Diabetes-related mortality in adults with cystic fibrosis. Role of genotype and sex

Abstract

Rationale: Diabetes is associated with increased mortality in cystic fibrosis. Aggressive screening and early institution of insulin treatment significantly reduced this risk over the period of 1992-2008.

Objectives: To determine if progressive improvement in cystic fibrosis-related diabetes (CFRD) mortality has continued since 2008, and examine associations with CFTR genotypes linked to pancreatic insufficiency and to sex.

Methods: Chart review was performed on 664 patients followed from 2008 to 2012.

Measurements and main results: Overall mortality for patients with CFRD was 1.8 per 100 person-years, compared with 0.5 in patients with CF without diabetes (P = 0.0002); neither rate changed significantly from mortality reported for 2003-2008. Genotype impacted both mortality and diabetes risk: adults with severe CFTR genotypes experienced greater mortality at every age older than 32 years than those with mild genotypes (P = 0.002), and the risk of developing CFRD was also greatly increased in those with severe genotypes (prevalence 60% in adult patients with severe vs. 14% in adults with mild mutations). CFRD had a direct influence on mortality because it was associated with increased risk of death within each genotype category (20 vs. 2%, P = 0.007 for mild; 12 vs. 4%, P = 0.012 for severe). There was also a sex difference in adults with severe CFTR genotypes; both mortality and CFRD prevalence were higher at every age in females than males.

Conclusions: Despite substantial improvement over time, mortality for CFRD patients greater than 30 years remains higher than for patients with CF without diabetes.

Keywords: cystic fibrosis–related diabetes; prognosis; sex differences; survival.

Figure 1.

University of Minnesota mortality rates per 100 patient-years for cystic fibrosis (CF) patients with and without diabetes (DM) by sex and age decade over four time periods: 1992–1997; 1998–2002; 2003–September 15, 2008; and September 16, 2008–2012. Patients with CF with DM are shown with solid lines, and patients with CF without DM are shown with dashed lines. Females are shown in red and males in blue. The bottom three panels were previously published in Diabetes Care (13).

Figure 2.

(A) Kaplan-Meier estimates of survival curves for adult cystic fibrosis patients age 20 and older during the current period, divided into three groups: all with mild genotype, males with severe genotype, and females with severe genotype. Vertical dashes indicate patients still alive at last visit (censored), and the number of patients under observation at each age decade is shown at the bottom. (B) Kaplan-Meier estimates of cystic fibrosis–related diabetes (CFRD) prevalence by age for adult cystic fibrosis patients age 20 and older during the current period, divided into three groups: all with mild genotype, males with severe genotype, and females with severe genotype. Vertical dashes indicate patients without CFRD at last visit (censored).