Oral or injectable semaglutide for the management of type 2 diabetes in routine care: A multicentre observational study comparing matched cohorts.

AIM: To investigate the real-world utilization and comparative clinical outcomes of injectable and oral semaglutide in individuals with type 2 diabetes (T2D) with the aim of enhancing understanding of the practical implications associated with choosing between these formulations. METHODS: New users of oral or injectable semaglutide were selected from a cohort of 14 079 initiators of glucagon-like peptide-1 receptor agonists. Propensity-score matching (PSM) was employed to create balanced groups, ensuring comparability. The analysis encompassed dose exposure, drug persistence, and clinical outcomes, including changes in glycated haemoglobin (HbA1c) and body weight, with up to 18 months' follow-up. RESULTS: We analysed two matched groups of 107 participants each, who comprised on average 63.6% men, aged 64 years, with diabetes duration of approximately 10 years, body mass index of 29 kg/m2 and HbA1c level of 7.7-7.8% (61-62 mmol/mol). The proportion of low, intermediate and high doses were similar with the oral and the injectable formulation. The change in HbA1c was similar between groups (-0.9% / -10 mmol/mol at 18 months) as was the proportion of individuals reaching HbA1c <6.5% (48 mmol/mol). The average change in body weight was similar in the two groups (-3.7 kg with injectable and -3.3 kg with oral at 18 months) but more new users of injectable semaglutide lost ≥5% body weight. Persistence on drug was longer with injectable than with oral semaglutide. CONCLUSION: In a real-world setting, improvements in HbA1c and body weight were similar after initiation of oral or injectable semaglutide. These results may be specific to the features of the matched cohorts under investigation, with limited generalizability to populations with different characteristics.

Circulating haematopoietic stem cells and long-term outcomes of COVID-19.

BACKGROUND AND AIMS: An acute depletion of circulating haematopoietic stem/progenitor cells (HSPCs) occurs during COVID-19, especially among patients with a poorer disease course. We herein examined whether HSPCs levels at hospital admission for COVID-19 predict 1-year mortality and the long-COVID syndrome. MATERIALS AND METHODS: Patients hospitalized for COVID-19 in an infectious disease ward were consecutively enrolled. Circulating HSPC levels were assessed by flow cytometry as cells expressing CD34 and/or CD133. Follow-up was performed for 12 months after hospitalization through the review of electronic medical records and demographic local registers. RESULTS: The study included 100 patients, 36 of whom reported symptoms of long-COVID and 20 died during follow-up. The reduction of 1-SD of HSPCs was associated with a 3- to 5-fold increase in the risk of 1-year mortality. Age, admission hyperglycaemia, C-reactive protein peak, liver enzymes, the need of high-flow oxygen and/or invasive ventilation were predictors of mortality at univariate analysis. Among pre-existing comorbidities, coronary heart disease and chronic kidney disease, but not diabetes, were associated with 1-year mortality. In multivariate analyses, HSPCs remained significantly associated with 1-year mortality independently of confounders. The development of pneumonia an in-hospital treatment with glucocorticoids and convalescent plasma were associated with long-COVID symptoms at follow-up. HSPCs, diabetes and other comorbidities were not predictors of long-COVID. CONCLUSIONS: In a cohort of patients hospitalized for COVID-19, lower HSPC levels at the time of admission were independent predictors of 1-year mortality. However, COVID-19 severity, but not HSPC level, was significantly associated with the development of long-COVID symptoms.

Improved prediction of long-term kidney outcomes in people with type 2 diabetes by levels of circulating haematopoietic stem/progenitor cells.

