Effect of Empagliflozin on Free Fatty Acids and Ketone Bodies in Japanese Patients with Type 2 Diabetes Mellitus: A Randomized Controlled Trial.

INTRODUCTION: We report a randomized, double-blind, placebo-controlled, 4-week study to investigate the effect of empagliflozin on free fatty acids and blood ketone bodies in Japanese patients with type 2 diabetes mellitus. METHODS: Patients (baseline mean [standard deviation] glycated hemoglobin 7.91% [0.80%]; body mass index 24.3 [3.2] kg/m2) were randomized to empagliflozin 10 mg (n = 20), empagliflozin 25 mg (n = 19), or placebo (n = 21) daily as monotherapy for 28 days. Meal tolerance tests (MTTs; breakfast, lunch, dinner) were performed on day - 1, day 1 (first day of treatment), and day 28. On day 1 and day 28, study drug was administered 1 h before breakfast. Free fatty acids and blood ketone bodies were measured before and 1, 2, and 3 h after each MTT, and the next morning (overnight fast). RESULTS: Empagliflozin significantly reduced plasma glucose and insulin and reduced body weight vs. placebo. Empagliflozin increased free fatty acids and total ketones bodies at day 1 and day 28. At day 28, the adjusted mean (95% confidence interval) difference vs. placebo in the time-corrected area under curve over 24 h for total ketone bodies was 67.1 (12.3, 121.8) µmol·h/L·h (P = 0.017) with empagliflozin 10 mg and 178.1 (123.9, 232.2) µmol·h/L·h (P < 0.001) with empagliflozin 25 mg. Increases in ketones with empagliflozin vs. placebo peaked just before and declined after meals, with the highest peak before breakfast. Changes in total ketone bodies appeared to be associated with changes in plasma glucose, insulin, and free fatty acids. CONCLUSION: Empagliflozin modestly increased free fatty acids and blood ketone bodies after a single dose and 28 days' treatment. Increases in ketones appeared to be related to the duration of fasting and were most pronounced before breakfast. Increases in ketones appeared to be associated with changes in well-known metabolic determinants of ketone production. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01947855. FUNDING: Boehringer Ingelheim & Eli Lilly and Company.

Safety and tolerability of empagliflozin in East Asian patients with type 2 diabetes: Pooled analysis of phase I-III clinical trials.

AIMS/INTRODUCTION: We investigated the safety and tolerability of empagliflozin (EMPA) in East Asian patients with type 2 diabetes. MATERIALS AND METHODS: Data were pooled from participants with type 2 diabetes evenly randomized to a placebo, EMPA 10 mg or EMPA 25 mg in 15 phase I-III trials. Adverse events (AEs) were analyzed in the subgroup of trial participants from East Asian countries/regions. RESULTS: In total, 709, 724 and 708 East Asian trial participants with type 2 diabetes received a placebo, EMPA 10 mg and EMPA 25 mg, respectively; total exposure was 953, 1,072, and 1,033 patient-years in these groups, respectively. The EMPA and placebo groups had similar incidences of severe AEs, serious AEs and AEs leading to discontinuation. Incidences of hypoglycemia differed according to anti-diabetes medication used at baseline. Higher rates of events consistent with genital infection were observed with EMPA (EMPA 1.5-1.7/100, placebo 0.2/100 patient-years). Rates of AEs consistent with volume depletion were comparable among treatment groups (0.8-1.4/100 patient-years), but in trial participants aged ≥65 years, the rate was greater with EMPA 25 mg (EMPA 25 mg 3.5/100, placebo 2.0/100 patient-years). Incidences of events consistent with urinary tract infection, thromboembolic events, renal events, hepatic AEs, diabetic ketoacidosis, fractures and lower limb amputation were similar between EMPA and the placebo. CONCLUSIONS: In the present pooled analysis, EMPA was well tolerated in East Asian type 2 diabetes patients based on >2,100 patient-years' exposure, consistent with results from the overall analysis population.

Analysis of Fractures in Patients With Type 2 Diabetes Treated With Empagliflozin in Pooled Data From Placebo-Controlled Trials and a Head-to-Head Study Versus Glimepiride.

