CoChat
Sign Up
Cited by 48Diabetes Treatment and ManagementDiabetes Management and ResearchPancreatic function and diabetes

Efficacy and safety of glimepiride with or without linagliptin treatment in patients with HNF1A diabetes (maturity-onset diabetes of the young type 3): a randomized, double-blinded, placebo-controlled, crossover trial (GLIMLINA)

Open access
Christensen, Alexander S., Hædersdal, Sofie, Støy, Julie, Storgaard, Heidi, Kampmann, Ulla, Forman, Julie L., Seghieri, Marta, Holst, Jens J. +3 more·2020·Diabetes Care
DOI 10.2337/dc20-0408PMC PMC7440905
Open this paper in CoChat — free accountOpen PDF

Abstract

OBJECTIVE: Sulfonylureas are first-line treatment of hepatocyte nuclear factor 1-α (HNF1A) diabetes (maturity-onset diabetes of the young type 3), but many patients do not achieve optimal glycemic control without episodes of hypoglycemia. We investigated the combination of the sulfonylurea glimepiride and the dipeptidyl peptidase 4 inhibitor linagliptin versus glimepiride monotherapy with respect to glycemic variability, glycemic control, and risk of hypoglycemia. RESEARCH DESIGN AND METHODS: In a randomized, double-blinded, crossover trial, patients with HNF1A diabetes (n = 19; mean ± SD age 43 ± 14 years, BMI 24.8 ± 2.8 kg/m2, and glycated hemoglobin [HbA1c] 7.4 ± 0.2% [57.1 ± 7.3 mmol/mol]) were randomly assigned to treatment with glimepiride + linagliptin 5 mg (16 weeks), washout (4 weeks), and glimepiride + placebo (16 weeks) (or vice versa). Glimepiride was titrated targeting a fasting plasma glucose of 4.5–6.0 mmol/L without hypoglycemia. Treatments were evaluated by continuous glucose monitoring (CGM), HbA1c, and meal test. RESULTS: Compared with glimepiride + placebo, glimepiride + linagliptin did not significantly improve the primary end point, mean amplitude of glycemic excursions (MAGE) (mean difference −0.7 mmol/L, P = 0.1540), but displayed significant reductions in coefficient of variation on CGM (−3.6%, P = 0.0401), HbA1c (−0.5%, P = 0.0048), and glimepiride dose (−0.7 mg/day, P = 0.0099). β-cell glucose sensitivity (assessed as C-peptide–to–glucose ratio) during meal test improved with glimepiride + linagliptin. Incidences of hypoglycemia were similar with both treatments. CONCLUSIONS: Linagliptin as add-on treatment to glimepiride improved glycemic variability and control without increasing risk of hypoglycemia in patients with HNF1A diabetes.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.2337/dc20-0408

Cites

3 of 3 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • For individuals with HNF1A mutations, addition of a DPP-4 inhibitor to sulfonylurea may help improve glycemic variability and attainment of glycemic goals.

    “For those with HNF1A mutations, addition of a DPP-4 inhibitor to the sulfonylurea may help improve glycemic variability and attainment of glycemic goals (235).”

    From 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes—2025 (2025) · cites this paper as [235]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 33

