Dapagliflozin effect on endothelial dysfunction in diabetic patients with atherosclerotic disease: a randomized active-controlled trial.

BACKGROUND: The glucose-lowering independent effect of sodium glucose cotransporter-2 inhibitors (SGLT2i) on arterial wall function has not yet been clarified. This study aims to assess whether SGLT2i treatment can attenuate endothelial dysfunction related to type 2 diabetes mellitus (T2D) compared with glucose-lowering equivalent therapy. METHODS: In a prospective, open-label, single-center, randomized clinical trial, 98 patients with T2DM and carotid intima-media thickness above the 75th percentile were randomized 1:1 to 12 weeks of therapy with dapagliflozin or glibenclamide in addition to metformin in glucose-lowering equivalent regimens. The coprimary endpoints were 1-min flow-mediated dilation (FMD) at rest and 1-min FMD after 15 min of ischemia followed by 15 min of reperfusion time (I/R). RESULTS: Ninety-seven patients (61% males, 57 ± 7 years) completed the study. The median HbA1c decreased by - 0.8 (0.7)% and -0.7 (0.95)% following dapagliflozin and glibenclamide, respectively. The first coprimary endpoint, i.e., rest FMD changed by + 3.3(8.2)% and - 1.2(7.5)% for the dapagliflozin and glibenclamide arms, respectively (p = 0.0001). Differences between study arms in the second coprimary endpoint were not significant. Plasma nitrite 1 min after rest FMD was higher for dapagliflozin [308(220) nmol/L] than for glibenclamide (258[110] nmol/L; p = 0.028). The resistive indices at 1 min [0.90 (0.11) vs. 0.93 (0.07); p = 0.03] and 5 min [0.93 (0.07) vs. 0.95 (0.05); p = 0.02] were higher for the glibenclamide group than for the dapagliflozin group. Plasma biomarkers for inflammation and oxidative stress did not differ between the treatments. CONCLUSIONS: Dapagliflozin improved micro- and macrovascular endothelial function compared to glibenclamide, regardless of glycemic control in patients with T2DM and subclinical carotid atherosclerotic disease.

Validation of surrogate indexes of insulin sensitivity in acute phase of myocardial infarction based on euglycemic-hyperinsulinemic clamp.

The decrease in insulin sensitivity (IS) during myocardial infarction (MI) is recognized as a possible contributor to poor patient outcomes. Despite its potential relevance, a standardized and convenient IS assessment tool has yet to be established for said clinical scenarios. This study aimed to validate the accuracy of surrogate indexes in determining IS in acute MI patients by comparison with the gold standard reference method for measuring IS, the euglycemic-hyperinsulinemic clamp (EHC). We performed EHCs in 31 consecutive nondiabetic patients who were admitted within the first 24 h of symptoms of ST-segment elevation MI. Patients with prior diagnosis of diabetes, use of hypoglycemic agents, or a glycosylated hemoglobin ≥6.5% were excluded. EHCs were performed at the second day (D2) and sixth day (D6) post-MI. Basal (12-h fasting) blood samples from D2 and D6 were used to evaluate patient blood glucose and insulin levels. We then calculated the following surrogate indexes: homeostatic model assessment of insulin sensitivity (HOMA2S), homeostatic model assessment of insulin resistance (HOMA-IR), and quantitative insulin sensitivity check index (QUICKI). The IS index measured by EHC (ISiclamp) was correlated to HOMA2S, HOMA-IR, and QUICKI at D2 (r = 0.485, P = 0.009; r = -0.384, P = 0.048; r = 0.479, P = 0.01, respectively) and D6 (r = 0.621, P = 0.002; r = -0.576, P = 0.006; r = 0.626, P = 0.002, respectively). Receiver operator characteristic curves made for discrimination of ISiclamp above the median in D2 and D6 depicted areas under the curve of 0.740, 0.734, and 0.760 for HOMA2S, HOMA-IR, and QUICKI, respectively. Bland-Altman plots displayed no apparent systematic error for indexes, but a propensity for proportional error, particularly with HOMA-IR. Thus, based on EHC, these simple surrogate indexes are feasible for assessing IS during MI.

