Pathophysiological basis of the cardiological benefits of SGLT-2 inhibitors: a narrative review.

In recent years, GLP-1 receptor agonists (GLP-1RA), and SGLT-2 inhibitors (SGLT-2i) have become available, which have become valuable additions to therapy for type 2 diabetes as they are associated with low risk for hypoglycemia and cardiovascular benefits. Indeed, SGLT-2i have emerged as a promising class of agents to treat heart failure (HF). By inhibiting SGLT-2, these agents lead to excretion of glucose in urine with subsequent lowering of plasma glucose, although it is becoming clear that the observed benefits in HF cannot be explained by glucose-lowering alone. In fact, multiple mechanisms have been proposed to explain the cardiovascular and renal benefits of SGLT-2i, including hemodynamic, anti-inflammatory, anti-fibrotic, antioxidant, and metabolic effects. Herein, we review the available evidence on the pathophysiology of the cardiological benefits of SGLT-2i. In diabetic heart disease, in both clinical and animal models, the effect of SGLT-2i have been shown to improve diastolic function, which is even more evident in HF with preserved ejection fraction. The probable pathogenic mechanisms likely involve damage from free radicals, apoptosis, and inflammation, and therefore fibrosis, many of which have been shown to be improved by SGLT-2i. While the effects on systolic function in models of diabetic heart disease and HF with preserved ejection fraction is limited and contrasting, it is a key element in patients with HF and reduced ejection fraction both with and without diabetes. The significant improvement in systolic function appears to lead to subsequent structural remodeling of the heart with a reduction in left ventricle volume and a consequent reduction in pulmonary pressure. While the effects on cardiac metabolism and inflammation appear to be consolidated, greater efforts are still warranted to further define the entity to which these mechanisms contribute to the cardiovascular benefits of SGLT-2i.

Predictive markers for clinical outcomes in a cohort of diabetic patients hospitalized for COVID-19.

INTRODUCTION: The role of glycemic control, both prior and during hospitalization, on mortality from COVID-19 in diabetic patients is debated. Furthermore, it is not clear whether hyperglycemia has a direct effect or requires inflammatory mechanisms. OBJECTIVE: To identify predictors of clinical outcomes (in-hospital mortality, length of hospitalization, respiratory failure, need for intensive care), considering hyperglycemia, inflammation markers and clinical history. METHODS: Retrospective observational study of 291 diabetic patients hospitalized with COVID-19 in the Spedali Civili di Brescia from February 1th 2020 to March 31th 2021, with also outpatient electronic records. Glucose, inflammatory parameters, creatinine were collected within 24 h after admission to the hospital. A causal mediation analysis allowed the estimation of the direct and indirect effects of hyperglycemia on mortality. RESULTS: Glucose at admission ≥ 165 mg/dL and reduced renal function were associated with an increased risk of in-hospital mortality and length of hospitalization (all p < 0.001), while an increase in inflammatory parameters was significantly associated with an increased risk of all outcomes. High basophil count was associated with reduced mortality (p < 0.001). Hyperglycemia had a direct effect on mortality (p < 0.001); the indirect, through inflammatory markers, was significant only for absolute neutrophil count, C-Reactive protein and procalcitonin (p = 0.007, p = 0.029, p = 0.042). Patients with microvascular complications and with chronic kidney disease showed higher mortality (p = 0.03, p = 0.01). CONCLUSIONS: Hyperglycemia at admission, renal function and inflammatory parameters were found to be predictors of in-hospital mortality, while an increased basophil count was protective. Hyperglycemia had a direct effect on mortality, the indirect effect was only through few markers and markedly lower than the direct one.

Migraine attack restores the response of vascular smooth muscle cells to nitric oxide but not to norepinephrine.

