SGLT2 Inhibitors: The Next Blockbuster Multifaceted Drug?

Sodium glucose cotransporter 2 inhibitor (SGLT2i) is a class of drugs that were originally intended for decreasing blood glucose in diabetes. However, recent trials have shown that there are other beneficial effects. Major clinical trials involving SGLT2i medications from 2015 to 2022 were reviewed using PUBMED search. Recent major SGLT2i landmark trials have demonstrated benefits for cardiovascular disease (reduce major adverse cardiovascular events (heart attack, stroke, cardiovascular death), hospitalization for heart failure, all-cause death), and renal disease (delay the onset of dialysis) regardless of diabetic status. The consistent cardiorenal benefits observed in major landmark trials have resulted in the rapid adoption of SGLT2i therapy not only in diabetes guidelines but also cardiovascular and renal guidelines.

Novel Drugs for Diabetes Also Have Dramatic Benefits on Hard Outcomes of Heart and Kidney Disease.

BACKGROUND: Diabetes is a major risk factor for developing cardiovascular disease. Patients with both diabetes and cardiovascular disease have even higher mortality. The convergence of cardiology and diabetology therapy is an important step in treating patients and advancing research. RESULTS: Major landmark trials and meta-analyses involving Sodium Glucose Cotransporter 2 inhibitors have shown dramatic clinical cardiorenal benefits in patients both with and without type 2 diabetes. In type 2 diabetes patients, Glucagon-like peptide-1 receptor agonists have been shown to improve major cardiac outcomes. CONCLUSION: This hot topic of research and clinical use of glucose lowering drugs intersects the fields of cardiovascular, renal, and diabetic medicine. The numerous cardiorenal benefits have led to the rapid adoption in clinical guidelines of these glucose lowering drugs in patients with Type 2 diabetes, cardiovascular disease, or renal disease.

Glucose intolerance, as reflected by hemoglobin A1c level, is associated with the incidence and severity of transplant coronary artery disease.

OBJECTIVES: The possible effect of plasma hemoglobin A(1c) (HbA(1c)) on the development of transplant coronary artery disease (TxCAD) was investigated. BACKGROUND: Glucose intolerance is implicated as a risk factor for TxCAD. However, a relationship between HbA(1c) and TxCAD has not been demonstrated. METHODS: Plasma HbA(1c) was measured in 151 adult patients undergoing routine annual coronary angiography at a mean period of 4.1 years after heart transplantation. Intracoronary ultrasound (ICUS) was also performed in 42 patients. Transplant CAD was graded by angiography as none, mild (stenosis in any vessel < or =30%), moderate (31% to 69%), or severe (> or =70%) and was defined by ICUS as a mean intimal thickness (MIT) > or =0.3 mm in any coronary artery segment. The association between TxCAD and established risk factors was examined. RESULTS: Plasma HbA(1c) increased with the angiographic grade of TxCAD (5.6%, 5.8%, 6.4%, and 6.2% for none, mild, moderate, and severe disease, respectively; p < 0.05 for none vs. moderate or severe) and correlated with disease severity (r = 0.24, p < 0.05). The HbA(1c) level was higher in patients with MIT > or =0.3 mm than in those with MIT <0.3 mm (6.4% vs. 5.7%, p < 0.05). Multivariate logistic regression analysis identified HbA(1c) as an independent predictor of TxCAD, as detected by angiography or ICUS (odds ratios 1.9 and 2.4, 95% confidence intervals 1.5 to 6.3 [p = 0.010] and 1.3 to 4.2 [p < 0.005], respectively). CONCLUSIONS: Persistent glucose intolerance, as reflected by plasma HbA(1c), is associated with the occurrence of TxCAD and may play an important role in its pathogenesis.

Improved assessment of graft function by echocardiography in cynomolgus monkey recipients of hDAF-transgenic pig cardiac xenografts.

