Case Report

Dipeptidyl Peptidase-IV Inhibitors Are EfficientAdjunct Therapy in HNF1A Maturity-Onset Diabetes

of the Young Patients—Report of Two Cases

Barbara Katra, M.D., Ph.D.,1,2 Tomasz Klupa, M.D., Ph.D.,1,2 Jan Skupien, M.D., Ph.D.,1,2,3

Magdalena Szopa, M.D., Ph.D.,1,2 Natalia Nowak, M.S.,1 Maciej Borowiec, Ph.D.,4

Elzbieta Kozek, M.D, Ph.D.,1,2 and Maciej T. Malecki, M.D., Ph.D.1,2

Abstract

Background: In HNF1A maturity-onset diabetes of the young (MODY), sulfonylurea (SU) is the first-line treat-ment. Over time, such therapy fails, and additional treatment is required. Dipeptidyl peptidase IV (DPP-IV)inhibitors are new agents that lower blood glucose by prolonging the activity of circulating incretins.Methods: We applied DPP-IV inhibitors in two HNF1A MODY patients whose earlier therapeutic regimenincluded SU.Results: Case 1, a 39-year-old woman, a carrier of the ArgR171X HNF1A mutation, with a 7-year history ofdiabetes was on 160 mg of gliclazide and 2,000 mg of metformin. Her initial hemoglobin A1c (HbA1c) level was7.2%, while the mean glucose level on the CGMS� (Medtronic, Northridge, CA) record was 162 mg=dL. Si-tagliptine, in a dose of 100 mg=day, was added to the previous treatment. Case 2, a 62-year-old woman, a carrier ofthe IVS7nt-6G>A mutation, with a 41-year history of diabetes was treated with 240 mg=day gliclazide and 6 IU ofinsulin=day. Her initial HbA1c was 8.8%, and average glycemia reached 172 mg=dL. In her case, we started thecombined therapy with 50 mg of vildagliptine twice daily. Patients were reexamined after 3 months, and HbA1cfell to 6.3% in both subjects. Similarly, significant improvement in glycemic control on CGMS was observed as theaverage glycemia decreased to 114 mg=dL and 134 mg=dL in Case 1 and Case 2, respectively. No episodes ofhypoglycemia or other side effects were recorded. As intravenous glucose tolerance tests (IVGTTs) were per-formed before and after DPP-IV implementation, we were able to assess their impact on insulin secretion underfasting conditions. We saw a substantial rise in insulin level increment during IVGTT (by 9.8 and13.4 mIU=L inCase 1 and Case 2, respectively).Conclusions: DPP-IV inhibitors may be an effective tool of combined therapy in HNF1A MODY, and they seemto improve beta-cell function under fasting conditions.

Introduction

Maturity-onset diabetes of the young (MODY) is aform of monogenic diabetes mellitus. Its most frequent

form is caused by HNF1A mutations (HNF1A MODY, previ-ously designated MODY3). In this subtype of MODY, apharmacogenetic phenomenon of marked sulfonylurea (SU)effectiveness has been well documented,1,2 and, as such, SUremain the first-line therapeutic agents. Over time, however,this treatment becomes insufficient in a substantial numberof subjects. For example, in the Polish MODY Family Collec-tion, roughly half of HNF1A mutation carriers with diabetes

require insulin.3 Moreover, lack of satisfactory glycemic con-trol on SU has been documented in HNF1A MODY patientswith long-term diabetes.4 Metformin may be added to SU inthe presence of marked insulin resistance indicators, such asobesity; however, its effectiveness in this form of diabetes islimited.1,2 Thus, currently it is insulin that seems to be thenext option after SU monotherapy turns ineffective. Dipepti-dyl peptidase IV (DPP-IV) inhibitors are a new class of ther-apeutic agents that lower blood glucose by prolonging theactivity of circulating incretins.5,6 They may, possibly, be avery useful tool in HNF1A MODY. In a clinical experiment,it was shown that HNF1A mutation carriers with diabetes

1Department of Metabolic Diseases, Jagiellonian University Medical College; and 2University Hospital, Krakow, Poland.3Section on Genetics and Epidemiology, Joslin Diabetes Center, Boston, Massachusetts.4Department of Pediatrics, Medical University of Lodz, Lodz, Poland.