Dapagliflozin increases retinal thickness in type 2 diabetic patients as compared with glibenclamide: A randomized controlled trial.

AIM: In patients with type 2 diabetes mellitus (T2DM) a progressive thinning in the central retinal thickness (CRT) is mainly related to neuroretinal degeneration and occurs before the decline in visual acuity or capillary density. We investigated the change in CRT by optical coherence tomography (OCT) in T2DM patients after 12 weeks of treatment with dapagliflozin or glibenclamide. METHODS: Ninety-seven patients (57 ± 7 years) with T2DM and clinical or subclinical atherosclerosis were randomized 1:1 to dapagliflozin (10 mg/day) or glibenclamide (5 mg/day) on top of metformin XR 1.5 g/day. OCT was obtained in all patients enrolled in the study, both at the time of randomization and at the end of the study. RESULTS: Baseline and post-treatment values of fasting glucose and glycated hemoglobin were equivalent in the two arms. There was no difference in change in diabetic retinopathy status after therapy. The center subfield thickness changed by +2(6)µm in the dapagliflozin group and by -1(7) µm in the glibenclamide group (P = 0.001). CONCLUSION: A short-term treatment with dapagliflozin may increase CRT as compared with equivalent glycemic control with glibenclamide.

Statin Short-term Inhibition of Insulin Sensitivity and Secretion During Acute Phase of ST-Elevation Myocardial Infarction.

Hyperglycemia during myocardial infarction (MI) has a strong and direct association with mortality. In stable patients and experimental models, statins favor the elevation of glycaemia. The present study investigated whether short-course treatment with statins during MI can influence glucose homeostasis and thus the clinical outcome. In this prospective study, euglycemic hyperinsulinemic clamp (EHC) was performed at second (D2) and sixth (D6) day after MI in patients randomized to simvastatin (S)10 or 80 mg/day during hospitalization (n = 27). In addition, patients (n = 550) were treated without (WS) or with simvastatin (S) at 20, 40 or 80 mg/day had HOMA2S on admission (D1) and fifth (D5) day after MI. According to EHC, insulin sensitivity increased by 20 ± 60% in S10 and decreased by -6 ± 28% in S80 (p = 0.025). Consistently, the changes in HOMA2S between D1 and D5 were 40 ± 145% (WS), 22 ± 117% (S20), 16 ± 61% (S40) and -2% ± 88% (S80) (p = 0.001). In conclusion, statin during the acute phase of MI reduces insulin sensitivity in a dose-dependent manner.

Assessment of dapagliflozin effect on diabetic endothelial dysfunction of brachial artery (ADDENDA-BHS2 trial): rationale, design, and baseline characteristics of a randomized controlled trial.

BACKGROUND: Endothelial dysfunction (ED) is a hallmark in type 2 diabetes mellitus (T2DM) that favor both atherogenesis and ischemia and reperfusion injury (IRI). Sodium-glucose-2 co-transporter inhibitors (SGLT2i) may hypothetically improve microvascular and macrovascular functions via a broad spectrum of mechanisms, being superior to traditional antidiabetic therapy such as sulfonylurea, even in subjects under equivalent glycemic control. Hence, the present clinical trial was designed to compare the effect of these two treatments on markers of arterial wall function and inflammation in T2DM patients as well as on the potential mediating parameters. METHOD AND RESULTS: ADDENDA-BHS2 is a prospective, single-center, active-controlled, open, randomized trial. Ninety-eight participants (40-70 years old) with HbA1c 7-9% were randomized (1:1, stratified by gender, BMI and HbA1c levels) to either dapagliflozin 10 mg/day or glibenclamide 5 mg/day on top of metformin. The primary endpoint was the change of flow-mediated dilation (FMD) after a 12-week period of treatment evaluated at rest and after IRI between dapagliflozin and glibenclamide arms. Secondary outcomes were defined as the difference between treatments regarding: plasma nitric oxide (NO) change after FMD, plasma isoprostane, plasma levels of vascular inflammatory markers and systemic inflammatory markers, plasma levels of adipokines, anthropometric measures, glucose control parameters, office and ambulatory BP control. Safety endpoints were defined as systolic and diastolic function assessed by echocardiography and retinopathy change. Serious adverse events were recorded. The study protocol was approved by the Independent Scientific Advisory Committee. CONCLUSION: The ADDENDA-BHS2 trial is an investigator-initiated clinical trial comparing the effect of dapagliflozin versus glibenclamide on several aspects of vascular function in high cardiovascular risk T2DM patients. Besides, a large clinical and biochemical phenotype assessment will be obtained for exploring potential mediations and associations.Trial registration Clinical trial registration: NCT02919345 (September, 2016).