AIM/HYPOTHESIS: We examined whether prediction of long-term kidney outcomes in individuals with type 2 diabetes can be improved by measuring circulating levels of haematopoietic stem/progenitor cells (HSPCs), which are reduced in diabetes and are associated with cardiovascular risk. METHODS: We included individuals with type 2 diabetes who had a baseline determination of circulating HSPCs in 2004-2019 at the diabetes centre of the University Hospital of Padua and divided them into two groups based on their median value per ml of blood. We collected updated data on eGFR and albuminuria up to December 2022. The primary endpoint was a composite of new-onset macroalbuminuria, sustained ≥40% eGFR decline, end-stage kidney disease or death from any cause. The analyses were adjusted for known predictors of kidney disease in the population with diabetes. RESULTS: We analysed 342 participants (67.8% men) with a mean age of 65.6 years. Those with low HSPC counts (n=171) were significantly older and had a greater prevalence of hypertension, heart failure and nephropathy (45.0% vs 33.9%; p=0.036), as evidenced by lower eGFR and higher albuminuria at baseline. During a median follow-up of 6.7 years, participants with high vs low HSPC counts had lower rates of the composite kidney outcome (adjusted HR 0.69 [95% CI 0.49, 0.97]), slower decline in eGFR and a similar increase in albuminuria. Adding the HSPC information to the risk score of the CKD Prognosis Consortium significantly improved discrimination of individuals with future adverse kidney outcomes. CONCLUSIONS/INTERPRETATION: HSPC levels predict worsening of kidney function and improve the identification of individuals with type 2 diabetes and adverse kidney outcomes over and beyond a clinical risk score.

Ketosis-prone Diabetes and Hypogonadism: A New Clinical Association to be Aware of ?

BACKGROUND: Ketosis-prone diabetes (KPD) is an emerging entity, sharing features of both type 1 diabetes mellitus and type 2 diabetes mellitus. Patients with KPD usually present with diabetic ketoacidosis without the classic phenotype of autoimmune type 1 diabetes. In most cases, they are Afro-American adults, who require insulin therapy for the management of acute decompensation, then usually encountering insulin-free remission for prolonged periods of time with diet or with non-insulin agents. Meanwhile, hypogonadism is a known condition that could be associated with higher risk of developing both type 1 and type 2 diabetes and could be a risk factor for decompensated diabetes. The association of KPD and hypogonadism is reported for the first time in literature. CASE PRESENTATION: Here we report two peculiar cases of young African patients, affected by KPD and hypergonadotropic hypogonadism, respectively Klinefelter's syndrome and primary ovarian failure. Both patients were treated promptly for the ketoacidosis with intravenous fluids combined with continuous insulin infusion, and then switched to subcutaneous regimen. After the correct clinical evaluation, oral antidiabetic drugs were added. CONCLUSION: KPD remains an under-recognized and under-diagnosed type of diabetes. As hypogonadism is strongly linked to dysmetabolic disorders, the evaluation of sex hormones should be performed at the onset of diabetes. Further studies should investigate the hypothalamic-pituitary-gonadal axis and its role in the development of KDP and its manifestations and complications.

Glycaemic Control Achieves Sustained Increases of Circulating Endothelial Progenitor Cells in Patients Hospitalized for Decompensated Diabetes: An Observational Study.

BACKGROUND AND AIM: Diabetes reduces the levels of circulating endothelial progenitor cells (EPCs), which contribute to vascular homeostasis. In turn, low EPCs levels predict progression of chronic complications. Several studies have shown that hyperglycaemia exerts detrimental effects on EPCs. Improvement in glucose control with glucose-lowering medications is associated with an increase of EPCs, but only after a long time of good glycaemic control. In the present study, we examined the effect of a rapid glycaemic amelioration on EPC levels in subjects hospitalized for decompensated diabetes. METHODS: We used flow cytometry to quantify EPCs (CD34+/CD133+KDR+) in patients hospitalized for/with decompensated diabetes at admission, at discharge, and 2 months after the discharge. During hospitalization, all patients received intensive insulin therapy. RESULTS: Thirty-nine patients with type 1 or type 2 diabetes were enrolled. Average (± SEM) fasting glucose decreased from 409.2 ± 25.9 mg/dl at admission to 190.4 ± 12.0 mg/dl at discharge and to 169.0 ± 10.3 at 2 months (both p < 0.001). EPCs (per million blood cells) significantly increased from hospital admission (13.1 ± 1.4) to discharge (16.4 ± 1.1; p = 0.022) and remained stable after 2 months (15.5 ± 1.7; p = 0.023 versus baseline). EPCs increased significantly more in participants with newly-diagnosed diabetes than in those with pre-existing diabetes. The increase in EPCs was significant in type 1 but not in type 2 diabetes and in those without chronic complications. CONCLUSION: In individuals hospitalized for decompensated diabetes, insulin therapy rapidly increases EPC levels for up to 2 months. EPC defect, reflecting impaired vascular repair capacity, may be reversible in the early diabetes stages.