  1. [2]Shields BM, Hicks S, Shepherd MH, Colclough K, Hattersley AT, Ellard S Maturity-onset diabetes of the young (MODY): how many cases are we missing? Diabetologia 2010; 53: 2504– 2508 20499044
  2. [3]Colclough K, Bellanne-Chantelot C, Saint-Martin C, Flanagan SE, Ellard S Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha and 4 alpha in maturity-onset diabetes of the young and hyperinsulinemic hypoglycemia. Hum Mutat 2013; 34: 669– 685 23348805
  3. [4]Isomaa B, Henricsson M, Lehto M, Chronic diabetic complications in patients with MODY3 diabetes. Diabetologia 1998; 41: 467– 473 9562352
  4. [5]Steele AM, Shields BM, Shepherd M, Ellard S, Hattersley AT, Pearson ER Increased all-cause and cardiovascular mortality in monogenic diabetes as a result of mutations in the HNF1A gene. Diabet Med 2010; 27: 157– 161 20546258
  5. [6]Stride A, Vaxillaire M, Tuomi T, The genetic abnormality in the beta cell determines the response to an oral glucose load. Diabetologia 2002; 45: 427– 435 11914749
  6. [7]Pearson ER, Velho G, Clark P, beta-cell genes and diabetes: quantitative and qualitative differences in the pathophysiology of hepatic nuclear factor-1alpha and glucokinase mutations. Diabetes 2001; 50(Suppl. 1): S101– S107 11272165
  7. [8]Wollheim CB Beta-cell mitochondria in the regulation of insulin secretion: a new culprit in type II diabetes. Diabetologia 2000; 43: 265– 277 10768087
  8. [9]Hansen T, Eiberg H, Rouard M, Novel MODY3 mutations in the hepatocyte nuclear factor-1α gene: evidence for a hyperexcitability of pancreatic β-cells to intravenous secretagogues in a glucose-tolerant carrier of a P447L mutation. Diabetes 1997; 46: 726– 730 9075819
  9. [10]Tripathy D, Carlsson Å-L, Lehto M, Isomaa B, Tuomi T, Groop L Insulin secretion and insulin sensitivity in diabetic subgroups: studies in the prediabetic and diabetic state. Diabetologia 2000; 43: 1476– 1483 11151756
  10. [11]Pearson ER, Starkey BJ, Powell RJ, Gribble FM, Clark PM, Hattersley AT Genetic cause of hyperglycaemia and response to treatment in diabetes. Lancet 2003; 362: 1275– 1281 14575972
  11. [12]Pearson ER, Liddell WG, Shepherd M, Corrall RJ, Hattersley AT Sensitivity to sulphonylureas in patients with hepatocyte nuclear factor-1α gene mutations: evidence for pharmacogenetics in diabetes. Diabet Med 2000; 17: 543– 545 10972586
  12. [14]American Diabetes Association 9. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes—2019. Diabetes Care 2019; 42(Suppl. 1): S90– S102 30559235
  13. [15]Østoft SH, Bagger JI, Hansen T, Glucose-lowering effects and low risk of hypoglycemia in patients with maturity-onset diabetes of the young when treated with a GLP-1 receptor agonist: a double-blind, randomized, crossover trial. Diabetes Care 2014; 37: 1797– 1805 24929431
  14. [16]Tuomi T, Honkanen EH, Isomaa B, Sarelin L, Groop LC Improved prandial glucose control with lower risk of hypoglycemia with nateglinide than with glibenclamide in patients with maturity-onset diabetes of the young type 3. Diabetes Care 2006; 29: 189– 194 16443858
  15. [17]Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) UK Prospective Diabetes Study (UKPDS) Group [published correction appears in Lancet 1999;354:602]. Lancet 1998; 352: 837– 853 9742976
  16. [18]Christensen MB, Calanna S, Holst JJ, Vilsbøll T, Knop FK Glucose-dependent insulinotropic polypeptide: blood glucose stabilizing effects in patients with type 2 diabetes. J Clin Endocrinol Metab 2014; 99: E418– E426 24423311
  17. [19]Weir GC, Mojsov S, Hendrick GK, Habener JF Glucagonlike peptide I (7-37) actions on endocrine pancreas. Diabetes 1989; 38: 338– 342 2645190
  18. [20]Mari A, Sallas WM, He YL, Vildagliptin, a dipeptidyl peptidase-IV inhibitor, improves model-assessed β-cell function in patients with type 2 diabetes. J Clin Endocrinol Metab 2005; 90: 4888– 4894 15886245
  19. [21]McGill JB Linagliptin for type 2 diabetes mellitus: a review of the pivotal clinical trials. Ther Adv Endocrinol Metab 2012; 3: 113– 124 23185685 PMC3498850
  20. [23]Aaboe K, Akram S, Deacon CF, Holst JJ, Madsbad S, Krarup T Restoration of the insulinotropic effect of glucose-dependent insulinotropic polypeptide contributes to the antidiabetic effect of dipeptidyl peptidase-4 inhibitors. Diabetes Obes Metab 2015; 17: 74– 81 25243647
  21. [24]Christensen AS, Hædersdal S, Storgaard H, GIP and GLP-1 potentiate sulfonylurea-induced insulin secretion in hepatocyte nuclear factor 1-α mutation carriers. Diabetes. 9 June 2020 [Epub ahead of print]. DOI: 10.2337/db20-0074 PMC7458039 32518064 · DOI
  22. [25]Sidelmann Christensen A, Storgaard H, Hædersdal S, Hansen T, Krag Knop F, Vilsbøll T Glimepiride monotherapy versus combination of glimepiride and linagliptin therapy in patients with HNF1A-diabetes: a protocol for a randomised, double-blinded, placebo-controlled trial. BMJ Open 2018; 8: e022517 PMC6194456 30287671
  23. [26]International Hypoglycaemia Study Group Glucose concentrations of less than 3.0 mmol/L (54 mg/dL) should be reported in clinical trials: a joint position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2017; 40: 155– 157 27872155
  24. [28]Liebl A, Henrichs HR, Heinemann L, Freckmann G, Biermann E, Thomas A; Continuous Glucose Monitoring Working Group of the Working Group Diabetes Technology of the German Diabetes Association Continuous glucose monitoring: evidence and consensus statement for clinical use. J Diabetes Sci Technol 2013; 7: 500– 519 23567009 PMC3737652
  25. [29]Hill NR, Oliver NS, Choudhary P, Levy JC, Hindmarsh P, Matthews DR Normal reference range for mean tissue glucose and glycemic variability derived from continuous glucose monitoring for subjects without diabetes in different ethnic groups. Diabetes Technol Ther 2011; 13: 921– 928 21714681 PMC3160264
  26. [30]Saisho Y, Tanaka C, Tanaka K, Relationships among different glycemic variability indices obtained by continuous glucose monitoring. Prim Care Diabetes 2015; 9: 290– 296 25456706
  27. [31]Baghurst PA Calculating the mean amplitude of glycemic excursion from continuous glucose monitoring data: an automated algorithm. Diabetes Technol Ther 2011; 13: 296– 302 21291334
  28. [32]Katra B, Klupa T, Skupien J, Dipeptidyl peptidase-IV inhibitors are efficient adjunct therapy in HNF1A maturity-onset diabetes of the young patients--report of two cases. Diabetes Technol Ther 2010; 12: 313– 316 20210571
  29. [33]Misra S, Owen KR Genetics of monogenic diabetes: present clinical challenges. Curr Diab Rep 2018; 18: 141 30377832 PMC6209016
  30. [34]Østoft SH, Bagger JI, Hansen T, Incretin effect and glucagon responses to oral and intravenous glucose in patients with maturity-onset diabetes of the young--type 2 and type 3. Diabetes 2014; 63: 2838– 2844 24677712
  31. [35]DeFronzo RA, Okerson T, Viswanathan P, Guan X, Holcombe JH, MacConell L Effects of exenatide versus sitagliptin on postprandial glucose, insulin and glucagon secretion, gastric emptying, and caloric intake: a randomized, cross-over study. Curr Med Res Opin 2008; 24: 2943– 2952 18786299
  32. [36]Ahrén B, Landin-Olsson M, Jansson P-A, Svensson M, Holmes D, Schweizer A Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes. J Clin Endocrinol Metab 2004; 89: 2078– 2084 15126524
  33. [37]Vella A, Bock G, Giesler PD, Effects of dipeptidyl peptidase-4 inhibition on gastrointestinal function, meal appearance, and glucose metabolism in type 2 diabetes. Diabetes 2007; 56: 1475– 1480 17303799

