Maturity-onset Diabetes of the Young Clinical Trial
Official title:
Phase 2 Study: A Double-blind, Randomised, Clinical Cross-over Trial to Investigate the Treatment Potential of Liraglutide Compared to Glimepiride in MODY Patients
The purpose of this study is to evaluate the treatment potential of GLP-1-analogues in patients with Maturity Onset Diabetes of the Young (MODY) compared to common treatment.
Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes responsible for
approximately 1-2% of all cases of diabetes. The disease is clinically defined by: 1)
autosomal dominant inheritance (diabetes for at least two consecutive generations), 2)
non-insulin dependent diabetes at onset (or measurable serum C-peptide three years after
onset), and 3) diagnosis in a young age (at least one family member with onset before the
age of 25 years). Clinically, MODY-patients resemble patients with type 2 diabetes (T2DM)
more than patients with type 1 diabetes mellitus (T1DM). MODY is genetically heterogeneous,
with known mutations in eight different genes and mutations in either of these genes leads
to specific forms of MODY. Based on a national epidemiological survey, we know that in
Denmark, approximately 50% of patients who are diagnosed with MODY have mutations in the
hepatocyte nuclear factor (HNF) 4 alpha (HNF4A) (MODY1), glucokinase (GCK) (MODY2), or HNF1A
(MODY3) genes.
MODY3 is the most common form of MODY in Denmark (approximately 60% of all patients with
MODY). Patients with MODY3 are often diagnosed around puberty, more than 50% of mutation
carriers will develop diabetes before the age of 25, and the lifetime risk of developing
diabetes is higher than 95%. The typical course of disease is characterised by a rapid
progression from impaired glucose tolerance to diabetes. After the diagnosis of diabetes,
the glucose tolerance is further impaired due to a continuous loss of beta cell function.
MODY3 often develops abruptly with classic hyperglycaemic symptoms such as polyuria and
polydipsia, which is why this form of diabetes is often misclassified as T1DM. Patients with
MODY3 have the same risk of developing microvascular and macrovascular late diabetic
complications as patients with T2DM, and, strict glycaemic control combined with proper
screening for diabetic late complications is crucial for a good prognosis.
About half of MODY3 patients are treated with diet or oral antidiabetic agents, the latter
mostly in the form of sulphonylureas (SU), which, if possible is preferred to insulin
injections. Due to a high sensitivity to SU combined with normal or even increased insulin
sensitivity (MODY3 patients are more insulin sensitive than age- and body mass index
(BMI)-matched patients with T2DM), this treatment is often associated with hypoglycaemia
even when rather low doses of SU are used. Although SU treatment offhand seems to constitute
a logical choice of treatment in MODY, due to beta cell dysfunction, the risk of
hypoglycaemia is a clinical drawback due to potential suboptimal glycaemic control and
decreased patient compliance. In a recent study, in which patients with MODY3 were exposed
to physical activity (light cycling for 30 minutes approximately 2 hours after meal
ingestion), hypoglycaemia was observed in 40% of subjects treated with short-acting SU
(glibenclamide) with one patient experiencing hypoglycaemia for 12 hours.
Glucagon-like peptide-1 (GLP-1) is an incretin hormone, which is secreted from endocrine L
cells of the small intestine in response to nutrients in the gut lumen. GLP-1 conveys an
insulinotropic effect through GLP-1 receptors (GLP-1R) on pancreatic beta cells thereby
decreasing plasma glucose (PG). Moreover, GLP-1 inhibits the secretion of glucagon from
pancreatic alpha cells, which further contributes to lowering of the PG levels. Both of
these effects are strictly glucose-dependent (more pronounced at higher PG levels) and the
effects cease as PG levels reaches values below 4-5 mM. Therefore, the hormones keep PG at
normal levels without increasing the risk of hypoglycaemia. In addition, GLP-1 inhibits
gastrointestinal motility including gastric emptying and leads to a centrally-mediated
inhibition of appetite resulting in reduced food intake. Thus, GLP-1 is essential for
glycaemic control. The GLP-1R agonist, liraglutide (Victoza®), has 97% homology to the
naturally occurring GLP-1 hormone, but has a longer half-life (11-15 hours).
Since the effects of the incretin hormones are strictly glucose-dependent, treatment with
GLP-1R agonists is rarely associated with hypoglycaemia. Thus, the current study aims to
elucidate whether liraglutide (Victoza®) could be a safe and efficacious new treatment
modality for patients with MODY.
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Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
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