Dapagliflozin acutely improves kidney function in type 2 diabetes mellitus. The PRECARE study.

Dapagliflozin has been demonstrated to improve glycemic control, blood pressure, and body weight in type 2 diabetes mellitus (T2D); indeed, it can also reduce the risk of progression to renal failure, of hospitalization for heart failure and of cardiovascular death. We aim to investigate the acute effect of Dapagliflozin on kidney function in the common clinical practice in T2D. This is a study including 1402 patients with T2D recruited from 11 centers in Lombardia, Italy, who were evaluated at baseline and after 6 months of treatment with Dapagliflozin 10 mg per day. The primary outcome of the study was the change in HbA1c, while the secondary outcomes were modification of weight, BMI, systolic and diastolic pressure, creatinine, eGFR and albuminuria status. After 24 weeks of treatment with Dapagliflozin, a reduction in Hb1Ac was observed (-0.6 ± 1.8%) as well as in BMI (-1.5 ± 5.2 kg/m2). Statistically significant changes were also found for systolic and diastolic blood pressure, cholesterol and triglycerides. Interestingly, a statistically significant acute improvement of kidney function was evident. Our analyses confirm the beneficial effects of dapagliflozin after 6 months of therapy, with improvements of glycemic and lipid profiles, blood pressure, BMI. Finally, an acute positive effect on albuminuria and KIDGO classes was observed during a 6 months treatment with dapagliflozin in patients with T2D.

Indirect and Direct Effects of SARS-CoV-2 on Human Pancreatic Islets.

Recent studies have shown that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may induce metabolic distress, leading to hyperglycemia in patients affected by coronavirus disease 19 (COVID-19). We investigated the potential indirect and direct effects of SARS-CoV-2 on human pancreatic islets in 10 patients who became hyperglycemic after COVID-19. Although there was no evidence of peripheral anti-islet autoimmunity, the serum of these patients displayed toxicity on human pancreatic islets, which could be abrogated by the use of anti-interleukin-1ß (IL-1ß), anti-IL-6, and anti-tumor necrosis factor α, cytokines known to be highly upregulated during COVID-19. Interestingly, the receptors of those aforementioned cytokines were highly expressed on human pancreatic islets. An increase in peripheral unmethylated INS DNA, a marker of cell death, was evident in several patients with COVID-19. Pathology of the pancreas from deceased hyperglycemic patients who had COVID-19 revealed mild lymphocytic infiltration of pancreatic islets and pancreatic lymph nodes. Moreover, SARS-CoV-2-specific viral RNA, along with the presence of several immature insulin granules or proinsulin, was detected in postmortem pancreatic tissues, suggestive of ß-cell-altered proinsulin processing, as well as ß-cell degeneration and hyperstimulation. These data demonstrate that SARS-CoV-2 may negatively affect human pancreatic islet function and survival by creating inflammatory conditions, possibly with a direct tropism, which may in turn lead to metabolic abnormalities observed in patients with COVID-19.

Immunogenicity and Safety of SARS-CoV-2 mRNA Vaccines in a Cohort of Patients With Type 1 Diabetes.

Patients with type 1 diabetes (T1D) may develop severe outcomes during coronavirus disease 2019 (COVID-19), but their ability to generate an immune response against the SARS-CoV-2 mRNA vaccines remains to be established. We evaluated the safety, immunogenicity, and glycometabolic effects of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines in patients with T1D. A total of 375 patients (326 with T1D and 49 subjects without diabetes) who received two doses of the SARS-CoV-2 mRNA vaccines (mRNA-1273, BNT162b2) between March and April 2021 at ASST Fatebenefratelli Sacco were included in this monocentric observational study. Local and systemic adverse events were reported in both groups after SARS-CoV-2 mRNA vaccination, without statistical differences between them. While both patients with T1D and subjects without diabetes exhibited a parallel increase in anti-SARS-CoV-2 spike titers after vaccination, the majority of patients with T1D (70% and 78%, respectively) did not show any increase in the SARS-CoV-2-specific cytotoxic response compared with the robust increase observed in all subjects without diabetes. A reduced secretion of the T-cell-related cytokines interleukin-2 and tumor necrosis factor-α in vaccinated patients with T1D was also observed. No glycometabolic alterations were evident in patients with T1D using continuous glucose monitoring during follow-up. Administration of the SARS-CoV-2 mRNA vaccine is associated with an impaired cellular SARS-CoV-2-specific cytotoxic immune response in patients with T1D.

One year of Hybrid Closed Loop on peritoneal dialysis: a case report.

BACKGROUND: Automated insulin delivery is a game changer for type 1 diabetes treatment. OBJECTIVE: To describe the benefits of automated insulin delivery in a specific complex setting. METHODS: We are herein presenting a case of a patient with type 1 diabetes, in which Hybrid Closed Loop (Medtronic Minimed 670G on Auto Mode) was used over a year during automated peritoneal dialysis. The patient was previously on insulin therapy with sensor augmented pump and we switched him to Hybrid Closed Loop shortly before the begin of dialysis. RESULTS: Automated insulin delivery produced an increase of time in range (70-180 mg/dl) from 63% to 72%, after 3 months and to 74% after one year. Moreover, no hypoglycemia/hyperglycemia urgencies occurred overall during the year. CONCLUSIONS: The case detailed here is the first report of Hybrid Closed Loop in a patient on automated peritoneal dialysis and it shows an improvement of time in range with a satisfying safety profile in a fragile, aged patient.

