The Changing Landscape of Treatment for Cystic Fibrosis Related Diabetes.

Objective: Patients with Cystic Fibrosis related diabetes [CFRD] are treated with insulin and high calorie diets to maintain body mass. The combined CFTR modulator elexacaftor/tezacaftor/ivacaftor [ETI] decreases pulmonary exacerbations and improves nutritional status. We reviewed the effects of ETI on BMI, HbA1c and diabetes regimen in patients with CFRD over a period of three years. Methods: Data of previously CFTR-modulator-naïve patients with CFRD and pancreatic insufficiency on ETI therapy were retrieved from an electronic health record database. Patients were followed for a mean duration of 2.7 ± 0.8 years after ETI initiation. Data pertaining to weight, BMI, HbA1c and diabetes regimen were collected at 6 months, 12 months, 2 years and at 3 years post-ETI initiation. Patients were then dichotomized based on their baseline BMI into a low BMI group and an "at target" BMI group. The effects of ETI on changes in weight, BMI, A1c and diabetes regimen were compared in both groups over a period of three years. Results: Twenty-seven patients with CFRD (15 men/12 women), age 30.6 ± 11.5 (SD) years, BMI 22.4 ± 4.0 kg/m2, were included. Fifteen patients had low BMI (<22 kg/m2 for women, <23 kg/m2 for men) and 12 patients had at target BMI (≥22 kg/m2for women, ≥BMI 23 kg/m2 for men). Patients with low BMI had an increase in their BMI from 19.5 ± 1.7 to 21.4 ± 2.2 kg/m2 at one year (p = 0.002), and 21.8 ± 1.8 kg/m2 at three years (p = 0.004) after ETI initiation. Four patients (out of 15) in the low BMI group had achieved normal BMI by the end of study follow up. There was no change in weight in the at target BMI group. HbA1c and basal insulin requirements did not change in either group. Five patients started non-insulin therapies. Conclusion: BMI increased after ETI therapy in CFRD patients with low BMI, but not in those with at target BMI. The use of non-insulin therapies is increasing in CFRD and should be evaluated in future studies.

Stroke Prevention by Antihyperglycemic Drugs in Type 2 Diabetes Mellitus.

OBJECTIVES: The American Heart Association/American Stroke Association and the American Association of Clinical Endocrinology provided guidelines for patients with transient ischemic attacks or strokes (TIA/stroke) and diabetes mellitus with the use of glucose-lowering agents (GLA) effective in preventing major adverse cardiovascular events (MACE). This review evaluated GLA for specific differences in TIA/stroke prevention. METHODS: Previous reviews and meta-analyses were evaluated for outcomes of MACE, cardiovascular death (CVD), hospitalization for heart failure, and TIA/stroke. The GLA were glucagon-like peptide 1-receptor agonists (GLP-1RA, 6-trials, n = 46 541), sodium-glucose transport 2 inhibitors (SGLT2i, 5-trials, n = 46 959), insulin-providing regimens (IP, 4-trials, n = 26 223), and thiazolidinediones (TZD, 1-trial, n = 5238). RESULTS: There were reductions in MACE for each class. Relative risk (rr) reductions for TIA/stroke were found with GLP-1RA (rr = 0.840, 95% CI: 0.759, 0.936, P =.001) but not with SGLT2i, IP, or TZD. Cardiovascular deaths were decreased with GLP-1RA (rr = 0.873, CI: 0.804, 0.947, P =.001) and SGLT2i (rr = 0.835, CI: 0.706, 0.987, P =.034), but not with TZD or IP. Hospitalizations for heart failure were decreased only with SGLT2i (rr = 0.699, CI: 0.626, 0.781, P <.001). Increased CVD correlated with aggressive lowering of A1c (r = -0.611, P =.012) and showed a trend with the relative risk of hypoglycemia (r = 0.447, P =.08). For GLP-1RA, there was no increase in hypoglycemia and a direct correlation with a decreased rr for stroke with decreases in A1c (r = 0.917, P =.010). CONCLUSION: Improvements in A1c with GLP-1RA were associated with stroke prevention in patients with diabetes and with TIA or stroke. Reductions in cardiovascular mortality include therapy with GLP-1RA and SGLT2i. Aggressive lowering of A1c, however, was associated with increased CVD.

Glucagon-like peptide 1-receptor agonists and A1c: Good for the heart but less so for the eyes?