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respond by enhanced insulin secretion to intravenous infu-sion of glucagon-like peptide-1.7 Two DPP-IV inhibitors,sitagliptin and vildagliptin, have been successfully intro-duced into clinical practice. These drugs have been approvedas an oral monotherapy or as a combination therapy withcurrent antidiabetes agents for the treatment of type 2 dia-betes. Recently, the first brief report has been published ofsitaglipitin use in a single case of HNF1A diabetes, and a goodresponse to this drug has been reported.8

Here, we describe the application of DPP-IV inhibitors asan adjuvant therapy in another two patients with HNF1AMODY who failed to respond to previous therapeutic regi-mens that included SU. In addition, we also provide data onthe results of intravenous glucose tolerance tests (IVGTTs)performed before and after DPP-IV implementation in thesepatients.

Descriptions of Cases

Case 1

A 39-year-old female patient with an ArgR171X HNF1Amutation and a 7-year history of diabetes was beingtreated with 160 mg of gliclazide and 2,000 mg of metformin.The family history included three generations of autosomaldominant early-onset diabetes with a clinical picture typicalfor HNF1A MODY. The ArgR171X HNF1A mutation segre-gated with diabetes in this family. She was not diagnosedwith chronic complications of diabetes. She revealed no otherchronic diseases but had a nontoxic nodular goiter. Her bodymass index at the beginning of observation was 26.3 kg=m2.Her initial hemoglobin A1c (HbA1c) and mean glucose levelson the CGMS� (Medtronic, Northridge, CA) record were7.2% and 162 mg=dL, respectively. Sitagliptine, a DPP-IV in-hibitor, at a dose of 100 mg=day was added to the patient’sprevious treatment regimen.

Case 2

A 62-year-old female patient with an IVS7nt-6G>Amutation and a 41-year history of diabetes was being treatedwith 240 mg=day gliclazide and 6 U of aspart insulin=day atmealtime. Her family history of diabetes included four gen-

erations with many affected individuals, and the segregationof the IVS7nt-6G>A mutation with diabetes was well docu-mented.9 She was diagnosed with preproliferative retinopa-thy in both eyes that required several laser treatments. Shealso suffered from peripheral polyneuropathy that was trea-ted with lipoinic acid. Because of hypertension and hyper-cholesterolemia she received antihypertensive treatment thatincluded an angiotensin-converting enzyme inhibitor, an ag-onist of the AT1 receptor, and a statin. Her initial body massindex was 22.2 kg=m2, while initial HbA1c was 8.8%, andaverage glycemia (on the CGMS record) reached 172 mg=dL.In addition to her previous regimen, we began therapy with50 mg of the DPP-IV inhibitor vildagliptine twice daily.

Follow-up in both cases

After addition of DPP-IV inhibitors, over a 3-month follow-up, pharmacological treatment in both patients was stable,and no dose of its components was changed. At reexamina-tion, HbA1c levels of both patients had fallen to 6.3%.Similarly, significant improvement in glycemic control onCGMS was observed, as the average glycemia decreased to114 mg=dL and 134 mg=dL in Case 1 and Case 2, respectively.The proportion of in-target measurements (defined as glyce-mia between 70 mg=dL and 180 mg=dL) was 96% and 69% forCase 1 and Case 2, respectively, compared to the initial 68%and 42%. Figure 1 illustrates a representative 24-h-long re-cording of CGMS of Case 1 before and after DPP-IV inhibitorintroduction. The weight was stable in both subjects overthe period of the observation. No episodes of hypoglycemiabelow 60 mg=dL were recorded, and no other side effectswere reported during the 3-month treatment period in bothpatients.

Importantly, we also saw a substantial rise in the insulinlevel increment during IVGTT performed in fasting condi-tions at the beginning and at the end of the observation inboth patients (by 9.8 and by 13.4 mIU=L in Case 1 and Case 2,respectively) (Fig. 2). We also saw a rise in C-peptide level(C-peptide Elisa Kit, Ely, UK) in IVGTT (in Case 1, 1.93 ng=mLat initial [0 min] and 2.18 ng=mL at 10 min and 1.99 ng=mL atthe end of follow-up [0 min] and 2.81 ng=mL at 10 min; in Case2, 0.84 ng=mL at initial [0 min] and 1.12 ng=mL at 10 min and

FIG. 1. One representative 24-h-long recording of glucose levels (left panel) before DPP-IV inhibitor treatment initiationand (right panel) after its inclusion in the therapeutic model in Case 1, performed by CGMS. Diamonds denote meals.Multiply glucose values by 0.0555 to get mmol=L. Color images available online at www.liebertonline.com=dia.