AIM: To clarify whether the vasoconstrictory response is impaired and to study vascular function in patients with migraine during the headache attack. METHODS: We studied vascular reactivity in the resistance arteries by using the forearm perfusion technique associated with plethysmography. We measured forearm blood flow by strain-gauge plethysmography during intra-brachial infusion of acetylcholine, sodium nitroprusside or norepinephrine in 11 controls and 13 patients with migraine, 11 of them (M) in the interval between the migraine attacks and 4 during a headache attack (MH). Written informed consent was obtained from patients and healthy controls, and the study was approved by the Ethics Committee of the University Federico II. RESULTS: Compared to healthy control subjects, in patients with migraine studied during the interictal period, the vasodilating effect of acetylcholine, that acts through the stimulation of endothelial cells and the release of nitric oxide, was markedly reduced, but became normal during the headache attack (P < 0.05 by analysis of variance). The response to nitroprusside, which directly relaxes vascular smooth muscle cells (VSMCs), was depressed in patients with migraine studied during the interictal period, but normal during the headache attack (P < 0.005). During norepinephrine infusion, forearm blood flow decreased in control subjects (-40% ± 5%, P < 0.001). In contrast, in patients with migraine, either when studied during or free of the headache attack forearm blood flow did not change compared to the baseline value (-3% ± 13% and -10.4% ± 15%, P > 0.05). CONCLUSION: In migrainers, the impaired relaxation of VSMCs is restored during the headache attack. The vasoconstrictory response is impaired and remains unchanged during the migraine attack.

Thyreotropin levels in diabetic patients on metformin treatment.

OBJECTIVE: A retrospective study to evaluate the changes in TSH concentrations in diabetic patients treated or not treated with metformin and/or L-thyroxine (L-T(4)). METHODS: Three hundred and ninety three euthyroid diabetic patients were divided into three groups on the basis of metformin and/or L-T(4) treatment: Group (M-/L-), 119 subjects never treated with metformin and L-T(4); Group (M+/L-), 203 subjects who started metformin treatment at recruitment; and Group (M+/L+), 71 patients on L-T(4) who started metformin recruitment. RESULTS: The effect of metformin on serum TSH concentrations was analyzed in relation to the basal value of TSH (below 2.5 mIU/L (Q1) or between 2.51 and 4.5 mIU/L (Q2)). In patients of group M+/L+, TSH significantly decreased independently from the basal level (Q1, from 1.450.53 to 1.011.12 mU/L (P=0.037); Q2, from 3.600.53 to 1.910.89 mU/L (P<0.0001)). In M+/L group, the decrease in TSH was significant only in those patients with a basal high-normal serum TSH (Q2: from 3.24±0.51 to 2.27±1.28 mU/l (P=0.004)); in M-/L- patients, no significant changes in TSH levels were observed. In patients of group M+/L showing high-normal basal TSH levels, a significant decrease in TSH was observed independently from the presence or absence of thyroid peroxidase antibodies (ABTPO; Q2 ABTPO +: from 3.38±0.48 to 1.87±1.08 mU/l (P<0.001); Q2 AbTPO -: from 3.21±0.52 to 2.34±1.31 mU/l (P<0.001)). CONCLUSIONS: These data strengthen the known TSH-lowering effect of metformin in diabetic patients on L-T(4) treatment and shows a significant reduction of TSH also in euthyroid patients with higher baseline TSH levels independently from the presence of AbTPO.

Predicting the risk of diabetic retinopathy in type 2 diabetic patients.

AIMS: Diabetic retinopathy (DR) is often asymptomatic even in its more advanced stages. Timely and repeated screening for DR avoids a late diagnosis of DR, but the high number of diabetic patients precludes a frequent screening; thus, the need for a method to identify patients at higher risk for DR becomes crucial. METHODS: A prospective analysis of 5034 type 2 diabetic patients followed from 1996 to 2007 and not affected by retinopathy at the time of the recruitment was performed. Patients were randomly divided (ratio 2:1) into two groups: the train data set and the test set (3327 and 1707 patients, respectively). Factors associated with the occurrence of DR were assessed by the Cox's proportional hazard model. RESULTS: Duration of diabetes, glycosylated hemoglobin, systolic blood Pressure, male gender, albuminuria and diabetes therapy other than diet were all significantly associated with the occurrence of DR. CONCLUSIONS: The nomogram could help in ranking the type 2 diabetic patients at higher risk to develop DR and thus with a need for more frequent ophthalmologic checks, without enhancing neither the time nor the costs.

Impaired endothelial- and nonendothelial-mediated vasodilation in patients with acute or chronic hypothyroidism.