Hematopoietic progenitor cell liabilities and alarmins S100A8/A9-related inflammaging associate with frailty and predict poor cardiovascular outcomes in older adults.

Frailty affects the physical, cognitive, and social domains exposing older adults to an increased risk of cardiovascular disease and death. The mechanisms linking frailty and cardiovascular outcomes are mostly unknown. Here, we studied the association of abundance (flow cytometry) and gene expression profile (RNAseq) of stem/progenitor cells (HSPCs) and molecular markers of inflammaging (ELISA) with the cardiorespiratory phenotype and prospective adverse events of individuals classified according to levels of frailty. Two cohorts of older adults were enrolled in the study. In a cohort of pre-frail 35 individuals (average age: 75 years), a physical frailty score above the median identified subjects with initial alterations in cardiorespiratory function. RNA sequencing revealed S100A8/A9 upregulation in HSPCs from the bone marrow (>10-fold) and peripheral blood (>200-fold) of individuals with greater physical frailty. Moreover higher frailty was associated with increased alarmins S100A8/A9 and inflammatory cytokines in peripheral blood. We then studied a cohort of 104 more frail individuals (average age: 81 years) with multidomain health deficits. Reduced levels of circulating HSPCs and increased S100A8/A9 concentrations were independently associated with the frailty index. Remarkably, low HSPCs and high S100A8/A9 simultaneously predicted major adverse cardiovascular events at 1-year follow-up after adjustment for age and frailty index. In conclusion, inflammaging characterized by alarmin and pro-inflammatory cytokines in pre-frail individuals is mirrored by the pauperization of HSPCs in frail older people with comorbidities. S100A8/A9 is upregulated within HSPCs, identifying a phenotype that associates with poor cardiovascular outcomes.

Hyperglycemia, Reduced Hematopoietic Stem Cells, and Outcome of COVID-19.

Admission hyperglycemia has emerged worldwide as a predictor of poor coronavirus disease 2019 (COVID-19) outcome. Hyperglycemia leads to a defect in circulating hematopoietic stem/progenitor cells (HSPCs), which, in turn, predicts diabetic complications. Here, we explored whether reduced HSPCs mediated at least part of the prognostic effect of hyperglycemia on COVID-19 outcome. We found that patients with COVID-19 (n = 100) hospitalized in a nonintensive setting displayed dramatically (50-60%) reduced levels of HSPCs measured by flow cytometry as CD34+, CD34+CD45dim, or CD34+CD133+ cells, compared with control subjects (n = 595). This finding was highly significant (all P < 10-10) after multivariable adjustment, or manual 1:1 patient match, or propensity score matching. Admission hyperglycemia (≥7.0 mmol/L) was present in 45% of patients, was associated with a significant further ∼30% HSPCs reduction, and predicted a 2.6-fold increased risk of the primary outcome of adverse COVID-19 course (admittance to the intensive care unit or death). Low HSPCs were also associated with advanced age, higher peak C-reactive protein, and neutrophil-to-lymphocyte ratio. Independently from confounders, 1 SD lower CD34+ HSPCs was associated with a more than threefold higher risk of adverse outcome. Upon formal analysis, reduction of HSPCs was a significant mediator of the admission hyperglycemia on COVID-19 outcome, being responsible for 28% of its prognostic effect.

Hematopoietic and Nonhematopoietic p66Shc Differentially Regulates Stem Cell Traffic and Vascular Response to Ischemia in Diabetes.

