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.