OBJECTIVE: Vascular dysfunction and accelerated atherosclerosis are prominent features of hypothyroidism. The relative roles of thyroid hormone (TH) deficiency and the associated vascular risk conditions are still unclear. We studied the impact of acute and chronic hypothyroidism on vascular reactivity. PATIENTS: We studied 12 patients with chronic primary hypothyroidism (cHY; TSH: 52 +/- 14 mU/l), seven patients with acute hypothyroidism secondary to total thyroidectomy (aHY; TSH: 97 +/- 24) and 13 healthy subjects (TSH: 1.2 +/- 0.5). MEASUREMENTS: We measured forearm blood flow (FBF) using plethysmography during intra-brachial infusion of: acetylcholine (ACh), sodium nitroprusside (NP) and norepinephrine (NE). We also measured serum C-reactive protein (CRP), TNF-alpha, asymmetric dimethylarginine (ADMA) and the forearm balance of nitric oxide (NO) during ACh infusion. RESULTS: As compared with the controls, the vasodilatory response to ACh was reduced in cHY (P = 0.001) and aHY (P = 0.04), as was the forearm release of NO (P < 0.05). During NP infusion, FBF rose to 24 +/- 2 ml/dl/min in the controls and to significantly lower values in cHY (12 +/- 1; P = 0.001) and aHY (15 +/- 2; P = 0.004). NE-induced vasoconstriction was similar in the controls and aHY, but blunted in cHY. Serum CRP, TNF-alpha and ADMA were not different in the three groups. CONCLUSIONS: (i) Hypothyroidism associates with endothelial and nonendothelial mediated vascular dysfunction; (ii) these defects are evident even after short-term hypothyroidism, indicating that TH deficiency per se is sufficient to alter vascular homeostasis; and (iii) chronic, but not acute, hypothyroidism impairs the vasoconstrictory effect of NE in the resistance vessels.

Acute effects of triiodothyronine on endothelial function in human subjects.

CONTEXT: Thyroid hormone regulates several cardiovascular functions, and low T(3) levels are frequently associated with cardiovascular diseases. Whether T(3) exerts any acute and direct effect on endothelial function in humans is unknown. OBJECTIVE: Our objective was to clarify whether acute changes in serum T3 concentration affect endothelial function. DESIGN, SETTING, AND SUBJECTS: Ten healthy subjects (age, 24 +/- 1 yr) participated in a double-blind, placebo-controlled trial at a university hospital. INTERVENTIONS: T3 (or placebo) was infused for 7 h into the brachial artery to raise local T3 to levels observed in moderate hyperthyroidism. Vascular reactivity was tested by intraarterial infusion of vasoactive agents. MAIN OUTCOME MEASURES: We assessed changes in forearm blood flow (FBF) measured by plethysmography. RESULTS: FBF response to the endothelium-dependent vasodilator acetylcholine was enhanced by T3 (P = 0.002 for the interaction between T3 and acetylcholine). The slopes of the dose-response curves were 0.41 +/- 0.06 and 0.23 +/- 0.04 ml/dl x min/microg in the T3 and placebo study, respectively (P = 0.03). T3 infusion had no effect on the FBF response to sodium nitroprusside. T3 potentiated the vasoconstrictor response to norepinephrine (P = 0.006 for the interaction). Also, the slopes of the dose-response curves were affected by T3 (1.95 +/- 0.77 and 3.83 +/- 0.35 ml/dl x min/mg in the placebo and T3 study, respectively; P < 0.05). The increase in basal FBF induced by T3 was inhibited by NG-monomethyl-L-arginine. CONCLUSIONS: T3 exerts direct and acute effects on the resistance vessels by enhancing endothelial function and norepinephrine-induced vasoconstriction. The data may help clarify the vascular impact of the low T3 syndrome and point to potential therapeutic strategies.

Red wine consumption improves insulin resistance but not endothelial function in type 2 diabetic patients.