Aims: Peripheral artery disease (PAD) is a severe complication of diabetes, characterized by defective traffic of hematopoietic stem/progenitor cells (HSPCs). We examined the hematopoietic versus nonhematopoietic role of p66Shc in regulating HSPC traffic and blood flow recovery after ischemia in diabetic mice. Results: Using streptozotocin-induced diabetes, chimeric mice with green fluorescent protein (GFP)+ bone marrow (BM), and the hind limb ischemia model, we found that the physiologic mobilization and homing of HSPCs were abolished by diabetes, along with impaired vascular recovery. Hematopoietic deletion of p66Shc, obtained by transplanting p66Shc-/- BM cells into wild-type (Wt) recipients, but not nonhematopoietic deletion, constrained hyperglycemia-induced myelopoiesis, rescued postischemic HSPC mobilization, and improved blood flow recovery in diabetic mice. In Wt diabetic mice transplanted with BM cells from GFP+p66Shc-/- mice, the amount of HSPCs homed to ischemic muscles was greater than in mice transplanted with GFP+p66Shc+/+ cells, with recruited cells displaying higher expression of adhesion molecules and Vegf. In 40 patients with diabetes, p66Shc gene expression in mononuclear cells was correlated with myelopoiesis and elevated in the presence of PAD. In 13 patients with diabetes and PAD, p66Shc expression in HSPC-mobilized peripheral blood cells was inversely correlated with VEGF expression. Innovation: For the first time, we dissect the role of hematopoietic versus nonhematopoietic p66Shc in regulating HSPC traffic and ischemic responses. Conclusion: Hematopoietic deletion of p66Shc was sufficient to rescue HSPC mobilization and homing in diabetes after ischemia and improved blood flow recovery. Inhibiting p66Shc in blood cells may be a novel strategy to counter PAD in diabetes. Antioxid. Redox Signal. 36, 593-607. Clinical Trial No.: NCT02790957.

Performance of intermittently scanned continuous glucose monitoring systems in people with type 1 diabetes: A pooled analysis.

AIMS: To conduct a pooled analysis to assess the performance of intermittently scanned continuous glucose monitoring (isCGM) in association with the rate of change in sensor glucose in a cohort of children, adolescents, and adults with type 1 diabetes. MATERIAL AND METHODS: In this pooled analysis, isCGM system accuracy was assessed depending on the rate of change in sensor glucose. Clinical studies that have been investigating isCGM accuracy against blood glucose, accompanied with collection time points were included in this analysis. isCGM performance was assessed by means of median absolute relative difference (MedARD), Parkes error grid (PEG) and Bland-Altman plot analyses. RESULTS: Twelve studies comprising 311 participants were included, with a total of 15 837 paired measurements. The overall MedARD (interquartile range) was 12.7% (5.9-23.5) and MedARD differed significantly based on the rate of change in glucose (P < 0.001). An absolute difference of -22 mg/dL (-1.2 mmol/L) (95% limits of agreement [LoA] 60 mg/dL (3.3 mmol/L), -103 mg/dL (-5.7 mmol/L)) was found when glucose was rapidly increasing (isCGM glucose minus reference blood glucose), while a -32 mg/dL (1.8 mmol/L) (95% LoA 116 mg/dL (6.4 mmol/L), -51 mg/dL (-2.8 mmol/L)) absolute difference was observed in periods of rapidly decreasing glucose. CONCLUSIONS: The performance of isCGM was good when compared to reference blood glucose measurements. The rate of change in glucose for both increasing and decreasing glucose levels diminished isCGM performance, showing lower accuracy during high rates of glucose change.

Fenofibrate increases circulating haematopoietic stem cells in people with diabetic retinopathy: a randomised, placebo-controlled trial.

