Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

TRABECULAR BONE SCORE AND DENTAL IMPLANT

The article brings in the same plan and unified views related to two different phenomena: dental implant (DI) and osteoporosis. 1. DI and osteoporosis. Successful DI depends on bone quality. One of the relative contraindications of DI is osteoporosis. However, there are studies showing that DI can be done in patients with osteoporosis. In cases of osteoporosis, success depends on the lack of previous antiosteoporotic bisphosphonate treatments. 2, Diagnosis of osteoporosis. It is based on the T-score obtained for Bone Mineral Density (BMD) in DEXA (dual X ray absortiometry) tests; they must be < -2.5. This value is the standard deviation applied to an average obtained from adults. What happens to bone quality in patients with possibly osteoporosis but with BMD > -2.5? The problem of diagnosis can be solved by a new DEXA technique: trabecular bone score.3. Trabecular bone score (TBS) is the mathematical estimation of vertebral microarhitectomy.The vertebra are formed by trabecular bone (the long bone is predominantly the cortical bone). TBS is obtained by DEXA analysis with specific software. A value < -2.5 means osteoporosis. Our data showed that through TBS analysis the prevalence of osteoporosis diagnosis increased by about 40% in patients who have BMD within the limits considered by osteopenia or normal. 4. Relationship between mandible/maxillary and trabecular bone. Mandible and the maxillary are mixed bones. At the surface it presents as a cortical bone, in depth, it presents with trabecular bone structure. The cortical bone (both of mandible & maxillary) is defined as that white structure without a trabecular pattern. The trabecular bone is that part of the mandible that is found between two cortical plates. It is appropriate to make an implant when the cortical bone is more abundant. It is also stated that the implants performed in over 60% trabecular (cancellous) bone are more efficient than those performed in less than 30% of the trabecular bone. The phenomenon arises from the fact that the trabecular bone is more metabolically active and contains more osteoblasts. TBS obtained by DEXA for the vertebrae can be surrogate for the assessment of the trabecular bone in the mandible and maxillary. 5. Drugs that improve the trabecular bone score. Following the re-analysis of the TBS-BMD difference by the TBS technique, the perception of antiosteoporotic drugs has changed. More important is to improve TBS than increase BMD. Thus, teriparatide, then denosumab, strontium, SERM, and lastly bisphosphonates would be preferentially used. Furthermore, teriparatide was the only treatment available for post-bisphosphonates jaw necrosis

Randomized, Double-Blind, Phase 3 Trial of Triple Therapy With Dapagliflozin Add-on to Saxagliptin Plus Metformin in Type 2 Diabetes

OBJECTIVE: To compare the efficacy and safety of treatment with dapagliflozin versus that with placebo add-on to saxagliptin plus metformin in patients whose type 2 diabetes is inadequately controlled with saxagliptin plus metformin treatment. RESEARCH DESIGN AND METHODS: Patients receiving treatment with stable metformin (stratum A) (screening HbA1c level 8.0-11.5% [64-102 mmol/mol]) or stable metformin and a dipeptidyl peptidase-4 (DPP-4) inhibitor (stratum B) (HbA1c 7.5-10.5% [58-91 mmol/mol]) for ≥8 weeks received open-label saxagliptin 5 mg/day and metformin for 16 weeks (stratum A) or 8 weeks (stratum B) (saxagliptin replaced any DPP-4 inhibitor). Patients with inadequate glycemic control (HbA1c 7-10.5% [53-91 mmol/mol]) were randomized to receive placebo or dapagliflozin 10 mg/day plus saxagliptin and metformin. The primary end point was the change in HbA1c from baseline to week 24. Secondary end points included fasting plasma glucose (FPG) level, 2-h postprandial glucose (PPG) level, body weight, and proportion of patients achieving an HbA1c level of <7% (53 mmol/mol). RESULTS: Treatment with dapagliflozin add-on to saxagliptin plus metformin resulted in a greater mean HbA1c reduction than placebo (-0.82 vs. -0.10% [-9 vs. -1.1 mmol/mol], P < 0.0001). Significantly greater reductions in FPG level, 2-h PPG level, and body weight were observed, and more patients achieved an HbA1c level of <7% (53 mmol/mol) with treatment with dapagliflozin versus placebo. Adverse events were similar across treatment groups, with a low overall risk of hypoglycemia (∼1%). Genital infections developed in more patients with dapagliflozin treatment (5%) than with placebo (0.6%). CONCLUSIONS: Triple therapy with dapagliflozin add-on to saxagliptin plus metformin improves glycemic control and is well tolerated in patients whose type 2 diabetes is inadequately controlled with saxagliptin plus metformin therapy.status: publishe

Characterization of the Open-Label Lead-In Period of Two Randomized Controlled Phase 3 Trials Evaluating Dapagliflozin, Saxagliptin, and Metformin in Type 2 Diabetes

