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Empagliflozin reduced long-term HbA1c variability and cardiovascular death: insights from the EMPA-REG OUTCOME trial.
Ceriello, A, Ofstad, AP, Zwiener, I, Kaspers, S, George, J, Nicolucci, A
Cardiovascular diabetology. 2020;(1):176
Abstract
BACKGROUND Glucose variability has been associated with cardiovascular outcomes in type 2 diabetes, however, the interplay between glucose variability, empagliflozin and cardiovascular death has not been explored. In the EMPA-REG OUTCOME trial, empagliflozin reduced the risk of cardiovascular death by 38%. We explore post-hoc the association between HbA1c variability and cardiovascular death, and the potential mediating effects of HbA1c variability on empagliflozin's cardiovascular death reductions. METHODS In total, 7,020 patients with type 2 diabetes and established cardiovascular disease received placebo, empagliflozin 10 mg or 25 mg. We defined within-patient HbA1c variability as standard deviation, coefficient of variation and range of HbA1c measurements (%) post-baseline. First, we compared HbA1c variability until week 28 and 52 by Wilcoxon tests. We explored the association between cardiovascular death and HbA1c variability in placebo and pooled empagliflozin arms separately with landmark analyses at week 28 and 52, and additionally with HbA1c variability as a time-dependent co-variate. We used Cox regression models adjusted for baseline risk factors including changes in HbA1c from baseline to week 12, and the interaction term HbA1c variability* treatment. RESULTS HbA1c variability was lower with empagliflozin compared to placebo. In all Cox analyses, high HbA1c variability increased the risk for cardiovascular death in both treatment arms with no interaction with treatment: e.g. an increase in HbA1c variability of one unit for the standard deviation at week 28 was associated with a subsequent increased risk of CV death with HRs of 1.97 (95% CI 1.36, 2.84) and 1.53 (1.01, 2.31) in the placebo and empagliflozin groups, separately, interaction p-value 0.3615. CONCLUSIONS HbA1c variability was reduced by empagliflozin and high values of HbA1c variability were associated with an increased risk of cardiovascular death. Empagliflozin's reduction in cardiovascular death did not appear to be mediated by reductions in HbA1c variability. ClinicalTrials.gov number, NCT01131676.
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Improved Glucose Profile in Patients With Type 2 Diabetes With a New, High-Protein, Diabetes-Specific Tube Feed During 4 Hours of Continuous Feeding.
Lansink, M, Hofman, Z, Genovese, S, Rouws, CHFC, Ceriello, A
JPEN. Journal of parenteral and enteral nutrition. 2017;(6):968-975
Abstract
BACKGROUND Hyperglycemia frequently occurs in hospitalized patients receiving nutrition support. In this study, the effects of a new diabetes-specific formula (DSF) on glucose profile during 4 hours of continuous feeding and 4 hours after stopping feeding were compared with a standard formula (SF). MATERIALS AND METHODS In this randomized, controlled, double-blind, crossover study, ambulant, nonhospitalized patients with type 2 diabetes received the DSF or an isocaloric, fiber-containing SF via a nasogastric tube. After overnight fasting, the formula was continuously administered to the patients during 4 hours. Plasma glucose and insulin concentrations were determined during the 4-hour period and in the subsequent 4 hours during which no formula was provided. RESULTS During the 4-hour feeding period, DSF compared with SF resulted in a lower mean delta glucose concentration in the 3- to 4-hour period (0.3 ± 1.0 and 2.4 ± 1.5 mmol/L; P < .001). Also, the (delta) peak concentrations, (delta) mean concentrations, and incremental area under the curve (iAUC) for glucose and insulin were significantly lower during DSF compared with SF feeding (all comparisons: P < .001). Furthermore, fewer patients experienced hyperglycemia (>10 mmol/L) on DSF compared with SF (2 vs 11, P = .003, respectively). No differences in number of patients with hypoglycemia (<3.9 mmol/L) were observed. No significant differences in tolerance were observed. CONCLUSION Administration of a new, high-protein DSF during 4 hours of continuous feeding resulted in lower glucose and insulin levels compared with a fiber-containing SF in ambulant, nonhospitalized patients with type 2 diabetes. These data suggest that a DSF may contribute to lower glucose levels in these patients.