AIM/HYPOTHESIS: In two large RCTs, fenofibrate reduced the progression of diabetic retinopathy. We investigated whether fenofibrate increases circulating haematopoietic stem/progenitor cells (HSPCs), which have vascular properties and have been shown to protect from retinopathy. METHODS: We conducted a 12 week parallel-group RCT comparing fenofibrate vs placebo. Patients with diabetic retinopathy and without other conditions that would affect HSPCs were enrolled at a tertiary diabetes outpatient clinic and randomised to receive fenofibrate or placebo based on a computer-generated sequence. Patients and study staff assessing the outcomes were blinded to group assignment. The primary endpoint was the change in the levels of circulating HSPCs, defined by expression of the stem cell markers CD34 and/or CD133. Secondary endpoints were the changes in endothelial progenitor cells, lipids, soluble mediators and gene expression. We used historical data on the association between HSPCs and retinopathy outcomes to estimate the effect of fenofibrate on retinopathy progression. RESULTS: Forty-two participants with diabetic retinopathy were randomised and 41 completed treatment and were analysed (20 in the placebo group and 21 in the fenofibrate group). Mean age was 57.4 years, diabetes duration was 18.2 years and baseline HbA1c was 60 mmol/mol (7.6%). When compared with placebo, fenofibrate significantly increased levels of HSPCs expressing CD34 and/or CD133. CD34+ HSPCs non-significantly declined in the placebo group (mean ± SD -44.2 ± 31.6 cells/106) and significantly increased in the fenofibrate group (53.8 ± 31.1 cells/106). The placebo-subtracted increase in CD34+ HSPCs from baseline was 30% (99.3 ± 43.3 cells/106; p = 0.027) which, projected onto the relationship between HSPC levels and retinopathy outcomes, yielded an OR of retinopathy progression of 0.67 for fenofibrate vs placebo. Endothelial differentiation of CD34+ cells, estimated by the %KDR (kinase insert domain receptor) expression, was significantly reduced by fenofibrate. Fenofibrate decreased serum triacylglycerols, but the change in triacylglycerols was unrelated to the change in HSPCs. No effect was observed for endothelial progenitor cells, cytokines/chemokines (stromal-cell derived factor-1, vascular endothelial growth factor, monocyte chemoattractant protein-1) and gene expression in peripheral blood mononuclear cells. CONCLUSIONS/INTERPRETATION: Fenofibrate increased HSPC levels in participants with diabetic retinopathy and this mechanism may explain why fenofibrate reduced retinopathy progression in previous studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT01927315.

Outcomes of patients with type 2 diabetes treated with SGLT-2 inhibitors versus DPP-4 inhibitors. An Italian real-world study in the context of other observational studies.

AIMS: We compared cardiovascular outcomes of patients with type 2 diabetes (T2D) receiving sodium glucose cotransporter-2 inhibitors (SGLT2i) or dipeptidyl peptidase-4 inhibitors (DPP4i) under routine care. METHODS: From an administrative claims database of >5.2M citizen, we identified patients with T2D who initiated SGLT2i or DPP4i from 2014 to 2018. Patients were matched by propensity scores. The primary outcome was the 3-point major adverse cardiovascular events (3P-MACE). RESULTS: After matching, we included 3216 patients/group, with mean age of 63 years, diabetes duration of 8.7 years, and 20% had cardiovascular disease. During a median follow-up of 18 months, the rate of 3P-MACE was lower among patients who initiated SGLT2i versus DPP4i (HR 0.74; 95 %C.I. 0.58-0.94). Initiators of SGLT2i also showed significantly lower rates of myocardial infarction (HR 0.75; 95 %C.I. 0.56-1.00), hospitalization for heart failure (HR 0.44; 95 %C.I. 0.25-0.95) or cardiovascular causes (HR 0.72; 95 %C.I. 0.60-0.87), and all-cause death (HR 0.49; 95 %C.I. 0.25-0.95). Renal failure was less common with SGLT2i than with DPP4i. Results were consistent to those obtained in a meta-analysis of 10 observational studies on ~1.5M patients. CONCLUSIONS: Patients with T2D who initiated SGLT2i under routine care had better cardio-renal outcomes and lower all-cause mortality than similar patients who initiated DPP4i.

SGLT-2 inhibitors and atrial fibrillation in the Food and Drug Administration adverse event reporting system.