Cited by

Sorted by citations

Authors
Christensen, A. S., Hædersdal, S., Støy, J., Storgaard, H., Kampmann, U., Forman, J. L., Seghieri, M., Holst, J. J., Hansen, T., Knop, F. K., & Vilsbøll, T.
Affiliations
  • University of Copenhagen (DK)
  • Aarhus University Hospital (DK)
Corresponding author
Vilsbøll, Tina
ORCID
Venue
Diabetes Care
Publisher
American Diabetes Association
Published
2020-07-13
Volume
43
Issue
9
Pages
2025-2033
ISSN
  • 0149-5992 (ISSN-L)
  • 1935-5548
DOI
10.2337/dc20-0408
PMC
PMC7440905
OpenAlex
W3041923253
Cited by
48
References
3
Citations by year
2026: 8 · 2025: 10 · 2024: 9 · 2023: 10 · 2022: 7 · 2021: 2 · 2020: 2
FWCI
3.96
Type
journal article
Language
en
Open access
Licence
www.diabetesjournals.org/content/license (vor, 38 d)
Locations
  • Diabetes Care (publishedVersion)
  • PubMed Central (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
  • PubMed (publishedVersion)
Funders
Boehringer Ingelheim
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
Keywords
glimepiride, linagliptin, MODY3, sulfonylureas, DPP-4 inhibitors, combination therapy, glycemic variability, hypoglycemia, HbA1c, beta-cell glucose sensitivity, continuous glucose monitoring
MeSH terms
Linagliptin, Adult, Blood Glucose, Denmark, Diabetes Mellitus, Type 2, Double-Blind Method, Female, Glycated Hemoglobin, Humans, Hypoglycemia, Male, Middle Aged, Placebos, Sulfonylurea Compounds, Blood Glucose Self-Monitoring, Treatment Outcome, Cross-Over Studies, Hepatocyte Nuclear Factor 1-alpha

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review