Diabetes
The impact of CFTR modulators on the development or control of diabetes
is a pertinent area of study as CF related diabetes (CFRD) affects up to
20% of adolescents and 50% of adults with CF38. Many
pwCF who do not yet have CFRD have impaired glucose tolerance (IGT).
Part of the pathophysiology of IGT and CFRD involves decreased insulin
secretion, insulin resistance and hepatic glucose control abnormalities,
along with other mechanisms of insulin insufficiency such as destruction
of the pancreas, islet cell inflammation, and oxidative
stress39. In past studies of those with the G551D
mutation, iva improved insulin secretion38. Therefore,
studies have been undertaken to evaluate if lum/iva improves glucose
tolerance in F508del homozygotes. A prospective, observational study in
France, examined the effect of lum/iva on glucose tolerance
abnormalities in pwCF between ages 12-61 years (average 24 years). At
baseline, 78% of 40 patients had IGT, and 22% had newly diagnosed
CFRD, while patients with fasting hyperglycemia, requiring insulin
therapy or, with normal glucose tolerance (NGT) were
excluded39. After 1 year of lum/iva treatment, based
on 2-hour glucose levels in the oral glucose tolerance test (OGTT),
57.5% improved their glucose tolerance, and 42.5% had no change
(p<0.001). Overall, after 1-year lum/iva, 50% (n=20) had NGT,
40% (n=16) had IGT and 10% (n=4) had CFRD. Specifically, out of those
with newly diagnosed CFRD (n=9), after 1 year of lum/iva, 2 had NGT, 3
had IGT and 4 continued to have CFRD. Out of 31 subjects with IGT, after
1 year of lum/iva, 18 had NGT, 13 had IGT and 0 developed CFRD.
Additionally, in the entire cohort, the 2-hour glucose levels decreased
from 171 mg/dL (153-197 mg/dL) to 139 mg/dL (117-162 mg/dL)
(p<0.001). HemoglobinA1c, C-peptide, fasting and one hour
glucose levels, and insulin levels were unchanged.
A separate study evaluated glucose alterations in 39 subjects, aged
12-51 years, prior to and 3, 6, and 12 months after initiation of
lum/iva38. At one year post treatment, the mean values
comparing baseline, 3-, 6-, and 12-month values did not differ for any
of the parameters, including fasting glucose levels (p=0.74), 2-hour
glucose levels (p=0.26), glucose area under the curve (p=0.67), insulin
area under the curve (p=0.82), and peak insulin levels (p=0.33).
Overall, there was no significant improvement with lum/iva in any of the
glucose tolerance categories. Out of those with CFRD (n=15), 2 (13%)
improved and 13 (87%) stayed the same. In those with NGT (n=9), 6
(67%) stayed the same and 3 (33%) worsened. In those with
indeterminate glycemia (defined as normal fasting and 2 hour, but
elevated mid OGTT glucose)40 and IGT (n=15), 7 (47%)
improved, 5 (33%) stayed the same and 3 (20%) worsened. No changes
were seen in fasting or 2-hour glucose levels, area under the curve for
glucose or insulin, time to peak insulin, or C-peptide levels. The
results of these two trials show benefit with iva and lack of benefit
with lum/iva in impacting OGTT results. However, the minimal effects and
the differential responses show that further studies will be needed to
truly understand the impact of different CFTR modulators on glucose
tolerance.