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Lispro insulin in people with non-alcoholic liver cirrhosis and type 2 diabetes mellitus.
Gentile, S, Guarino, G, Strollo, F, Romano, M, Genovese, S, Masarone, M, Ceriello, A
Diabetes research and clinical practice. 2016;:179-86
Abstract
AIMS: To compare metabolic control under lispro and recombinant regular human insulin (RHI) in people with diet-unresponsive type 2 diabetes mellitus (T2DM) and compensated non-alcoholic liver disease (CLD).
METHODS 108 people with T2DM and CLD were randomly allocated to RHI or lispro according to a 12+12 week cross-over protocol. A 1-week continuous glucose monitoring (CGM) session was performed at the end of each treatment period followed by a standard meal test with a 12IU lispro or RHI shot ahead.
RESULTS CGM showed higher glycemic excursions under RHI than under lispro (p<0.01) with lower glucose levels in the late post-absorption phase (p<0.05) and even more during the night (p<0.01). Post-challenge incremental areas under the curve (ΔAUC) were undistinguishable for insulin but lower for glucose, while insulin peaked higher and earlier and glycemic excursions were lower with lispro than with RHI (0.05
CONCLUSIONS Lispro granted lower early postprandial glucose levels and late postprandial hypoglycemic rates and therefore might represent the treatment of choice for people with T2DM and compensated CLD. This might depend on its faster/shorter-living effects, as well as, on the lower liver glucose output expected from its earlier hepatic distribution.
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The protective effect of the Mediterranean diet on endothelial resistance to GLP-1 in type 2 diabetes: a preliminary report.
Ceriello, A, Esposito, K, La Sala, L, Pujadas, G, De Nigris, V, Testa, R, Bucciarelli, L, Rondinelli, M, Genovese, S
Cardiovascular diabetology. 2014;:140
Abstract
BACKGROUND In type 2 diabetes, acute hyperglycemia worsens endothelial function and inflammation,while resistance to GLP-1 action occurs. All these phenomena seem to be related to the generation of oxidative stress. A Mediterranean diet, supplemented with olive oil, increases plasma antioxidant capacity, suggesting that its implementation can have a favorable effect on the aforementioned phenomena. In the present study, we test the hypothesis that a Mediterranean diet using olive oil can counteract the effects of acute hyperglycemia and can improve the resistance of the endothelium to GLP-1 action. METHODS Two groups of type 2 diabetic patients, each consisting of twelve subjects, participated in a randomized trial for three months, following a Mediterranean diet using olive oil or a control low-fat diet. Plasma antioxidant capacity, endothelial function, nitrotyrosine, 8-iso-PGF2a, IL-6 and ICAM-1 levels were evaluated at baseline and at the end of the study. The effect of GLP-1 during a hyperglycemic clamp, was also studied at baseline and at the end of the study. RESULTS Compared to the control diet, the Mediterranean diet increased plasma antioxidant capacity and improved basal endothelial function, nitrotyrosine, 8-iso-PGF2a, IL-6 and ICAM-1 levels. The Mediterranean diet also reduced the negative effects of acute hyperglycemia, induced by a hyperglycemic clamp, on endothelial function, nitrotyrosine, 8-iso-PGF2a, IL-6 and ICAM-1 levels. Furthermore, the Mediterranean diet improved the protective action of GLP-1 on endothelial function, nitrotyrosine, 8-iso-PGF2a, IL-6 and ICAM-1 levels, also increasing GLP-1-induced insulin secretion. CONCLUSIONS These data suggest that the Mediterranean diet, using olive oil, prevents the acute hyperglycemia effect on endothelial function, inflammation and oxidative stress, and improves the action of GLP-1, which may have a favorable effect on the management of type 2 diabetes, particularly for the prevention of cardiovascular disease.
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Simultaneous GLP-1 and insulin administration acutely enhances their vasodilatory, antiinflammatory, and antioxidant action in type 2 diabetes.