BACKGROUND: Sodium glucose cotransporter-2 inhibitors (SGLT2i) reduce the risk of heart failure and new data show they can prevent atrial fibrillation (AF). We examined the association between SGLT2i and AF in the Food and Drug Administration adverse event reporting system (FAERS). METHODS: We mined the FAERS from 2014q1 to 2019q4 to compare AF reporting for SGLT-2 i versus reports for other glucose lowering medications (ATC10 class). Several exclusions were sequentially applied for: concomitant medications; diabetes, cardiovascular or renal disease indication; reports for competing adverse events (genitourinary tract infections, ketoacidosis, Fournier's gangrene, amputation). We provide descriptive statistics and calculated proportional reporting ratios (PRR). RESULTS: There were 62,098 adverse event reports for SGLT2i and 642,031 reports for other ATC10 drugs. The reporting of AF was significantly lower with SGLT2i than with other ATC10 drugs (4.8 versus 8.7/1000; p < 0.001) with a PRR of 0.55 (0.49-0.62). Results did not change substantially after excluding reports listing insulin (PRR 0.49) or anti-arrhythmics (PRR 0.59) as suspect or concomitant drugs, excluding reports with indications for cardiovascular disease (PRR 0.49) or renal disease (PRR 0.55), and those filed for competing adverse events (PRR 0.63). Results were always statistically significant whether the diabetes indication was specified. Negative and positive controls confirmed internal validity of the database. CONCLUSIONS: In a large pharmacovigilance database, AF was robustly and consistently reported more frequently for diabetes medications other than SGLT2i. This finding complements available evidence from trials supporting a protective role of SGLT2i against the occurrence of AF.

Deintensification of basal-bolus insulin after initiation of GLP-1RA in patients with type 2 diabetes under routine care.

AIMS: We evaluated de-intensification of basal-bolus insulin (BBI) after initiation of a GLP-1 receptor agonist (GLP-1RA) under routine care. RESEARCH DESIGN AND METHODS: This retrospective, multicenter study conducted at outpatient clinics in North-East Italy collected data on patients with T2D on BBI who initiated a GLP-1RA. Patients were divided according to whether they de-intensified BBI at the end of observation by stopping prandial insulin. RESULTS: We included 425 patients with mean age of 61.3 years and 13 years of diabetes duration. Baseline HbA1c was 8.6% and BMI was 35.5 kg/m2. After 14 months. 58.6% of patients de-intensified BBI after initiating GLP-1RA: they were younger, had a shorter disease duration, lower HbA1c and insulin dose, and less frequent microangiopathy than those who continued BBI. A probability estimation based on these variables was validated in an independent cohort of 40 patients. Body weight improved in both groups, but HbA1c and fasting plasma glucose significantly declined only among patients who de-intensified BBI. Patients who de-intensified BBI and persisted on GLP-1RA at the last observation (80.7%) had greater HbA1c reductions. CONCLUSION: Under routine care, GLP-1RA initiation frequently allowed discontinuing BBI, especially among patients with shorter disease duration, lower insulin requirement, and better glucose control.

Diabetes pharmacotherapy and circulating stem/progenitor cells. State of the art and evidence gaps.

Diabetes is burdened with the development of several end-organ complications leading to excess mortality. Though the causes of such organ damage are far from being clarified, diabetes has been redefined as a disease of impaired damage control, wherein ongoing damage is not adequately compensated by activation of repair processes. Bone marrow-derived hematopoietic stem/progenitor cells (HSPCs) and their descendants endothelial progenitor cells (EPCs) have been extensively studied as major players in tissue homeostasis as well as biomarkers of diabetic complication risk. Thus, strategies to raise the levels of circulating HSPCs/EPCs have attracted interest for their potential to modify the future risk of complications. We herein discuss state-of-the-art of the effects exerted by diabetes pharmacotherapy on such cell populations. Further, we highlight which outstanding questions remain to be addressed for a more comprehensive understanding of this topic.

Newly-diagnosed diabetes and admission hyperglycemia predict COVID-19 severity by aggravating respiratory deterioration.

AIMS: We investigated whether pre-existing diabetes, newly-diagnosed diabetes, and admission hyperglycemia were associated with COVID-19 severity independently from confounders. METHODS: We retrospectively analyzed data on patients with COVID-19 hospitalized between February and April 2020 in an outbreak hospital in North-East Italy. Pre-existing diabetes was defined by self-reported history, electronic medical records, or ongoing medications. Newly-diagnosed diabetes was defined by HbA1c and fasting glucose. The primary outcome was a composite of ICU admission or death. RESULTS: 413 subjects were included, 107 of whom (25.6%) had diabetes, including 21 newly-diagnosed. Patients with diabetes were older and had greater comorbidity burden. The primary outcome occurred in 37.4% of patients with diabetes compared to 20.3% in those without (RR 1.85; 95%C.I. 1.33-2.57; p < 0.001). The association was stronger for newly-diagnosed compared to pre-existing diabetes (RR 3.06 vs 1.55; p = 0.004). Higher glucose level at admission was associated with COVID-19 severity, with a stronger association among patients without as compared to those with pre-existing diabetes (interaction p < 0.001). Admission glucose was correlated with most clinical severity indexes and its association with adverse outcome was mostly mediated by a worse respiratory function. CONCLUSION: Newly-diagnosed diabetes and admission hyperglycemia are powerful predictors of COVID-19 severity due to rapid respiratory deterioration.