BACKGROUND AND AIMS: Glucagon-like peptide1-receptor agonists (GLP1-RA) decrease major adverse cardiovascular events (MACE) in people with type 2 diabetes mellitus and cardiovascular disease (CVD). Caution is recommended for semaglutide and dulaglutide with risk of exacerbating diabetic retinopathy (DR). Analyses were performed to determine if worsening of DR was dependent on drug class or fall in A1c. RESEARCH DESIGN AND METHODS: Meta-analyses and meta-regressions (MR) were performed on the 7 major cardiovascular outcome trial (CVOTs) (n = 56004 patients) of GLP1-RA. A second analysis of 11 studies (n = 11894 subjects) with semaglutide documenting DR followed. RESULTS: Six of the CVOTs evaluated DR. For the GLP1-RA class, there was no increase in the relative rate (rr) for retinopathy (rr = 1.09,95%CI; 0.925,1.289, p = 0.30), with only an increase with parenteral semaglutide (rr = 1.73; 1.10:2.71, p = 0.02). MR showed that decreases in A1c correlated with decreases in MACE (log rr = 0.364∗(Δ A1c), p = 0.014), but increases in DR (log rr= (-0.67∗(ΔA1c), p = 0.076). The change in DR was predominantly found for subcutaneous semaglutide given for >1 year (rr = 1.559,1.068,2.276, p = 0.022) and with decreases in A1c > 1.0% (rr = 1.59; 1.092,2.316, p = 0.016). For the class of GLP1-RA, the rate difference (rd) for worsening retinopathy was = 0.001 (and number needed to harm [NNH] = 1000) compared with rd for MACE = -0.013 (number needed to treat [NNT] = 77). The computation for semaglutide was NNH = 77 and NNT = 43. CONCLUSIONS: This meta-analysis may assist in decisions balancing the relative risk (of existing retinopathy) versus benefits (to existing CVD). There should be close collaboration with ophthalmology to grade the baseline degree of retinopathy when initiating and following patients.

Association of Male Hypogonadism With Risk of Hospitalization for COVID-19.

Importance: Male sex is associated with severe COVID-19. It is not known whether the risk of hospitalization differs between men with hypogonadism, men with eugonadism, and those receiving testosterone therapy (TTh). Objective: To compare COVID-19 hospitalization rates for men with hypogonadism who were not receiving TTh, men with eugonadism, and men receiving TTh. Design, Setting, and Participants: This cohort study was conducted in 2 large academic health systems in St Louis, Missouri, among 723 men with a history of COVID-19 who had testosterone concentrations measured between January 1, 2017, and December 31, 2021. Exposures: The primary exposure was gonadal status (hypogonadism, eugonadism, and TTh). Hypogonadism was defined as a total testosterone concentration below the limit of normal provided by the laboratory (which varied from 175 to 300 ng/dL [to convert to nanomoles per liter, multiply by 0.0347]). Main Outcomes and Measures: The primary outcome was rate of hospitalization for COVID-19. Statistical adjustments were made for group differences in age, body mass index, race and ethnicity, immunosuppression, and comorbid conditions. Results: Of the 723 study participants (mean [SD] age, 55 [14] years; mean [SD] body mass index, 33.5 [7.3]), 116 men had hypogonadism, 427 had eugonadism, and 180 were receiving TTh. Men with hypogonadism were more likely than men with eugonadism to be hospitalized with COVID-19 (52 of 116 [45%] vs 53 of 427 [12%]; P < .001). After multivariable adjustment, men with hypogonadism had higher odds than men with eugonadism of being hospitalized (odds ratio, 2.4; 95% CI, 1.4-4.4; P < .003). Men receiving TTh had a similar risk of hospitalization as men with eugonadism (odds ratio, 1.3; 95% CI, 0.7-2.3; P = .35). Men receiving inadequate TTh (defined as subnormal testosterone concentrations while receiving TTh) had higher odds of hospitalization compared with men who had normal testosterone concentrations while receiving TTh (multivariable adjusted odds ratio, 3.5; 95% CI, 1.5-8.6; P = .003). Conclusions and Relevance: This study suggests that men with hypogonadism were more likely to be hospitalized after COVID-19 infection compared with those with eugonadism, independent of other known risk factors. This increased risk was not observed among men receiving adequate TTh. Screening and appropriate therapy for hypogonadism need to be evaluated as a strategy to prevent severe COVID-19 outcomes among men.