Benedetta Maria Bonora

SGLT2 inhibitors and diabetic ketoacidosis: data from the FDA Adverse Event Reporting System

Aims/hypothesisSodium-glucose co-transporter-2 inhibitors (SGLT2i) are indicated for the treatment of type 2 diabetes and may also improve glucose control in type 1 diabetes. In 2015, regulatory agencies warned that SGLT2i may favour diabetic ketoacidosis (DKA). We provide a detailed analysis of DKA reports in which an SGLT2i was listed among suspect or concomitant drugs in the US Food and Drug Administration Adverse Event Reporting System (FAERS).MethodsWe first analysed the entire public FAERS up to September (third quarter [Q3]) 2016 to extract the number of reports, background indications and concomitant medications, and to calculate proportional reporting ratios (PRRs) and safety signals. We then mined single FAERS files from the first quarter (Q1) of 2014 to 2016 Q3 to obtain detailed information on DKA reports.ResultsThe FAERS database contains >2500 DKA reports in which SGLT2i are listed as suspect or concomitant drugs. The PRR of DKA in reports including vs those not including an SGLT2i and having a diabetes indication was 7.9 (95% CI 7.5, 8.4) and was higher for type 1 diabetes. Several concomitant conditions were less prevalent in DKA reports with SGLT2i vs DKA reports filed for other drugs. A detailed analysis of 2397 DKA reports for SGLT2i from 2014 Q1 to 2016 Q3 revealed a predominance of women, an extremely wide range of age and body weight, and a highly variable duration of SGLT2i treatment before onset of DKA. In 37 individuals (1.54%), DKA was fatal.Conclusions/interpretationBased on the profile of these reports, SGLT2i-associated DKA may not be limited to any particular demographic or comorbid subpopulation and can occur at any duration of SGLT2i use.Data availabilityA list of FDA reports analysed in the study is available in the figshare repository, 10.6084/m9.figshare.4903211. Other data are available from the corresponding author on reasonable request.

Acute Effects of Linagliptin on Progenitor Cells, Monocyte Phenotypes, and Soluble Mediators in Type 2 Diabetes

CONTEXT Circulating cells, including endothelial progenitor cells (EPCs) and monocyte subtypes, are involved in diabetic complications. Modulation of these cells may mediate additional benefits of glucose-lowering medications. OBJECTIVE We assessed whether the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin acutely modifies EPCs and monocyte subsets in patients with type 2 diabetes. DESIGN This was a randomized, crossover, placebo-controlled trial. SETTING The study was conducted at a tertiary referral diabetes outpatient clinic. PATIENTS Forty-six type 2 diabetes patients with (n = 18) or without (n = 28) chronic kidney disease (CKD) participated in the study. INTERVENTION Intervention included a 4-day treatment with linagliptin 5 mg or placebo during two arms separated by a 2-week washout. MAIN OUTCOME MEASURES Before and after each treatment, we determined the levels of circulating progenitor cells (CD34, CD133, KDR) and monocyte subtypes (CD14/CD16, chemokine and scavenger receptors) and the concentrations of soluble mediators. RESULTS Compared with placebo, linagliptin increased CD34(+)CD133(+) progenitor cells (placebo subtracted effect 40.4 ± 18.7/10(6); P = .036), CD34(+)KDR(+) EPCs (placebo subtracted effect 22.1 ± 10.2/10(6); P = .036), and CX3CR1(bright) monocytes (placebo subtracted effect 1.7 ± 0.8%; P = .032). Linagliptin abated DPP-4 activity by greater than 50%, significantly increased active glucagon-like peptide-1 and stromal cell-derived factor-1α, and reduced monocyte chemotactic protein-1, CCL22, and IL-12. Patients with CKD, as compared with those without, had lower baseline CD133(+) and CD34(+)CD133(+) cells and had borderline reduced CD34(+) and CD34(+)KDR(+) cells. The effects of linagliptin on progenitor cells and monocyte subtypes were similar in patients with or without CKD. Fasting plasma glucose, triglycerides and free fatty acids were unaffected. CONCLUSIONS DPP-4 inhibition with linagliptin acutely increases putative vasculoregenerative and antiinflammatory cells. Direct effects of DPP-4 inhibition may be important to lower vascular risk in diabetes, especially in the presence of CKD.