Ceriello, A, Novials, A, Canivell, S, La Sala, L, Pujadas, G, Esposito, K, Testa, R, Bucciarelli, L, Rondinelli, M, Genovese, S
Diabetes care. 2014;(7):1938-43
Abstract
OBJECTIVE To test the hypothesis that the simultaneous administration of GLP-1 and insulin may increase their vasodilatory, antiinflammatory, and antioxidant action in type 2 diabetes. RESEARCH DESIGN AND METHODS In two groups of persons with type 2 diabetes, two sets of experiments were performed. The first group had two normoglycemic-normoinsulinemic clamps with or without GLP-1 and two normoglycemic-hyperinsulinemic clamps with or without GLP-1. The second group had two hyperglycemic-normoinsulinemic clamps and two hyperglycemic-hyperinsulinemic clamps with or without GLP-1. RESULTS During the normoglycemic-hyperinsulinemic clamp, flow-mediated dilatation (FMD) increased, while soluble intercellular adhesion molecule (sICAM-1), plasma 8-iso-prostaglandin F2α (8-iso-PGF2α), nitrotyrosine, and interleukin (IL)-6 decreased compared with normoglycemic-normoinsulinemic clamp. Similar results were obtained with the infusion of GLP-1 during the normoglycemic-normoinsulinemic clamp. The combination of hyperinsulinemia and GLP-1 in normoglycemia was accompanied by a further FMD increase and sICAM-1, 8-iso-PGF2α, nitrotyrosine, and IL-6 decrease. During the hyperglycemic-normoinsulinemic clamp, FMD significantly decreased, while sICAM-1, 8-iso-PGF2α, nitrotyrosine, and IL-6 significantly increased. When hyperglycemia was accompanied by hyperinsulinemia or by the simultaneous infusion of GLP-1, these phenomena were attenuated. The simultaneous presence of hyperinsulinemia and GLP-1 had an increased beneficial effect. CONCLUSIONS Our results show that the combination of insulin and GLP-1 is more effective than insulin or GLP-1 alone in improving endothelial dysfunction, inflammation, and oxidative stress in type 2 diabetes.
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Hyperglycemia following recovery from hypoglycemia worsens endothelial damage and thrombosis activation in type 1 diabetes and in healthy controls.
Ceriello, A, Novials, A, Ortega, E, Pujadas, G, La Sala, L, Testa, R, Bonfigli, AR, Genovese, S
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2014;(2):116-23
Abstract
BACKGROUND AND AIMS Hypoglycemia produces thrombosis activation, but little attention has been paid to the effects of hyperglycemia following recovery from hypoglycemia on thrombosis activation. METHODS AND RESULTS In both twenty-two healthy subjects and twenty-one matched persons with type 1 diabetes, recovery from a 2-h induced hypoglycemia was obtained by reaching normo-glycemia or hyperglycemia for another 2 h. After this, normal glycemia was maintained for the following 6 h. Hyperglycemia after hypoglycemia was also repeated with the concomitant infusion of vitamin C. In both controls and people with diabetes, the recovery with normo-glycemia was accompanied by a significant improvement of Von Willebrand factor (vWF), prothrombin fragment 1 + 2 (F1 + 2), thrombin-antithrombin III-complexes (TAT), P-selectin, plasminogen activator inhibitor-1 (PAI-1), nitrotyrosine and 8-iso-prostaglandin F2α (8-iso-PGF2α) (p < 0.01 vs hypoglycemia for all the parameters), all directly affected by hypoglycemia itself (p < 0.01 vs baseline for all the parameters). On the contrary, the recovery with hyperglycemia after hypoglycemia worsens all these parameters (p < 0.01 vs normoglycemia for all the parameters), an effect persisting even after the additional 6 h of normo-glycemia. The effect of hyperglycemia following hypoglycemia was partially counterbalanced when vitamin C was infused (p < 0.01 vs hyperglycemia alone for all the parameters), suggesting that hyperglycemia following hypoglycemia may activate thrombosis through the oxidative stress production. CONCLUSION This study shows that, in type 1 diabetes as well as in controls, the way in which recovery from hypoglycemia takes place could play an important role in favoring the activation of thrombosis and oxidative stress, widely recognized cardiovascular risk factors.