INTRODUCTION: To examine the utility of sequential versus dual add-on approaches in patients who have type 2 diabetes and inadequate glycemic control with metformin therapy alone, we characterized the efficacy and safety of dual therapy with dapagliflozin or saxagliptin added to metformin in the open-label lead-in periods of two phase 3 trials (study 1, NCT01619059; study 2, NCT01646320) that evaluated triple therapy in patients with inadequately controlled type 2 diabetes. METHODS: During the lead-in periods of each trial, patients [glycated hemoglobin (HbA1c) 8.0-11.5%] who had been receiving metformin ≥ 1500 mg/day for ≥ 8 weeks received metformin immediate release at an equivalent dose plus dapagliflozin 10 mg/day (study 1; N = 482) or saxagliptin 5 mg/day (study 2; N = 349) for 16 weeks. Efficacy end points were assessed at week - 2 before randomization. RESULTS: Mean change in HbA1c [95% confidence interval (CI)] from lead-in baseline (study 1, 9.3%; study 2, 9.4%) was - 1.6% (- 1.7, - 1.5) in study 1 and - 1.3% (- 1.5, - 1.2) in study 2. Mean changes (95% CI) from lead-in baseline in weight and fasting plasma glucose were - 2.4 kg (- 2.6, - 2.1) and - 47.5 mg/dL (- 52.8, - 42.3) for study 1 and - 0.5 kg (- 0.8, - 0.2) and - 28.5 mg/dL (- 35.8, - 21.2) for study 2. At the end of the lead-in period, 22.0% of patients achieved HbA1c < 7.0% in study 1 and 17.5% in study 2. Dual therapy was well tolerated, with hypoglycemia incidence < 1% in both studies. CONCLUSION: Dual therapy improved glycemic control and was well tolerated; however, most patients required additional therapy to further improve HbA1c towards target, suggesting that an early move to triple therapy with oral glucose-lowering drugs rather than a stepwise approach may be beneficial for patients with high HbA1c levels on metformin therapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT01619059, NCT01646320. FUNDING: AstraZeneca.status: publishe

MRI Evolution of a Patient with Viral Tick-Borne Encephalitis and Polymorphic Seizures

Some neurotropic viruses induce specific lesions in the deep structures, such as basal ganglia and thalamus. These anatomical structures play an important role in initiating and maintaining different types of epileptic seizures. We present the case of a 25-year-old male, transferred to our clinic one week after the onset of the symptomatology, with a recent history of traveling to Turkey and Egypt. At the moment of his hospital admission, his symptoms included altered consciousness, agitation, and seizures. Shortly after, his state worsened, requiring intubation. Viral tick-borne encephalitis diagnoses were favored by the CSF (cerebrospinal fluid) analysis, EEG (Electroencephalography), MRI (magnetic resonance imaging) images presenting symmetric hyper signal in the basal ganglia, and IgM antibodies for anti-tick-borne encephalitis. These lesions persisted for several weeks, and the patient&rsquo;s seizures were polymorphic, originally generalized onset motor, generalized onset non-motor, and focal myoclonic. The patient achieved his independence, seizures decreasing both in intensity and frequency; the MRI images became almost normal. The reduction in antiepileptic doses was not followed by seizure recurrence

Challenges in Cerebral Venous Thrombosis Management&mdash;Case Reports and Short Literature Review

Cerebral venous thrombosis (CVT) is a rare type of stroke, with a complex clinical presentation that can make it a diagnostic challenge for the swift initiation of anticoagulation. When a hemorrhagic transformation is added, therapeutic management becomes even more complex. We describe a series of four cases, aged between 23 and 37 years old, with cerebral venous thrombosis. They were admitted to our clinic between 2014 and 2022. All cases presented significant challenges in either diagnostic, therapeutic or etiologic evaluation, at different stages of the disease. Late complications such as epilepsy or depression and other behavioral disorders represent long-term sequelae for the patient. Therefore, through its late complications, CVT is not only an acute disease but a chronic disorder with long-term follow-up requirements. The first case of the series is of a postpartum woman with focal neurological deficit caused by CVT with hemorrhagic transformation that presented multiple thrombotic complications and severe depression. The second case is of a man with extensive cerebral thrombosis who developed bilateral papillary edema under therapeutic anticoagulation treatment. The third case is of a woman with bilateral cavernous sinus thrombosis who later developed depressive disorder and focal seizures. The fourth case is of a pregnant woman in the first trimester presenting with a steep decline in consciousness level secondary to deep cerebral vein thrombosis requiring intensive care and subsequently developing a memory disorder. For a long period of time, due to being underdiagnosed, few things were known about CVT. Nowadays, we have all the tools to diagnose, treat, and follow up cases of CVT