Acute and long-term disruption of glycometabolic control after SARS-CoV-2 infection.

Patients with coronavirus disease 2019 (COVID-19) are reported to have a greater prevalence of hyperglycaemia. Cytokine release as a consequence of severe acute respiratory syndrome coronavirus 2 infection may precipitate the onset of metabolic alterations by affecting glucose homeostasis. Here we describe abnormalities in glycometabolic control, insulin resistance and beta cell function in patients with COVID-19 without any pre-existing history or diagnosis of diabetes, and document glycaemic abnormalities in recovered patients 2 months after onset of disease. In a cohort of 551 patients hospitalized for COVID-19 in Italy, we found that 46% of patients were hyperglycaemic, whereas 27% were normoglycaemic. Using clinical assays and continuous glucose monitoring in a subset of patients, we detected altered glycometabolic control, with insulin resistance and an abnormal cytokine profile, even in normoglycaemic patients. Glycaemic abnormalities can be detected for at least 2 months in patients who recovered from COVID-19. Our data demonstrate that COVID-19 is associated with aberrant glycometabolic control, which can persist even after recovery, suggesting that further investigation of metabolic abnormalities in the context of long COVID is warranted.

Acute parathyroid hormone increase by oral peptones administration after roux-en-Y gastric bypass surgery in obese subjects: role of phosphate in the rapid control of parathyroid hormone release.

BACKGROUND: It is generally considered that changes in serum phosphate levels do not alter parathyroid hormone (PTH) secretion in the absence of concomitant changes in ionized serum calcium level in humans. An acute rise in PTH was shown after phosphate administration by intraduodenal gavage in rats. We aimed to study gastrin, phosphate, PTH, ionized calcium (iCa), and blood pH responses to oral peptones in morbidly obese patients before and after roux-en-Y gastric bypass (RYGB) surgery. METHODS: These parameters were evaluated in response to an oral peptone load in 24 (18 male and 6 female) obese subjects before and 6 months after RYGB surgery. In 12 gastric bypass patients, we also evaluated PTH and phosphate after peptones plus aluminum hydroxide administration to suppress phosphate absorption. RESULTS: Before RYGB, peptones increased gastrin (P < .001), and decreased iCa (P < .01) without changes in PTH or pH. Both phosphate and PTH markedly increased after RYGB with the peptones oral load (P < .01), without changes in pH, iCa, or gastrin. There was a significant, direct relationship between the increase of phosphate and the increase of PTH in the patients treated with aluminum hydroxide (r(2) = 0.78; P < .0001). CONCLUSION: Rapid delivery of peptones in the jejunum in bypassed obese patients results in a significant rise in phosphate and PTH, in the absence of changes of other PTH regulators, possibly mediated by a signaling from the gastrointestinal tract. RYGB patients provide an opportunity to study the control of PTH secretion, with potential relevant clinical implications.

Effects of fluvastatin slow-release (XL 80 mg) versus simvastatin (20 mg) on the lipid triad in patients with type 2 diabetes.

The lipid triad is the association of small, dense (sd) low-density lipoprotein (LDL), low high-density lipoprotein (HDL), and hypertriglyceridemia, all of which play a role in coronary artery disease in patients with type 2 diabetes. Although statins have demonstrated clear positive effects on cardiovascular morbidity/mortality in patients with diabetes and on single components of the lipid triad, it remains controversial whether they affect all components of the triad in these patients. Therefore, we performed a single-center, parallel-group, prospective, randomized, open-label, blinded-endpoint (PROBE)-type comparison of fluvastatin extended-release (XL) 80 mg (n=48) and simvastatin 20 mg (n=46), each given once daily for 2 months to patients with type 2 diabetes with the lipid triad, who were enrolled after a 1-month lifestyle modification and dietary intervention program. After fluvastatin therapy, LDL (-51%; P<.01), apolipoprotein B (ApoB; -33%; P<.01), intermediate-density LDL (idLDL) (-14.3%; P<.05), sdLDL (-45%; P<.01), and triglycerides (-38%; P<.01) were significantly decreased, and HDL (+14.3%; P<.05) and apolipoprotein A-I (ApoA-I; +7%; P<.05) were increased; large buoyant (lb) LDL did not change (P=NS). Simvastatin therapy decreased LDL (-55.1%; P<.01), ApoB (-46%; P<.01), lbLDL (-33.3%; P<.05), idLDL (-22.7%; P<.05), sdLDL (-33.3%; P<.05), and triglycerides (-47.9%; P<.01); HDL was not changed (P=NS) after simvastatin, but ApoA-I was increased (+11.3%; P<.01). HDL increases (P<.01) and sdLDL decreases (P<.01) were significantly greater after fluvastatin compared with simvastatin therapy; LDL, triglycerides, ApoB, and idLDL changes were similar after both therapies (P=NS), and lbLDL decreases were greater with simvastatin therapy (P<.05). With both treatments, classic mean LDL and ApoB target levels were achieved in most patients. We conclude that the lipid triad can be controlled with fluvastatin XL 80 mg in patients with type 2 diabetes.