OBJECTIVE: To assess the effect of empagliflozin on bone fractures and bone mineral density in patients with type 2 diabetes in pooled placebo-controlled trial data and a head-to-head study versus glimepiride. RESEARCH DESIGN AND METHODS: Pooled data were analyzed from patients who were randomized 1:1:1 to empagliflozin 10 mg, empagliflozin 25 mg, or placebo in phase I-III clinical trials. Data were also analyzed from the EMPA-REG H2H-SU trial in which patients received empagliflozin 25 mg or glimepiride as an add-on to metformin for 104 weeks with a 104-week extension. Bone fracture adverse events (AEs) were evaluated through a search of investigator-reported (nonadjudicated) events. RESULTS: In the pooled analysis, bone fracture AEs were reported in 119 of 4,221 (2.8%), 105 of 4,196 (2.5%), and 123 of 4,203 (2.9%) patients in the empagliflozin 10 mg, empagliflozin 25 mg, and placebo groups, respectively (rates of 1.55, 1.36, and 1.69/100 patient-years, respectively). In the EMPA-REG H2H-SU trial, bone fracture AEs were reported in 31 of 765 (4.1%) patients receiving empagliflozin 25 mg and in 33 of 780 (4.2%) patients receiving glimepiride (rates of 1.28 and 1.40/100 patient-years, respectively). CONCLUSIONS: Empagliflozin did not increase the risk of bone fracture compared with placebo in a pooled analysis of >12,000 patients or compared with glimepiride in a 4-year head-to-head study.

Safety and Tolerability of Combinations of Empagliflozin and Linagliptin in Patients with Type 2 Diabetes: Pooled Data from Two Randomized Controlled Trials.

INTRODUCTION: Two 52-week Phase III studies evaluated the efficacy and safety of once-daily combinations of empagliflozin/linagliptin as monotherapy or add-on to metformin in patients with type 2 diabetes (T2DM). The aim of this analysis was to further assess the safety and tolerability of empagliflozin/linagliptin compared with their individual components in patients with T2DM, using pooled data from these trials. METHODS: A total of 1363 patients were treated with empagliflozin 25 mg/linagliptin 5 mg (n = 273), empagliflozin 10 mg/linagliptin 5 mg (n = 272), empagliflozin 25 mg (n = 276), empagliflozin 10 mg (n = 275), or linagliptin 5 mg (n = 267). Adverse events (AEs) were assessed descriptively in patients who took ≥ 1 dose of study drug. RESULTS: Total exposure was 251, 255, 256, 249, and 243 patient-years in the empagliflozin 25 mg/linagliptin 5 mg, empagliflozin 10 mg/linagliptin 5 mg, empagliflozin 25 mg, empagliflozin 10 mg, and linagliptin 5 mg groups, respectively. The proportion of patients with ≥ 1 AE was similar across groups (70.4-74.9%). The percentage of patients with confirmed hypoglycemic AEs (plasma glucose ≤ 70 mg/dL and/or requiring assistance) was low in all groups (1.1-2.2%); none required assistance. Events consistent with urinary tract infection were reported in similar percentages of patients in all groups (11.4-13.8%), and in a greater proportion of female than male patients. Events consistent with genital infection were reported in higher percentages of patients on empagliflozin/linagliptin or empagliflozin (4.0-6.5%) than linagliptin 5 mg (2.6%), and in a greater proportion of females than males. The risks of hypersensitivity reactions and events consistent with volume depletion were low across treatment groups. CONCLUSION: Empagliflozin/linagliptin as monotherapy or add-on to metformin for 52 weeks was well tolerated in patients with T2DM, with safety profiles similar to individual components, including a low risk of hypoglycemia. FUNDING: The Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance. TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT01422876 & NCT01422876.

Safety and Tolerability of Empagliflozin in Patients with Type 2 Diabetes: Pooled Analysis of Phase I-III Clinical Trials.