Long-term Prediction of Cardiovascular Outcomes by Circulating CD34+ and CD34+CD133+ Stem Cells in Patients With Type 2 Diabetes

OBJECTIVE Cardiovascular risk varies substantially in the population with diabetes, and biomarkers can improve risk stratification. Circulating stem cells predict future cardiovascular events and death, but data for the population with diabetes are scant. In this study we evaluated the ability of circulating stem cell levels to predict future cardiovascular outcomes and improve risk discrimination in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS A cohort of 187 patients with type 2 diabetes was monitored for a median of 6.1 years. The primary outcome was time to a first cardiovascular event, defined as 3-point major adverse cardiovascular event (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) plus hospitalization for cardiovascular causes. At baseline, we measured six stem/progenitor cell phenotypes in peripheral blood based on expression of CD34, CD133, and KDR. RESULTS The primary outcome occurred in 48 patients (4.5/100 patient-years). Patients with incident cardiovascular events had significantly lower CD34+ and CD34+CD133+ cells than those without. Higher rates of cardiovascular events occurred in patients with below median levels of CD34+ and CD34+CD133+. In Cox proportional hazards regression analyses, a reduced CD34+ (hazard ratio 2.21 [95% CI 1.14–4.29]) and CD34+CD133+ (2.98 [1.46–6.08]) cell count independently predicted future events. Addition of the CD34+ cell count to the reference model or the UK Prospective Diabetes Study risk engine improved C statistics, continuous net reclassification improvement, and/or integrated discrimination index. CONCLUSIONS In patients with type 2 diabetes, a reduced baseline level of circulating CD34+ stem cells predicts adverse cardiovascular outcomes up to 6 years later and improves risk stratification.

Dipeptidyl peptidase-4 inhibitors moderate the risk of genitourinary tract infections associated with sodium-glucose co-transporter-2 inhibitors

Genitourinary tract infections (GUTIs) are the most common adverse event (AE) occurring during therapy with sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors. We evaluated whether dipeptidyl peptidase‐4 inhibitors moderate the risk of GUTI during SGLT2 inhibitor therapy, using two approaches. First, we screened the literature for randomized controlled trials (RCTs) directly comparing the frequency of GUTIs in patients receiving DPP‐4 inhibitor/SGLT2 inhibitor combination therapy vs those receiving an SGLT2 inhibitor only. In the five trials we retrieved, the pooled risk ratio for genital tract infections (GTIs) in patients on DPP‐4 inhibitor/SGLT2 inhibitor combination therapy vs those on SGLT2 inhibitors alone was 0.51 (95% confidence interval [CI] 0.28‐0.92). Second, we found that within the Food and Drug Administration AE Reporting System, the frequency of GUTIs among reports listing both SGLT2 and DPP‐4 inhibitors as suspect or concomitant drugs was significantly lower than among reports listing SGLT2 inhibitors without DPP‐4 inhibitors, with a proportional reporting ratio of 0.74 (95% CI 0.61‐0.90). In conclusion, in RCTs and in a large pharmacovigilance database, combination therapy with a DPP‐4 inhibitor appears to reduce the frequency of G(U)TIs associated with SGLT2 inhibitors.

Sodium-glucose co-transporter-2 inhibitors and diabetic ketoacidosis: An updated review of the literature

Sodium‐glucose cotransporter‐2 inhibitors (SGLT2is) are increasingly used for the treatment of type 2 diabetes (T2D) and can improve glucose control also in type 1 diabetes (T1D). In May 2015, regulatory agencies issued a warning that SGLT2is may cause diabetic ketoacidosis (DKA). We report details on 2 new cases of SGLT2i‐associated DKA and review the literature for similar cases within randomized controlled trials (RCTs), cohort studies and single reports. We searched the medical literature for reports of SGLT2i‐associated DKA cases. A quantitative analysis of frequency and clinical characteristics is reported. The 2 narrative cases illustrate that SGLT2i‐associated DKA can occur in patients with T1D incorrectly diagnosed as T2D, perhaps without the presence of obvious DKA precipitating factors. The incidence of SGLT2i‐associated DKA was less than 1/1000 in randomized controlled trials and 1.6/1000 person‐years in cohort studies. We retrieved detailed data on 105 SGLT2i‐associated DKA case reports, wherein 35% showed glucose levels of less than 200 mg/dL and 22% were not associated with typical triggers. In case reports and in pharmacovigilance databases, duration of SGLT2i treatment before DKA onset was extremely variable. Fatal SGLT2i‐associated DKA episodes were found only in pharmacovigilance databases and represented 1.6% of all reported cases. DKA is a rare adverse event during SGLT2i therapy. Predisposing and precipitating factors are still incompletely understood, although a minority of cases lacked typical DKA triggers. More narrative case series and cohort studies are needed to better understand the true risk and the spectrum of this adverse event.

