Place of sodium-glucose co-transporter type 2 inhibitors for treatment of type 2 diabetes

Inhibitors of sodium-glucose co-transporter type 2 (SGLT2), such as canagliflozin and dapagliflozin, are recently approved for treatment of type 2 diabetes. These agents lower blood glucose mainly by increasing urinary glucose excretion. Compared with placebo, SGLT2 inhibitors reduce hemoglobin A1c (HbA1c) levels by an average of 0.5%-0.8% when used as monotherapy or add-on therapy. Advantages of this drug class include modest weight loss of approximately 2 kg, low risk of hypoglycemia, and decrease blood pressure of approximately 4 mmHg systolic and 2 mmHg diastolic. These characteristics make these agents potential add-on therapy in patients with HbA1c levels close to 7%-8.0%, particularly if these patients are obese, hypertensive, and/or prone for hypoglycemia. Meanwhile, these drugs are limited by high frequency of genital mycotic infections. Less common adverse effects include urinary tract infections, hypotension, dizziness, and worsening renal function. SGLT2 inhibitors should be used with caution in the elderly because of increased adverse effects, and should not be used in chronic kidney disease due to decreased or lack of efficacy and nephrotoxicity. Overall, SGLT2 inhibitors are useful addition for treatment of select groups of patients with type 2 diabetes, but their efficacy and safety need to be established in long-term clinical trials.     

SGLT-2 inhibitors in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus: A systematic review

BACKGROUND Non-alcoholic fatty liver disease(NAFLD) is a common comorbidity with type 2 diabetes. The existing therapeutic options for NAFLD are not adequate.Hypocaloric diet and exercise is the cornerstone of therapy in NAFLD.Pioglitazone is the only drug recommended in diabetes patients with biopsy proven non-alcoholic steatohepatitis. The frequent coexistence of NAFLD and type 2 diabetes with their combined adverse health consequences and inadequate therapeutic options makes it necessary to search for newer alternatives.AIM To assess the effect of sodium glucose cotransporter-2(SGLT-2) inhibitors on liver enzymes in type 2 diabetes patients with NAFLD.METHODS We searched Pub Med/MEDLINE, Cochrane library, Google scholar, and Clinicaltrials.gov for the relevant articles to be included in this systematic review.Human studies done in type 2 diabetes patients with NAFLD treated with SGLT-2 inhibitors for at least 12 wk were included. Data from eight studies(four randomised controlled trials and four observational studies) were extracted and a narrative synthesis was done. A total of 214 patients were treated with SGLT-2 inhibitors in these studies(94 in randomised controlled trials and 120 in observational studies).RESULTS The primary outcome measure was change in serum alanine aminotransferase level. Out of eight studies, seven studies showed a significant decrease in serum alanine aminotransferase level. Most of the studies revealed reduction in serum level of other liver enzymes like aspartate aminotransferase and gamma glutamyl transferase. Five studies that reported a change in hepatic fat exhibited a significant reduction in hepatic fat content in those treated with SGLT-2 inhibitors. Likewise, among the three studies that evaluated a change in indices of hepatic fibrosis, two studies revealed a significant improvement in liver fibrosis. Moreover, there was an improvement in obesity, insulin resistance,glycaemia, and lipid parameters in those subjects taking SGLT-2 inhibitors. The studies disclosed that about 17%(30/176) of the subjects taking SGLT-2 inhibitors developed adverse events and more than 40%(10/23) of them had genitourinary tract infections.CONCLUSION Based on low to moderate quality of evidence, SGLT-2 inhibitors improve the serum level of liver enzymes, decrease liver fat, and fibrosis with additional beneficial effects on various metabolic parameters in type 2 diabetes patients with NAFLD.     

Renal protective effect and safety of sodium-glucose cotransporter-2 inhibitors in patients with chronic kidney disease and type 2 diabetes mellitus: a network meta-analysis and systematic review

International Urology and Nephrology - A network meta-analysis was conducted to evaluate the renal protective effect and safety of sodium-glucose cotransporter-2 inhibitors in patients with chronic...     

