapy together with insulin secretagogues.

SGLT2 inhibitors are not associated with increased rates of hypoglycaemia except when used in combination with SU or insulin. In this case series, hypoglycaemia was not reported despite all persons being SU-treated during follow-up. Meanwhile, insulin exposure was low due to discontinuation or dose reduction. Down-titration of insulin and SU (if treated with high doses) could prevent hypoglycaemia.

Initiation of SGLT2 inhibitor treatment in these seven persons with HNF1A-MODY was associated with clinically relevant reductions in HbA1c, body weight and insulin use and was well-tolerated. To further investigate the glucose-lowering effects of empagliflozin in person with HNF1A-MODY, we have initiated a randomized controlled, crossover trial (EUCT 2023-503760-17-00).

None.

T.V. has served on scientific advisory panels, been part of speaker's bureaus, served as a consultant to and/or received research support from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, GSK, Mundipharma, Novo Nordisk, Roche, Sanofi, Sun Pharmaceuticals and Zealand Pharma. F.K.K. is employed by Novo Nordisk and has been on advisory panel of, consultant for, in the speaker's bureau of, owns shares in and/or has received research support from 89bio, AstraZeneca, Boehringer Ingelheim, Cytoki Pharma, Eli Lilly, Gubra, Novo Nordisk, Merck Sharp & Dohme, Sanofi, Structure Therapeutics, Zealand Pharma and Zucara; and is co-founder of and minority shareholder in Antag Therapeutics. S.H. has served as a consultant to Novo Nordisk. No other potential conflicts of interest relevant to this article were reported.