Shift of monocyte subsets along their continuum predicts cardiovascular outcomes

BACKGROUND AND AIMS Distribution of monocyte subsets has been shown to predict cardiovascular outcomes. However, monocytes form a continuum and categorization into discrete subsets may be an oversimplification. We herein aimed at establishing whether distribution of monocytes based on CD14 and CD16 fluorescence intensity provides incremental and complementary information on cardiovascular outcomes beyond enumeration of traditional subsets. METHODS A cohort of 227 patients at high cardiovascular risk was characterized at baseline and followed for a median of 4 years. We quantified monocytes subsets by flow cytometry based on CD14 and CD16 expression and evaluated the continuous distribution of CD14 and CD16 fluorescence within each subset. RESULTS A consistent shift toward higher CD16 fluorescence intensity within each monocyte subset was observed in patients with type 2 diabetes, despite no change in their frequencies. Patients with coronary artery disease (CAD) at baseline showed a doubling of CD14++CD16+ intermediate monocytes and a shift of non-classical and classical monocytes towards intermediates ones. During follow-up, cardiovascular death or cardiovascular events occurred in 26 patients, who showed monocyte skewing similar to those of patients with baseline CAD. In fully adjusted Cox proportional hazard regression models, higher CD16 expression on classical monocytes, but not the level of intermediate monocytes or other subsets, independently predicted adverse cardiovascular outcomes. CONCLUSIONS Shift of monocyte subsets along the CD14/CD16 continuum, more than their frequencies, predicted adverse cardiovascular outcomes. This finding illustrates how the concept of monocyte continuum can be used to model the cardiovascular risk.

DPP-4 inhibition has no acute effect on BNP and its N-terminal pro-hormone measured by commercial immune-assays. A randomized cross-over trial in patients with type 2 diabetes

AbstractBackgroundUse of dipeptidyl peptidase-4 inhibitors (DPP4-i) for the treatment of type 2 diabetes (T2D) has been associated with a possible increase in the risk for heart failure (HF). B-type natriuretic peptide (BNP), which is both a biomarker of HF and a hemodynamically active hormone, is a substrate of DPP-4. We herein tested the acute effects of the DPP-4i linagliptin on BNP and NT-proBNP in a cross-over placebo-controlled trial in patients with T2D with and without chronic kidney disease (CKD).MethodsB-type natriuretic peptide and NT-proBNP were measured using commercially available clinical-grade immune-assays at baseline and at the end of a 4-day treatment with placebo and linagliptin. Changes from baseline during each treatment arm, as well as placebo-subtracted effects of linagliptin on BNP and NT-proBNP were calculated.Results46 patients completed the study, 18 of whom were affected by CKD. Baseline BNP and NT-proBNP levels increased with age, were elevated in CKD patients, and inversely correlated with estimated glomerular filtration rate. No significant change was detected in BNP and NT-proBNP levels after treatment with linagliptin or placebo in patients with or without CKD. Only in CKD patients the placebo-subtracted effect of linagliptin indicated a significant reduction in NT-proBNP levels, but this finding was not statistically robust.ConclusionsAcute treatment with a DPP-4i exerts no clinically-meaningful effects on BNP and NT-proBNP. As routinely used immunoassays do not discriminate between intact/active and cleaved BNP, these data cannot rule out an effect of DPP-4i on HF pathophysiology. Trial registration NCT01617824

Circulating Stem Cells Associate With Adiposity and Future Metabolic Deterioration in Healthy Subjects

CONTEXT Obesity and metabolic syndrome are associated with mild leukocytosis, but whether hematopoietic stem/progenitor cells (HSPCs) play a role in metabolic deterioration is unknown. OBJECTIVE Our objective was to analyze the cross-sectional and longitudinal associations between CD34(+) HSPCs, adiposity, and metabolic syndrome features. DESIGN This is a cross-sectional study on 242 participants, 155 of whom were followed and included in a longitudinal assessment. SETTING This study took place in a tertiary referral center for metabolic diseases. PARTICIPANTS Healthy working individuals attending a cardiovascular screening program (total n = 3158) and having a baseline measure of circulating CD34(+) cells participated. MAIN OUTCOME MEASURES We collected demographic and anthropometric data, cardiovascular risk factors, and metabolic syndrome parameters. RESULTS Participants (34.7% males, mean age 45.9 ± 0.5 years) were free from diabetes and cardiovascular disease. Cross-sectionally, absolute CD34(+) cell counts were directly correlated with body mass index and waist circumference, inversely correlated with high-density lipoprotein cholesterol and the quantitative insulin sensitivity check index, and were higher in individuals with the metabolic syndrome. The hematopoietic component contributed most to the association of CD34(+) cells with adiposity. During a 6.3-year follow-up, high absolute levels of CD34(+) cells were associated with increasing waist circumference, declining quantitative insulin sensitivity check index and high-density lipoprotein cholesterol, and with incidence of metabolic syndrome. Relative CD34(+) cell counts showed weaker associations with metabolic parameters than absolute levels, but were longitudinally associated with increasing waist circumference and metabolic syndrome development. CONCLUSIONS A mild elevation of circulating CD34(+) progenitor cells, reflecting expansion of HSPCs, is associated with adiposity and future metabolic deterioration in healthy individuals.