Genetic immune and inflammatory markers associated with diabetes in solid organ transplant recipients

New‐onset diabetes mellitus after transplantation (NODAT) is a complication following solid organ transplantation (SOT) and may be related to immune or inflammatory responses. We investigated whether single nucleotide polymorphisms (SNPs) within 158 immune‐ or inflammation‐related genes contribute to NODAT in SOT recipients. The association between 263 SNPs and NODAT was investigated in a discovery sample of SOT recipients from the Swiss Transplant Cohort Study (STCS, n₁ = 696). Positive results were tested in a first STCS replication sample (n₂ = 489) and SNPs remaining significant after multiple test corrections were tested in a second SOT replication sample (n₃ = 156). Associations with diabetic traits were further tested in several large general population‐based samples (n > 480 000). Only SP110 rs2114592C>T remained associated with NODAT in the STCS replication sample. Carriers of rs2114592‐TT had 9.9 times (95% confidence interval [CI]: 3.22‐30.5, P = .00006) higher risk for NODAT in the combined STCS samples (n = 1184). rs2114592C>T was further associated with NODAT in the second SOT sample (odds ratio: 4.8, 95% CI: 1.55‐14.6, P = .006). On the other hand, SP110 rs2114592C>T was not associated with diabetic traits in population‐based samples, suggesting a specific gene‐environment interaction, possibly due to the use of specific medications (ie, immunosuppressants) in transplant patients and/or to the illness that may unmask the gene effect.     

Clinical outcomes of polyvalent immunoglobulin use in solid organ transplant recipients: A systematic review and meta‐analysis

Polyvalent immunoglobulin is commonly used for desensitization and treatment of antibody‐mediated rejection in kidney transplantation but its impact on other outcomes is not known. This systematic review investigated the impact of immunoglobulin prophylaxis on infection, rejection, graft loss, and death following kidney transplantation. A comprehensive literature search located 18 studies (n = 8 randomized controlled trials). None examined the effect of immunoglobulin prophylaxis in transplant recipients with hypogammaglobulinemia. Quality of included studies was variable with high to very high risk of bias. In the randomized trials, immunoglobulin use did not reduce cytomegalovirus infection (OR 0.68 [0.39, 1.21]; 6 studies, n = 295), rejection (OR 0.96 [0.50, 1.82]; 4 studies, n = 187), or graft loss (OR 1.03 [0.46, 2.30]; 6 studies, n = 265). In non‐randomized studies, immunoglobulin did not reduce cytomegalovirus infection (OR 0.63 [0.20, 1.94]; 6 studies, n = 361) or death (OR 1.32 [0.05, 38.79]; 3 studies, n = 222) but reduce rejection (OR 0.47 [0.24, 0.94]; 4 studies, n = 268) and graft loss (OR 0.15 [0.05, 0.43]; 2 studies, n = 118). Data were scarce and sample size of current evidence was small. Adequately powered randomized trials are needed to determine if immunoglobulin is an effective intervention to reduce infection, rejection, graft loss, or death following kidney transplantation with and without hypogammaglobulinemia.     

Treatment of cytomegalovirus infection or disease in solid organ transplant recipients with valganciclovir

Valganciclovir (VGC) has proved efficacious and safe for the prophylaxis against cytomegalovirus (CMV) in high-risk transplant recipients and for the treatment of CMV retinitis in AIDS patients. We used VGC for the treatment of CMV infection (viremia without symptoms) or disease (CMV syndrome or tissue-invasive disease) in kidney, heart, and lung transplant recipients. Fourteen transplant recipients were treated: five for asymptomatic CMV infection and nine for CMV disease. VGC was administered in doses adjusted to renal function for 4 to 12 weeks (induction and maintenance therapy). Clinically, all nine patients with CMV disease responded to treatment. Microbiologically, treatment with VGC turned blood culture negative for CMV within 2 weeks in all patients and was associated with a > or =2 log decrease in blood CMV DNA within 3 weeks in 8 of 8 tested patients. With a follow-up of 6 months (n = 12 patients), asymptomatic recurrent CMV viremia was noted in five cases, and CMV syndrome noted in one case (all cases in the first 2 months after the end of treatment). VGC was clinically well tolerated in all patients; however, laboratory abnormalities occurred in three cases (mild increase in transaminases, thrombocytopenia, and pancytopenia). This preliminary experience strongly suggests that therapy with VGC is effective against CMV in organ transplant recipients; however, the exact duration of therapy remains to be determined: a longer course may be necessary to prevent early recurrence.     