Challenges in Cerebral Venous Thrombosis Management—Case Reports and Short Literature Review

Cerebral venous thrombosis (CVT) is a rare type of stroke, with a complex clinical presentation that can make it a diagnostic challenge for the swift initiation of anticoagulation. When a hemorrhagic transformation is added, therapeutic management becomes even more complex. We describe a series of four cases, aged between 23 and 37 years old, with cerebral venous thrombosis. They were admitted to our clinic between 2014 and 2022. All cases presented significant challenges in either diagnostic, therapeutic or etiologic evaluation, at different stages of the disease. Late complications such as epilepsy or depression and other behavioral disorders represent long-term sequelae for the patient. Therefore, through its late complications, CVT is not only an acute disease but a chronic disorder with long-term follow-up requirements. The first case of the series is of a postpartum woman with focal neurological deficit caused by CVT with hemorrhagic transformation that presented multiple thrombotic complications and severe depression. The second case is of a man with extensive cerebral thrombosis who developed bilateral papillary edema under therapeutic anticoagulation treatment. The third case is of a woman with bilateral cavernous sinus thrombosis who later developed depressive disorder and focal seizures. The fourth case is of a pregnant woman in the first trimester presenting with a steep decline in consciousness level secondary to deep cerebral vein thrombosis requiring intensive care and subsequently developing a memory disorder. For a long period of time, due to being underdiagnosed, few things were known about CVT. Nowadays, we have all the tools to diagnose, treat, and follow up cases of CVT

Diagnostic and treatment difficulties in insulinomas

Background: Neuroendocrine tumors of the pancreas (NTP) comprise a unique and relatively rare group of tumors, of which gastrinoma and insulinoma are the most common types. Insulinomas tend to be small, solitary and benign, with surgical resection curable in most cases. Introduction: Insulinomas are localized preoperatively using conventional imaging studies as transabdominal ultrasonography (US), computed tomography (CT), and/or magnetic resonance imaging (MRI). Purpose: Endoscopic ultrasound (EUS) is a valuable tool in the diagnosis of insulinomas. Goals & methods: We performed a retrospective study on 21 patients with insulinoma (6 male and 15 female, 25 to 73 years of age), who were hospitalized and operated on between 2003 and 2012 at “Dr. Carol Davila” Central Military Emergency University Hospital, Bucharest. Results: US view was positive in 10% of patients (2 of 20), that presented proximal location. The sensitivity of CT was unsatisfactory, 21.05% (4 positive results of 19). CT failed to detect liver metastases, but identified nodal metastasis in one patient. MRI was performed in 18 patients and was diagnostic in 11 of them, recording a detection sensitivity of 61.11%, including infracentimetric tumor size. EUS has a high resolution which allows detection of lesions with very small diameter is safe and minimally invasive. EUS was performed in all patients, being able to identify formations in 17, was inconclusive in 3, showing a diagnosis sensitivity of 81%. Liver metastases were demonstrated in 3 patients, one by US and all 3 by MRI. Conclusions: - CT with intravenous iodinated contrast agent had a poor sensitivity in detecting the primary tumors, was insensitive in detecting liver metastases, but showed metastases in lymph nodes. - MRI has higher sensitivity than CT in detecting primary tumors, including insulinomas with infracentimetric size, and is the imaging test of choice for possible liver metastases. - EUS is the preoperative imaging test of choice

Characterization of the Open-Label Lead-In Period of Two Randomized Controlled Phase 3 Trials Evaluating Dapagliflozin, Saxagliptin and Metformin in Type 2 Diabetes

<p><b> </b></p> <p><b>Article full text</b></p><p><br></p><p>The full text of this article can be found here<b>. </b><a href="https://link.springer.com/article/10.1007/s13300-018-0445-x">https://link.springer.com/article/10.1007/s13300-018-0445-x</a></p><p></p><p><br></p><p><b>Provide enhanced content for this article</b></p><p><br></p><p>If you are an author of this publication and would like to provide additional enhanced content for your article then please contact <a href="http://www.medengine.com/Redeem/”mailto:[email protected]”"><b>[email protected]</b></a>.</p><p><br></p><p>The journal offers a range of additional features designed to increase visibility and readership. All features will be thoroughly peer reviewed to ensure the content is of the highest scientific standard and all features are marked as ‘peer reviewed’ to ensure readers are aware that the content has been reviewed to the same level as the articles they are being presented alongside. Moreover, all sponsorship and disclosure information is included to provide complete transparency and adherence to good publication practices. This ensures that however the content is reached the reader has a full understanding of its origin. No fees are charged for hosting additional open access content.</p><p><br></p><p>Other enhanced features include, but are not limited to:</p><p><br></p><p>• Slide decks</p><p>• Videos and animations</p><p>• Audio abstracts</p><p> </p><p>• Audio slides</p> <p><b> </b></p