Glycosylated hemoglobin is associated with decreased endothelial function, high inflammatory response, and adverse clinical outcome in non-diabetic STEMI patients.

OBJECTIVE: Chronic dysglycemia was recently identified as a predictor for adverse outcomes in patients with ST-elevation myocardial infarction (STEMI) treated by percutaneous coronary intervention. Data for non-diabetic patients who underwent thrombolysis is scarce. In this context, we aimed to study the effect of HbA1c on cardiovascular outcome after STEMI. METHODS: A prospective cohort of 326 non-diabetic STEMI individuals was used for the analyses. We measured plasma glucose, hemoglobin A1c [HbA1c], lipid profile, C-reactive protein (CRP), and nitrate/nitrite (NOx) upon admission and five days after STEMI (D5). Flow-mediated dilation (FMD) was performed 30 days after STEMI. During clinical follow-up, we assessed patients for incident diabetes (progression to HbA1c ≥ 6.5%) and major adverse cardiac events (MACE), defined as a composite of fatal and non-fatal MI, sudden cardiac death, and angina requiring hospitalization. RESULTS: Using ROC-curve analysis, a 5.8% HbA1c best predicted MACE with a sensitivity of 75% and specificity of 53% (AUC 0.673, p = 0.001). Patients were categorized as high HbA1c if ≥ 5.8% and low HbA1c if <5.8%. Compared with patients with low HbA1c, those with high HbA1c presented with 20% higher CRP-D5 (p = 0.009) and 19% higher ΔCRP (p = 0.01), a 32% decrease in ΔNOx (p < 0.001), and 33% lower FMD (p < 0.001). After a median follow-up of 1.9 (1.1-2.8) years, patients with high HbA1c had more incident diabetes (HR 2.3 95% CI 1.01-5.2; p = 0.048) and MACE (HR 3.32 95% CI 1.09-10.03; p = 0.03). CONCLUSION: Non-diabetic STEMI patients with high HbA1c present with decreased endothelial function and increased inflammatory response and long-term risk of MACE.

High-density lipoprotein levels are strongly associated with the recovery rate of insulin sensitivity during the acute phase of myocardial infarction: a study by euglycemic hyperinsulinemic clamp.

BACKGROUND: The decrease of insulin sensitivity (IS) during myocardial infarction (MI) is strongly associated with increased morbidity and mortality. Recent data suggest that in individuals under stable conditions, high-density lipoprotein (HDL) may improve IS. To date, the role of HDL in the modulation of IS in acute metabolic stress conditions such as MI remains unknown. OBJECTIVE: To explore the association between plasma HDL-C and the change in IS during the acute phase of MI. METHODS: Consecutive nondiabetic patients with ST-segment elevation MI (n = 22) underwent direct measurement of IS through the euglycemic hyperinsulinemic clamp on the first morning and on the fifth day after onset of MI. Patients were grouped according to HDL-C levels at admission above and below the median value (35 mg/dL). RESULTS: At admission, there was no significant difference in baseline IS index, clinical, anthropometric, or treatment characteristics between low and high HDL groups. Between admission and fifth day, there was a decrease of 8% in IS index in the low HDL group and an 11% increase in the high HDL group (P = .001 for intragroup and P = .012 for intergroup difference). This difference remained significant after we controlled for the sex, age, waist circumference, triglycerides, baseline IS index, and statin dose during hospitalization. CONCLUSION: This is the first study to provide evidence that plasma levels of HDL-C are strongly associated with the recovery rate of IS during the acute phase of MI.