Effects of SGLT2 Inhibitors on Circulating Stem and Progenitor Cells in Patients With Type 2 Diabetes

Context Reduction in the levels of circulating stem cells (CSCs) and endothelial progenitor cells (EPCs) predicts development or progression of microangiopathy and macroangiopathy in patients with type 2 diabetes (T2D). Objective We tested whether treatment with sodium glucose cotransporter-2 (SGLT2) inhibitors affected the levels of CSCs and EPCs. Design A randomized trial of dapagliflozin vs placebo with open-label extension, and an open-label observational study of empagliflozin treatment. Setting Tertiary referral diabetes outpatient clinic. Patients Patients with T2D aged 18 to 75 years. Intervention Dapagliflozin at 10 mg vs placebo (n = 31); empagliflozin at 10 mg (n = 15). Main Outcome Measures We measured CSCs (CD34+) and EPCs (CD34+KDR+) by flow cytometry at baseline, at 12 weeks, and after the extension period. Results After 12 weeks, CSCs declined nonsignificantly in the dapagliflozin group, remained stable in the placebo group, and the change from baseline was not significantly different between the two groups. EPCs declined nonsignificantly in the dapagliflozin group, increased nonsignificantly in the placebo group, and the change from baseline was significantly different between the two groups. After an open-label extension period of about 1.5 years, CSCs remained stable over time, whereas EPCs significantly increased in patients who received dapagliflozin. In all patients, irrespectively of treatment, EPCs increased significantly from baseline to the end of observation, concomitantly with improvement in HbA1c. In a cohort of 15 patients who received open-label empagliflozin for 12 weeks, CSCs declined nonsignificantly, whereas EPCs remained stable. Conclusion SGLT2 inhibitors do not significantly increase CSCs or EPCs. Thus, cardiovascular protection by SGLT2 inhibitors may not directly involve stem/progenitor cells.

Effects of Hypoglycemia on Circulating Stem and Progenitor Cells in Diabetic Patients

Context Iatrogenic hypoglycemia is the most common acute diabetic complication, and it significantly increases morbidity. In people with diabetes, reduction in the levels of circulating stem and progenitor cells predicts adverse outcomes. Objective To evaluate whether hypoglycemia in diabetes affects circulating stem cells and endothelial progenitor cells (EPCs). Design We performed an experimental hypoglycemia study (Study 1) and a case-control study (Study 2). Setting Tertiary referral inpatient clinic. Patients and Other Participants Type 1 diabetic patients (Study 1, n = 19); diabetic patients hospitalized for severe iatrogenic hypoglycemia, matched inpatient and outpatient controls (Study 2, n = 22/group). Interventions Type 1 diabetic patients underwent two in-hospital sessions of glucose monitoring during a breakfast meal with or without induction of hypoglycemia in random order. In Study 2, patients hospitalized for hypoglycemia and matched controls were compared. Main Outcome Measure Circulating stem cells and EPCs were measured by flow cytometry based on the expression of CD34 and kinase insert domain receptor (KDR). Results In Study 1, the physiologic decline of CD34+KDR+ EPCs from 8 am to 2 pm was abolished by insulin-induced hypoglycemia in type 1 diabetic patients. In Study 2, diabetic patients hospitalized for severe iatrogenic hypoglycemia had significantly lower levels of CD34+ stem cells and CD34+KDR+ EPCs compared with diabetic inpatients or outpatient controls. Conclusions In diabetic patients, a single mild hypoglycemic episode can compromise the physiologic EPC fluctuation, whereas severe hypoglycemia is associated with a marked reduction in stem cells and EPCs. These data provide a possible link between hypoglycemia and adverse outcomes of diabetes.