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1.32 ng=mL at the end of follow-up [0 min] and 1.53 ng=mLat 10 min). The initial fasting plasma glucose level was 9.4and 6.1 mmol=L, whereas the maximal increment in glucosevalues during IVGTT was 10.8 (at min 2) and 17.1 mmol=L(at min 1) for Case 1 and Case 2, respectively. During theexperiment, at the end of the follow-up, the fasting glucoselevel was 5.9 and 4.00 mmol=L, with the maximal incrementof 10.5 (at min 2) and 14.21 mmol=L (at min 2) for Case 1 andCase 2, respectively.

Discussion

The scientific developments of the last few decades haveshown that individual treatment in some forms of diabetes,mainly monogenic ones, could be successfully tailored on thebasis of an accurate differential diagnosis.10 Such a treatment,selected on the basis of genetic testing, may be helpful inachieving metabolic control of the disease and may increasequality of life. Eventually, this may lead to a reduction in theprevalence of diabetes complications and prolonged life ex-pectancy. The first spectacular example of pharmacogeneticsin diabetes was HNF1A MODY, in which effectiveness of SUwas substantially higher compared to metformin.1,2 Althoughlong-term data with patients’ important end points, such aschronic complications or survival, are still lacking, SU agentsare widely considered as the treatment of choice in carriers ofHNF1A mutations with diabetes. There were a few facts thatprompted us to choose DPP-IV inhibitors in these patients asan adjunct therapy to previous therapeutic regimen alreadyincluding SU agents. First, they are available as tablets, and asan adjunct therapy to SU they may provide a better quality oflife than insulin injections. Second, similarly to SU, they actthrough the enhancement of beta-cell function.6 Additionally,although no data for incretin axis abnormalities in MODYare available, a clinical experiment showed that in HNF1Amutation carriers with diabetes, beta-cells may respond toglucagon-like peptide-1 with enhanced insulin secretion.5 Therecent promising report on short-term sitaglipitin use in asingle case of HNF1A MODY suggested its efficacy in this

monogenic diabetes.8 Finally, in another form of monogenicdiabetes associated with a Kir6.2 mutation, the incretin axiswas involved in a therapeutic mechanism of SU action.11

Indeed, we saw a substantial improvement in glycemiccontrol in our two patients as measured by HbA1c level andCGMS record. In addition, we provided evidence of im-proved beta-cell function as documented by increased insulinsecretion shown during IVGTT performed in fasting condi-tions. These data seem to confirm the very recent reportfrom type 2 diabetes suggesting that DPP-IV inhibitors havemetabolic benefits additional to enhancing meal-inducedglucagon-like peptide-1 and gastric inhibitory polypeptideactivity.12 These data suggest the necessity for new researchfocused on a new, yet unidentified, mechanism of action ofDPP-IV inhibitors in patients with diabetes.

Our observation should be considered a case report with allits limitations. In addition, both patients were already re-ceiving other medications as a second-line therapy, metfor-min and insulin, respectively. This report was not able toanswer the question about any special advantage of usingDPP-IV inhibitors in HNF1A MODY over and above the effectwe would expect to see in type 2 diabetes. In addition, oneshould also consider a possibility that reduced glucotoxicitydue to the improvement in glycemic control could have, atleast partially, contributed to the increase in insulin secretionduring IVGGT in our patients.

Nevertheless, we believe that we collected enough evi-dence to show that DPP-IV inhibitors may be an effectivecomponent of combined therapy in HNF1A MODY patients.They should be considered in HNF1A1 mutation carrierswith suboptimally controlled diabetes whose therapeuticregimen already includes SU agents. We postulate that a fu-ture randomized controlled trial or at least a very carefullyconstructed large case series should be carried out to deter-mine the place for DPP-IV in HNF1A MODY in both mono-therapy and combination treatment.

Acknowledgments

This research was supported by the EU Framework 7CEED3 grant and funds from the Jagiellonian UniversityMedical College (grant K=ZDS=000399) and from the PolishDiabetes Association. The authors are grateful to AleksandraMalecka for her linguistic help in the preparation of thismanuscript.

Author Disclosure Statement

M.T.M. has given lectures for Novartis, the manufacturerof sitagliptin. The other authors declare no competing in-terests.

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Address correspondence to:Maciej T. Malecki, M.D., Ph.D.

Department of Metabolic DiseasesJagiellonian University Medical College

15 Kopernika Street31-501 Krakow, Poland

E-mail: malecki_malecki@yahoo.com

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2. M.P. Kyithar, S. Bacon, K.K. Pannu, S.R. Rizvi, K. Colclough, S. Ellard, M.M. Byrne. 2011. Identification of HNF1A-MODYand HNF4A-MODY in Irish families: Phenotypic characteristics and therapeutic implications. Diabetes & Metabolism . [CrossRef]

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