High plasma HDL-C attenuates stress hyperglycemia during acute phase of myocardial infarction.

OBJECTIVE: During myocardial infarction (MI), a transient decrease of both insulin sensitivity and secretion triggers stress hyperglycemia, which is followed by a substantial increase in mortality. Recent findings in cellular models indicate that HDL may act on glucose homeostasis by improving insulin sensitivity and secretion. In this study, we explored this potential effect in patients during the acute phase of MI. METHODS: Plasma glucose, insulin and C-peptide were measured at admission in the first 24h and on the fifth day after MI with ST-segment elevation in 183 consecutive non-diabetic patients. Patients were divided into HDL-C quartiles for the analyses (Q1: <31, Q2: 31-38, Q3: 38-47 and Q4: >47mg/dL). The Homeostasis Model Assessment version 2 was used to assess insulin sensitivity (HOMA2S) and beta-cell function (HOMA2B). RESULTS: On admission, no difference was found between the quartiles in glucose (p=0.6), insulin (p=0.6) or C-peptide (p=0.5) levels, HOMA2S (p=0.9) or HOMA2B (p=1.0). On the fifth day there was a reduction in glucose levels whose intensity was directly proportional to the HDL-C quartile (p<0.001). At the same time, there was a reduction in plasma insulin (p<0.001) and C-peptides (p<0.001) whose magnitude was inversely proportional to the HDL-C quartile. Consistently, the increase of HOMA2S (p<0.001) and HOMA2B (p=0.01) were also positively associated with HDL-C levels. Furthermore, plasma HDL-C levels were inversely and independently associated with blood glucose change during the acute phase. CONCLUSION: This study demonstrates the association between low plasma HDL-C levels and increased duration of stress hyperglycemia during MI and suggests in humans the interaction between HDL and insulin secretion and sensitivity.

Rebound inflammatory response during the acute phase of myocardial infarction after simvastatin withdrawal.

OBJECTIVE: The present study aimed to verify the existence of a rebound inflammatory effect after statin withdrawal in the acute phase of myocardial infarction (MI). METHODS: In a prospective observational cohort, changes in C-reactive protein (CRP) between the first and the fifth day after MI were evaluated in 249 consecutive patients who were using statins prior to and during MI (SS), statins prior to but not during MI (SN), no statin prior to but during MI (NS), and no statin prior to nor during MI (NN). Data are presented as median (interquartile range). RESULTS: At baseline, statin users presented a trend to lower CRP values as compared with those without this treatment before the MI (NN: 1.0(0.4-1.5)mg/dL vs. NS: 1.0(0.3-2.8)mg/dL vs. SS: 0.5(0.3-1.0)mg/dL vs. SN: 0.6(0.4-1.0)mg/dL; p=0.08). By the fifth day, median CRP was significantly higher in the SN (18.1(16.1-23.2)mg/dL) group as compared with other groups (NN: 10.5(9.3-13.2)mg/dL vs. NS: 2.9(1.5-4.5)mg/dL vs. SS: 1.1(0.8-2.4)mg/dL; p<0.0001). At the fifth day, the median CRP in the NN group was lower than in the SN group (p<0.0001), but higher than the NS and SS groups (p<0.0001). There was no significant correlation between CRP change and the change of LDL-cholesterol, HDL-cholesterol or triglycerides. CONCLUSION: The present study has, for the first time, provided evidence for the existence of a rebound inflammatory effect after statin cessation. This rebound reaction may contribute for the adverse outcome of patients who stop statin treatment during MI.