BACKGROUND: The current practice of evaluating heterotopic heart xenografts by palpation allows only detection of severe graft dysfunction, which indicates terminal graft failure. Therefore, we evaluated whether echocardiography is a better method of detecting early graft dysfunction as a marker of rejection in abdominal pig heart xenografts in cynomolgus monkeys. METHODS: Six cynomolgus monkeys received heterotopic heart transplants from pig donors transgenic for human decay-accelerating factor (hDAF). Induction therapy consisted of either cyclophosphamide or rabbit anti-thymocyte globulin. Maintenance therapy consisted of cyclosporine or tacrolimus, steroids, and sodium mycophenolate or mycophenolate mofetil, GAS914 (alphaGal oligosaccharide containing glycoconjugate), and for some animals TP10 (soluble complement receptor type 1). Echocardiography was performed immediately after transplantation and 3 times a week after surgery. We scored contractility and measured left ventricular wall thickness. Impaired contractility or increased wall thickness were considered graft dysfunction and were treated with pulse steroids. Palpation score was recorded daily. We also obtained myocardial biopsy specimens. RESULTS: Palpation score remained at 4 out of 4 in all animals until 2 to 5 days before final graft failure, whereas echocardiography detected several episodes of impaired graft function, either decreased left ventricular contractility or increased left ventricular wall thickness before graft failure. Treatment with pulse steroids improved graft function only during early episodes of graft impairment. Final graft failure was steroid resistant and caused by severe vascular rejection. CONCLUSIONS: Echocardiography is a better method of assessing graft dysfunction than is palpation. Therefore, echocardiography may detect early rejection episodes of heterotopic heart xenografts in non-human primates.

The impact of brain death on survival after heart transplantation: time is of the essence.

BACKGROUND: It has been suggested that the modality of brain death and time from brain death until harvest impact survival and rejection after heart transplantation. METHODS: Donor files from 475 adult heart-transplant recipients were examined. From these files, a total management time (time from incident leading to brain death until aortic cross clamp) was determined, and the cause of brain death was noted. Recipient characteristics, details of postoperative course, as well as survival were obtained from the Stanford University Medical Center Heart Transplantation Database. RESULTS: Two hundred and thirty (48.4%) donors sustained traumatic injuries, 112 (23.6%) suffered a subarachnoid hemorrhage, and 102 (21.4%) died of a gunshot wound to the head. The modality of brain death did not influence medium and long-term survival. A management time longer than 72 hours was associated with poorer outcome of the heart-transplant recipients. There were significantly more treated rejection episodes in recipients whose donor sustained traumatic injuries. CONCLUSION: Modality of brain death does not impact survival but appears to influence rejection. Increased management time is associated with adverse survival trends in heart-transplant recipients.

Analysis of survivors more than 10 years after heart transplantation in the cyclosporine era: Stanford experience.

BACKGROUND: Truly long term survival post heart transplantation has become increasingly frequent over the past two decades. METHODS: We analyzed multiple clinical outcomes in the cohort of 140 patients in the Stanford database who underwent heart transplantation after the introduction of cyclosporine-based immunosuppression in 1980 and survived >10 years after transplantation. RESULTS: We found generally excellent functional status in these patients, but a high incidence of hypertension, renal dysfunction, and graft CAD as well as malignancy. CONCLUSION: With continued improvement in post-transplant survival rates, providing complex care for such long-term recipients as these will assume increasing clinical importance in the everyday practice of transplant medicine and these data highlight the problems to be anticipated.

Longer-term risks associated with 10-year survival after heart transplantation in the cyclosporine era.

BACKGROUND: Long-term survival after heart transplantation is common in the cyclosporine era. However, there are few data documenting pre-transplant/peri-operative factors predictive of truly long-term survival (>10 years). The purpose of this study is to identify factors associated with 10-year survival after heart transplantation. METHODS: Our study population included 197 adults who survived >6 months and died <10 years after heart transplant (medium-term group) and 140 adults who survived >10 years after heart transplant (long-term group) between December 1980 and May 2001. A comparison was done between the two groups and we used multivariate analysis to identify which factors predicted 10-year survival. RESULTS: The long-term group had younger recipient and donor age, lower recipient body mass index at transplant, shorter waiting time and lower percentages of ischemic etiology/male recipient/non-white recipient. Kaplan-Meier plots of freedom from graft coronary artery disease and malignancy showed later onset patterns in the long-term group compared with the medium-term group. Multivariate analysis showed that white recipient, younger recipient and lower recipient body mass index at heart transplant were factors significantly associated with 10-year survival. CONCLUSIONS: Several pre-transplant/peri-operative factors were associated with survival beyond 10 years after heart transplantation. Stratified/tailored strategies based on these factors may be helpful to attain longer-term survival of recipients with higher risks.

Post-operative conversion from cyclosporine to tacrolimus in heart transplantation: a single-center experience.