Sleeve gastrectomy and type 2 diabetes mellitus: a systematic review

BackgroundExisting evidence has suggested that bariatric surgery produces sustainable weight loss and remission or cure of type 2 diabetes mellitus (DM). Laparoscopic sleeve gastrectomy (LSG) has garnered considerable interest as a low morbidity bariatric surgical procedure that leads to effective weight loss and control of co-morbid disease. The objective of the present study was to systematically review the effect of LSG on type 2 DM.MethodsAn electronic data search of MEDLINE, PubMed, Embase, Scopus, Dare, Clinical Evidence, TRIP, Health Technology Database, Conference abstracts, clinical trials, and the Cochrane Library database was completed. The search terms used included LSG, vertical gastrectomy, bariatric surgery, metabolic surgery, and diabetes (DM), type 2 DM, or co-morbidities. All human studies, not limited to those in the English language, that had been reported from 2000 to April 2010 were included.ResultsAfter an initial screen of 3621 titles, 289 abstracts were reviewed, and 28 studies met the inclusion criteria and the full report was assessed. One study was excluded after a careful assessment because the investigators had combined LSG with ileal interposition. A total of 27 studies and 673 patients were analyzed. The baseline mean body mass index for the 673 patients was 47.4 kg/m² (range 31.0–53.5). The mean percentage of excess weight loss was 47.3% (range 6.3–74.6%), with a mean follow-up of 13.1 months (range 3–36). DM had resolved in 66.2% of the patients, improved in 26.9%, and remained stable in 13.1%. The mean decrease in blood glucose and hemoglobin A1c after sleeve gastrectomy was ?88.2 mg/dL and ?1.7%, respectively.ConclusionMost patients with type 2 DM experienced resolution or improvement in DM markers after LSG. LSG might play an important role as a metabolic therapy for patients with type 2 DM.     

Neoplasia in solid organ transplant recipients: single-center experience

The incidence of neoplasms among transplanted patients is increasing, being estimated at between 4% and 18% (mean = 6%). In this article we review the neoplasms in 2514 patients who underwent transplantation in our hospital between 1981 and 2002 including 1579 kidneys, 418 hearts, 430 livers, 70 lungs, and 17 pancreas. We observed 170 tumors in 117 patients. The most frequent neoplasm was skin and lip carcinoma (30 patients) followed by PTLD (18 patients). Our results concur with the literature with one exception, a low incidence of PTLD in heart transplants, which may only be explained due to the use of preventive therapy with antiretroviral drugs.     

Atrial fibrillation in renal or liver transplant recipients: A systematic review and meta-analysis

Background

The prevalence of atrial fibrillation (AF) in patients undergoing renal (RT) or liver transplantation (LT) has increased during the last decades. Yet, there is still uncertainty on the association between AF and patient and graft survival.

Impact of MBL2 gene polymorphisms on the risk of infection in solid organ transplant recipients: A systematic review and meta‐analysis

Mannose‐binding lectin (MBL) is a soluble pattern recognition molecule involved in complement activation. Single nucleotide polymorphisms (SNPs) in the MBL2 gene have been associated with susceptibility to infection, although data in solid organ transplant recipients remains inconclusive. This meta‐analysis was primarily aimed at investigating the association between posttransplant bacterial and fungal infection and variant alleles of MBL2 gene SNPs in the promoter/5’ untranslated region and exon 1. Cytomegalovirus (CMV) infection and/or disease were considered secondary outcomes. PubMed, EMBASE, and Web of Knowledge were searched for relevant articles up to August 2018. Eleven studies (comprising 1858 patients) were included, with liver transplant (LT) recipients accounting for 80.4% of the pooled population. As compared to high‐MBL expression haplotypes (YA/YA, YA/XA), any MBL‐deficient haplotype was associated with an increased risk of posttransplant bacterial and fungal infections (risk ratio [RR]: 1.30; P = .04). Low/null‐MBL expression haplotypes (XA/O, O/O) also increased the risk of primary outcome (RR: 1.51; P = .008) and CMV events (RR: 1.50; P = .006). No effect was observed for individual promoter SNPs. In conclusion, MBL‐deficient haplotypes are associated with a significant, albeit moderate, increase in the risk of posttransplant infection, with this association being mainly restricted to LT recipients.     

Conversion from calcineurin inhibitors to mycophenolate mofetil in liver transplant recipients with diabetes mellitus

Diabetes mellitus, a frequent metabolic complication in liver transplant recipients, may be produced by the diabetogenic effect of calcineurin inhibitors cyclosporine and tacrolimus. The aim of this study was to investigate the safety and metabolic effects of a gradual switch from cyclosporine or tacrolimus to mycophenolate mofetil among 12 diabetic liver transplant recipients. One patient was withdrawn from the study due to gastrointestinal side effects. Of the 11 remaining patients, cyclosporine or tacrolimus was completely withdrawn in five patients. Two patients developed suspected acute rejection episodes that were controlled by increasing the tacrolimus dosage. Glycosylated hemoglobin A1C and C-peptide levels were significantly lower at 3 and 6 months after the initiation of mycophenolate mofetil (P<.03 in all cases). Furthermore, urea and uric acid levels were significantly reduced after the change of treatment. In conclusion, a switch from cyclosporine/tacrolimus to mycophenolate mofetil may produce beneficial metabolic effects in diabetic liver transplant recipients, but poses a risk of graft rejection.     