Metabolic effects of fluvastatin extended release 80 mg and atorvastatin 20 mg in patients with type 2 diabetes mellitus and low serum high-density lipoprotein cholesterol levels: a 4-month, prospective, open-label, randomized, blinded-end point (probe) trial.

BACKGROUND: Diabetic dyslipidemia is characterized by greater triglyceridation of all lipoproteins and low levels of plasma high-density lipoprotein cholesterol (HDL-C). In this condition, the serum level of low-density lipoprotein cholesterol (LDL-C) is only slightly elevated. The central role of decreased serum HDL-C level in diabetic cardiovascular disease has prompted the establishment of a target of ≥50 mg/dL in patients with diabetes mellitus (DM). OBJECTIVE: The aim of the study was to assess the effects of once-daily administration of fluvastatin extended release (XL) 80 mg or atorvastatin 20 mg on serum HDL-C levels in patients with type 2 DM and low levels of serum HDL-C. METHODS: This 4-month, prospective, open-label, randomized, blinded-end point (PROBE) trial was conducted at Endocrinology and Diabetology Service, L. Sacco-Polo University Hospital (Milan, Italy). Patients aged 45 to 71 years with type 2 DM receiving standard oral antidiabetic therapy, with serum HDL-C levels <50 mg/dL, and with moderately high serum levels of LDL-C and triglycerides (TG) were enrolled. After 1 month of lifestyle modification and dietary intervention, patients who were still showing a decreased HDL-C level were randomized, using a 1:1 ratio, to receive fluvastatin XL 80-mg tablets or atorvastatin 20-mg tablets, for 3 months. Lipoprotein metabolism was assessed by measuring serum levels of LDL-C, HDL-C, TG, apolipoprotein (apo) A-I (the lipoprotein that carries HDL), and apo B (the lipoprotein that binds very low-density lipoprotein cholesterol, intermediate-density lipoprotein, and LDL on a molar basis). Patients were assessed every 2 weeks for treatment compliance and subjective adverse events. Serum creatine phosphokinase and liver enzymes were assessed before the run-in period, at the start of the trial, and at 1 and 3 months during the study. RESULTS: One hundred patients were enrolled (50 patients per treatment group; fluvastatin XL group: 33 men, 17 women; mean [SD] age, 58 [12] years; atorvastatin group: 39 men, 11 women; mean [SD] age, 59 [11] years). In the fluvastatin group after 3 months of treatment, mean (SD) LDL-C decreased from 149 (33) to 95 (25) mg/dL (36%; P < 0.01), TG decreased from 437 (287) to 261 (164) mg/dL (40%; P < 0.01), and HDL-C increased from 41 (7) to 46 (10) mg/dL (12%; P < 0.05). In addition, apo A-I increased from 118 (18) to 124 (15) mg/dL (5%; P < 0.05) and apo B decreased from 139 (27) to 97 (19) mg/dL (30%; P < 0.05). In the atorvastatin group, LDL-C decreased from 141 (25) to 84 (23) mg/dL (40%; P < 0.01) and TG decreased from 411 (271) to 221 (87) mg/dL (46%; P < 0.01). Neither HDL-C (41 [7] vs 40 [6] mg/dL; 2%) nor apo A-I (117 [19] vs 114 [19] mg/dL; 3%) changed significantly. However, apo B decreased significantly, from 131 (20) to 92 (17) mg/dL (30%; P < 0.05). Mean changes in HDL-C (+5 [8] vs -1 [2] mg/dL; P < 0.01) and apo A-I (+6 [18] mg/dL vs -3 [21] mg/dL; P < 0.01) were significantly greater in the fluvastatin group than in the atorvastatin group, respectively. However, the decreases in LDL-C (54 [31] vs 57 [32] mg/ dL), TG (177 [219] vs 190 [65] mg/dL), and apo B (42 [26] vs 39 [14] mg/dL) were not significantly different between the fluvastatin and atorvastatin groups, respectively. No severe adverse events were reported. CONCLUSIONS: Fluvastatin XL 80 mg and atorvastatin 20 mg achieved mean serum LDL-C (≤ 100 mg/dL) and apo B target levels (≤ 100 mg/dL) in the majority of this population of patients with type 2 DM, but mean serum HDL-C level was increased significantly only with fluvastatin-16 patients (32%) in the fluvastatin group compared with none in the atorvastatin group achieved HDL-C levels ≥50 mg/dL. The increase in HDL-C in the fluvastatin-treated patients was associated with an increase in apo A-I, suggesting a potential pleiotropic and selective effect in patients with low HDL-C levels.