Exposure to dipeptidyl-peptidase 4 inhibitors and the risk of pneumonia among people with type 2 diabetes: Retrospective cohort study and meta-analysis.

AIM: Concerns have been raised that dipeptidyl-peptidase 4 inhibitors (DPP-4i) may increase the risk of pneumonia. We analysed observational data and clinical trials to explore whether use of DPP-4i modifies the risk of pneumonia. METHODS: We identified patients with diabetes in the Veneto region administrative database and performed propensity score matching between new users of DPP-4 inhibitors and new users of other oral glucose-lowering medications (OGLMs). We compared the rate of hospitalization for pneumonia between matched cohorts using the Cox proportional hazard model. The same analysis was repeated using the database of a local diabetes outpatient clinic. We retrieved similar observational studies from the literature to perform a meta-analysis. Results from trials reporting pneumonia rates among patients randomized to DPP-4 inhibitors versus placebo/active comparators were also meta-analysed. RESULTS: In the regional database, after matching 6495 patients/group, new users of DPP-4 inhibitors had a lower rate of hospitalization for pneumonia than new users of other OGLMs (HR 0.76; 95% CI 0.61-0.95). In the outpatient database, after matching 867 patients/group, new users of DPP-4 inhibitors showed a non-significantly lower rate of hospitalization for pneumonia (HR 0.65; 95% CI 0.41-1.04). The meta-analysis of observational studies yielded an overall non-significant lower risk of hospitalization for pneumonia among DPP-4 inhibitor users (RR 0.81; 95% CI 0.65-1.01). The meta-analysis of randomized controlled trials showed no overall effect of DPP-4 inhibitors on pneumonia risk (RR 1.06; 95% CI 0.93-1.20). CONCLUSION: The use of DPP-4 inhibitors can be considered as safe with regard to the risk of pneumonia.

Stem cell mobilization with plerixafor and healing of diabetic ischemic wounds: A phase IIa, randomized, double-blind, placebo-controlled trial.

Bone marrow-derived cells contribute to tissue repair, but traffic of hematopoietic stem/progenitor cells (HSPCs) is impaired in diabetes. We therefore tested whether HSPC mobilization with the CXCR4 antagonist plerixafor improved healing of ischemic diabetic wounds. This was a pilot, phase IIa, double-blind, randomized, placebo-controlled trial (NCT02790957). Patients with diabetes with ischemic wounds were randomized to receive a single subcutaneous injection of plerixafor or saline on top of standard medical and surgical therapy. The primary endpoint was complete healing at 6 months. Secondary endpoints were wound size, transcutaneous oxygen tension (TcO2 ), ankle-brachial index (ABI), amputations, and HSPC mobilization. Twenty-six patients were enrolled: 13 received plerixafor and 13 received placebo. Patients were 84.6% males, with a mean age of 69 years. HSPC mobilization was successful in all patients who received plerixafor. The trial was terminated after a preplanned interim analysis of 50% of the target population showed a significantly lower healing rate in the plerixafor vs the placebo group. In the final analysis data set, the rate of complete healing was 38.5% in the plerixafor group vs 69.2% in the placebo group (chi-square P = .115). Wound size tended to be larger in the plerixafor group for the entire duration of observation. No significant difference was noted for the change in TcO2 and ABI or in amputation rates. No other safety concern emerged. In conclusion, successful HSPC mobilization with plerixafor did not improve healing of ischemic diabetic wounds. Contrary to what was expected, outside the context of hematological disorders, mobilization of diabetic HSPCs might exert adverse effects on wound healing.