Safety of anidulafungin in solid organ transplant recipients

The aim of this study was the evaluation of the safety of anidulafungin in adult solid organ transplantation (SOT) recipients. During the study period (14 months), we included all consecutive SOT recipients from 14 centers who received anidulafungin for at least 48 hours for the treatment of invasive fungal infections (IFIs) or as prophylaxis. Relevant clinical and analytical information on clinical charts was reviewed. Clinical side effects, liver function tests, and serum creatinine levels were assessed at least weekly. The need for the modification of immunosuppressive drugs was also recorded by the investigators. All patients were followed for at least 1 week after the end of treatment (EOT) or until death. Eighty-six SOT recipients were evaluated (56 transplant recipients, 20 lung transplant recipients, 8 kidney transplant recipients, and 2 heart transplant recipients). Sixty-two patients (72%) received anidulafungin for prophylaxis, and 24 (28%) received anidulafungin for the treatment of IFIs [candidemia/invasive candidiasis (16) or invasive aspergillosis (8)]. At the baseline, only 5% of the patients were neutropenic (<500 neutrophils/mL). There was no need for the modification of immunosuppressive drug doses because of anidulafungin therapy. No patient discontinued anidulafungin because of severe adverse effects. While receiving anidulafungin, 1 patient developed mild liver toxicity, but the liver function normalized without the discontinuation of anidulafungin. At EOT, the median serum creatinine, aspartate aminotransferase, and alanine aminotransferase levels were significantly lower than the baseline levels, even in liver transplant recipients and patients who had higher baseline levels of serum creatinine. In conclusion, these results show that anidulafungin is a well-tolerated drug in SOT recipients.     

Pregnancy outcomes in solid organ transplant recipients with exposure to mycophenolate mofetil or sirolimus

BACKGROUND: Animal and limited human studies have raised concerns as to the safety of in utero exposure to mycophenolate mofetil (MMF) and sirolimus (SRL) in transplant recipients. This study examined the outcomes of pregnancies with exposure to MMF or SRL from 30 female transplant recipients (39 pregnancies) who have reported pregnancies to the National Transplantation Pregnancy Registry. METHODS: Data were collected via questionnaires, phone interviews and medical records. RESULTS: There were 18 kidney recipients reporting 26 pregnancies with exposure to MMF: 15 livebirths (LB), 11 spontaneous abortions (SA). Structural malformations were reported in four of the 15 children (26.7%) including: hypoplastic nails and shortened fifth fingers (one), microtia with cleft lip and palate (one), microtia alone (one), and neonatal death with multiple malformations (one). One kidney/pancreas (K/P) recipient reported one SA. Three liver recipients reported three pregnancies; two LB (no malformations), and one second trimester SA. Two heart recipients reported one LB (no malformations) and two SA. SRL exposures included seven recipients (four kidney, one K/P and two liver) reporting four LB (one infant whose mother was switched from MMF to SRL during late pregnancy had cleft lip and palate and microtia) and three SA. CONCLUSIONS: A higher incidence of structural malformations was seen with MMF exposures during pregnancy compared to the overall kidney transplant recipient offspring, while no structural defects have as yet been reported with early pregnancy sirolimus exposures. Centers are encouraged to report all pregnancy exposures in transplant recipients.     

Dermatopathology of skin cancer in solid organ transplant recipients

Skin cancers occur more frequently in solid organ transplant recipients relative to the general population. Transplant recipients are at particularly high risk of squamous cell carcinoma, with up to a 100-fold increase in the relative risk when compared to the nontransplanted population. This compares with a 10- to 16-fold increase in basal cell carcinoma for renal transplant recipients. An increased incidence of melanoma in transplant patients has also been reported. Other types of skin cancer associated with immunosuppression in transplant patients include Kaposi sarcoma, Merkel cell carcinoma, and posttransplant lymphoproliferative disorder. This review discusses the epidemiology and pertinent pathologic features of each of these tumors. A brief clinical management strategy is outlined. In addition, the contribution of viral induced carcinogenesis with respect to Kaposi sarcoma, Merkel cell carcinoma, and posttransplant lymphoproliferative disorder is discussed.     

Impact of COVID-19 in solid organ transplant recipients

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exploded onto the world stage in early 2020. The impact on solid organ transplantation (SOT) has been profound affecting potential donors, candidates, and recipients. Importantly, decreased donations and the pressure of limited resources placed on health care by the pandemic also disrupted transplant systems. We address the impact of COVID-19 on organ transplantation globally and review current understanding of the epidemiology, outcomes, diagnosis, and treatment of COVID-19 in SOT recipients.