BACKGROUND: Tacrolimus is a potent calcineurin inhibitor that was introduced to heart transplantation in the early 1990s. The side-effect profile of tacrolimus is more favorable than that of cyclosporine and some reports have suggested an advantage of tacrolimus in the treatment of rejection. The present study was undertaken to determine whether a late conversion to tacrolimus affords these benefits to heart transplant recipients. METHODS: Charts from 109 patients who underwent conversion from cyclosporine to tacrolimus for recurrent rejection or adverse effects were retrospectively reviewed. RESULTS: During the year after conversion to tacrolimus, there was a significant decrease in treated rejection episodes. Conversion to tacrolimus rapidly resulted in an improved lipid profile. Two years after conversion blood pressure was significantly reduced. Apart from rejection, these benefits were found mainly among individuals converted to tacrolimus within 1 year of heart transplantation. CONCLUSIONS: Conversion from cyclosporine to tacrolimus is safe and results in a more favorable risk factor profile. However, most of the benefits are seen in individuals converted within 1 year of transplantation.

Immediate protamine administration and sheath removal following percutaneous coronary intervention: a prospective study of 429 patients.

We tested the approach of reversing anticoagulation following PCI and immediate sheath removal in 429 consecutive patients. On completion of the PCI, protamine was administered, and the vascular sheath was immediately removed. Stents were used in 364 patients (85%) and GP IIb/IIIa inhibitors were used in 52 patients (12%). Time to achieve hemostasis was 30 +/- 17 min. Minor groin bleeding occurred in six patients. One patient required repair of femoral pseudoaneurysm. Mean creatine kinase at 8 and 16 hr post-PCI were 129 +/- 35 and 145 +/- 32 units, respectively. Creatine kinase rose to > 3 times normal in 12 out of 350 patients (3.4%). Prior to 48 hr, eight patients (1.9%) required emergency PCI or coronary bypass surgery. Follow-up at 30 days observed no deaths and only three target vessel revascularizations (0.7%). In conclusion, immediate reversal of anticoagulation and sheath removal after PCI is safe and feasible.

Apolipoprotein(a) phenotypes predict the severity of coronary artery stenosis.

BACKGROUND: Studies on the impact of elevated levels of lipoprotein(a) (Lp[a]) or apolipoprotein(a) (apo[a]) on the development of coronary artery disease have given controversial results. The relationship between apo(a) phenotypes and coronary artery stenosis remains unclear. METHODS: Lipid profiles, and apo(a) levels and phenotypes were analyzed in 225 patients who underwent elective coronary angiography. Coronary artery stenosis, as indicated by angiography, was estimated by a newly devised minimal lesion (ML) grading system. Relationships between lipoprotein variables and coronary artery stenosis were examined by linear and logistic regression models. RESULTS: On the basis of ML score, patients with larger apo(a) phenotypes (S3, S3a or S4) had a lower rate of coronary artery stenosis (68%-76%) than those with smaller phenotypes (S1, S1a, S2 or S2a - 79%-95%). The odds of coronary artery stenosis in patients with smaller apo(a) phenotypes were significantly different from those of patients with larger phenotypes (p < 0.001). Also, patients with a history of myocardial infarction, angina, hypertension, diabetes or hypercholesterolemia were more likely to show coronary artery stenosis on angiography. With respect to lipid levels, 20.2% of patients had an elevated serum total cholesterol (TC) level and 16.1% an elevated low-density lipoprotein cholesterol (LDL-c) level. In 21.3%, the high-density lipoprotein cholesterol (HDL-c) level was decreased. There were significant positive correlations of serum TC with those of the TC/HDL-c ratio, LDL-c, triglycerides and HDL-c (p < 0.05 and 0.001), of LDL-c with TC and apo(a) (p < 0.001) and of ML scores with the TC/HDL-c ratio and patient age (p < 0.01 and 0.001). There were significant negative correlations of TC and apo(a) levels with apo(a) phenotypes (p < 0.05 and 0.001) and of ML scores with HDL-c (p < 0.001). The odds of coronary artery stenosis in patients with abnormally high apo(a) levels (44.6%) were not significantly different from those of patients with apo(a) levels in the normal range. INTERPRETATION: Smaller apo(a) phenotypes, but not elevated levels of apo(a), may help to predict the rate and severity of coronary artery stenosis. HDL-c independently and negatively correlated with the extent of the stenosis.