Acute systemic hyperglycemia causes oxidative stress and a pro-inflammatory response. The
pro-inflammatory cytokines induced by hyperglycemia are toxic to islet insulin producing
cells, and thus worsen glucose intolerance. Patients with cystic fibrosis (CF) have a high
prevalence of CF related diabetes (CFRD) and up to 40% of CF adults develop CFRD. During the
prediabetic phase in CF, there is progression from normal glucose homeostasis to high risk
prediabetes characterized by episodes of acute hyperglycemia after meals and during
respiratory exacerbations. The mild hyperglycemia seen in CF patients with high risk
prediabetes following a meal would be expected to induce a degree of systemic inflammation
and oxidative stress. These repetitive episodes, if left unchecked, could lead to progression
of glucose impairment, worsening severity of oxidative stress and inflammation, and
ultimately the development of CFRD, all via hyperglycemia-induced toxicity to beta cells.
Furthermore, this process may be accelerated in CF because lung disease and resultant
respiratory exacerbations are associated with oxidative stress and inflammation and this will
further contribute to beta cell damage.
Sitagliptin is a recently approved agent for type 2 diabetes and markedly enhances insulin
secretion in the presence of hyperglycemia and has been shown to be effective in preventing
postprandial hyperglycemia. The hypothesis to be tested in this project is that sitagliptin
will prevent the development of CFRD in CF subjects with high risk prediabetes by blocking
postprandial hyperglycemia. The investigators propose a randomized, double-blind,
placebo-controlled, multicenter, 15-month longitudinal study in 118 CF subjects with high
risk prediabetes to test this hypothesis. Specifically, the investigators aim to show that
chronic treatment with sitagliptin: prevents the conversion to diabetes; results in
preservation of beta cell function; reduces systemic measures of oxidative stress and
inflammation; and slows the rate of progression of lung disease.
Funding Source - FDA Office of Orphan Products Development