Epidemiological studies have shown that red wine consumption is associated with less cardiovascular mortality in the general population and in the diabetic patients. To determine whether red wine improves insulin resistance in diabetic patients and to explore the relation between insulin sensitivity and endothelial function, we studied vascular reactivity and insulin-mediated glucose uptake in 9 type 2 diabetic patients before and after 2 weeks of red wine consumption (360 mL/d, wine-treated diabetics) and 8 type 2 diabetic patients who did not consume wine (control diabetics). Vascular reactivity was evaluated by plethysmography during intraarterial infusion of acetylcholine (Ach), sodium nitroprusside, and L-N-monomethylarginine. Forearm nitrite balance was measured during Ach infusion. Insulin sensitivity was measured by euglycemic hyperinsulinemic clamp at 1 mU/kg per minute. The basal forearm blood flow and the response to Ach, to sodium nitroprusside, and to L-N -monomethylarginine were unchanged both in the wine-treated and in the control diabetics. In contrast, insulin-mediated whole body glucose disposal improved by 43% after red wine consumption (from 2.79 +/- 0.4 to 4.02 +/- 0.5 mg/kg of lean body mass per minute, P = .02), but did not change in the control group. In conclusion, red wine consumption for 2 weeks markedly attenuates insulin-resistance in type 2 diabetic patients, without affecting vascular reactivity and nitric oxide production.

Food and red wine do not exert acute effects on vascular reactivity.

Experimental hyperglycemia and hyperinsulinemia have been shown to affect vascular reactivity. Chronic red wine consumption is associated with less cardiovascular mortality. Whether ingestion of a natural meal and red wine causes acute changes in vascular homeostasis is poorly understood. The aim of the current study was to clarify whether meal ingestion, with and without red wine, exert acute effects on vascular reactivity in healthy humans. We studied vascular reactivity and forearm nitrite balance in 10 healthy subjects under 3 different circumstances: (1) fasting; (2) after ingestion of a standard natural meal (1,050 kcal); and (3) after the same meal enriched with a glass of red wine. We measured forearm blood flow (FBF) by strain-gauge plethismography during intrabrachial, graded infusion of acetylcholine (ACh), sodium nitroprusside (NP), and norepinephrine (NE). We also measured the forearm balance of nitrite before and during ACh infusion. Despite significant increases in plasma glucose and insulin concentrations, the vasodilatory response to Ach and NP after meal ingestion was not different from the fasting response. Similarly, the vasoconstrictory response to NE was similar postprandially and during fasting. Addition of red wine did not modify the response to any of the vasoactive agents. Finally, the forearm nitrite production during Ach infusion was not different in the 3 experimental settings. Food intake, whether associated or not with red wine, does not affect vascular reactivity in normal human subjects.

Acute effects of growth hormone on vascular function in human subjects.

GH is involved in the long-term regulation of peripheral vascular resistance and vascular reactivity. We determined whether GH plays a role in the acute regulation of vascular function in humans. The acute vascular effects of GH were studied in eight healthy subjects according to a double-blind, placebo-controlled design. Forearm blood flow (FBF), vascular resistance, and nitric oxide (NO) production were monitored during a 4-h infusion of GH into the brachial artery at a rate chosen to raise local GH to stress levels (approximately 40 ng/ml). During GH infusion, FBF rose 75% (P < 0.05), whereas forearm vascular resistance decreased comparably (P < 0.05). These changes were paralleled by augmented forearm release of NO (P < 0.02). GH heightened the response of FBF to the endothelium-dependent vasodilator acetylcholine (Ach; P < 0.02). With the highest Ach dose, FBF reached 30.4 +/- 4.2 and 16.9 +/- 3.1 ml/dl x min in the GH and placebo studies, respectively (P < 0.005). The slopes of the dose-response curves also differed markedly (0.45 +/- 0.07 and 0.25 +/- 0.05 ml/dl x min/ microg in the GH and placebo studies, respectively; P < 0.01). GH caused an upward shift of the FBF response to the endothelium-independent vasodilator sodium nitroprusside (P < 0.01), but did not affect the slope of the dose-response curve. GH infusion did not cause any appreciable increment in the venous IGF-I concentration in the test arm. In conclusion, GH acutely lowers peripheral vascular resistance and stimulates endothelial function. These effects are mediated by activation of the NO pathway and appear to be independent of IGF-I.