INTRODUCTION: We characterized the safety and tolerability of empagliflozin in patients with type 2 diabetes (T2DM) randomized 1:1:1 to placebo, empagliflozin 10 mg, or empagliflozin 25 mg in clinical trials. METHODS: Pooled data were analyzed from patients with T2DM treated with placebo (N = 4203), empagliflozin 10 mg (N = 4221), or empagliflozin 25 mg (N = 4196) in 15 randomized phase I-III trials plus four extension studies. Adverse events (AEs) were assessed descriptively in participants who took at least one dose of study drug. AE incidence rates per 100 patient-years were calculated to adjust for differences in drug exposure between trials. RESULTS: Total exposure was 7369, 7782, and 7754 patient-years in the placebo, empagliflozin 10 mg, and 25 mg groups, respectively. The incidence of any AEs, severe AEs, serious AEs, and AEs leading to discontinuation was no higher in participants treated with empagliflozin vs. placebo. Empagliflozin was not associated with an increased risk of hypoglycemia vs. placebo, except in participants on background sulfonylurea. The incidence of events consistent with urinary tract infection was similar across treatment groups (8.7-9.5/100 patient-years). Events consistent with genital infection occurred more frequently in participants treated with empagliflozin 10 and 25 mg (3.5 and 3.4/100 patient-years, respectively) than placebo (0.9/100 patient-years). The incidence of AEs consistent with volume depletion was similar across treatment groups (1.7-1.9/100 patient-years) but was higher with empagliflozin 10 mg and 25 mg vs. placebo in participants aged 75 years or older (3.2 and 3.0 vs. 2.3/100 patient-years, respectively). The rates of bone fractures, cancer events, renal AEs, venous thromboembolic events, hepatic injury, acute pancreatitis, lower limb amputations, and diabetic ketoacidosis were similar across treatment groups. CONCLUSION: This analysis of pooled safety data based on more than 15,000 patient-years' exposure supports a favorable benefit-risk profile of empagliflozin in patients with T2DM. FUNDING: Boehringer Ingelheim Pharma GmbH.

Empagliflozin and Cerebrovascular Events in Patients With Type 2 Diabetes Mellitus at High Cardiovascular Risk.

BACKGROUND AND PURPOSE: In the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), empagliflozin added to standard of care in patients with type 2 diabetes mellitus and high cardiovascular risk reduced the risk of 3-point major adverse cardiovascular events, driven by a reduction in cardiovascular mortality, with no significant difference between empagliflozin and placebo in risk of myocardial infarction or stroke. In a modified intent-to-treat analysis, the hazard ratio for stroke was 1.18 (95% confidence interval, 0.89-1.56; P=0.26). We further investigated cerebrovascular events. METHODS: Patients were randomized to empagliflozin 10 mg, empagliflozin 25 mg, or placebo; 7020 patients were treated. Median observation time was 3.1 years. RESULTS: The numeric difference in stroke between empagliflozin and placebo in the modified intent-to-treat analysis was primarily because of 18 patients in the empagliflozin group with a first event >90 days after last intake of study drug (versus 3 on placebo). In a sensitivity analysis based on events during treatment or ≤90 days after last dose of drug, the hazard ratio for stroke with empagliflozin versus placebo was 1.08 (95% confidence interval, 0.81-1.45; P=0.60). There were no differences in risk of recurrent, fatal, or disabling strokes, or transient ischemic attack, with empagliflozin versus placebo. Patients with the largest increases in hematocrit or largest decreases in systolic blood pressure did not have an increased risk of stroke. CONCLUSIONS: In patients with type 2 diabetes mellitus and high cardiovascular risk, there was no significant difference in the risk of cerebrovascular events with empagliflozin versus placebo. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01131676.

Safety and Tolerability of Empagliflozin in Patients with Type 2 Diabetes.

PURPOSE: The aim of this analysis was to establish the safety profile and tolerability of empagliflozin in patients with type 2 diabetes mellitus (T2DM) according to pooled data from several clinical trials. METHODS: Pooled data were analyzed from patients with T2DM treated with placebo (n = 3695), empagliflozin 10 mg (n = 3806), or empagliflozin 25 mg (n = 4782) in 17 randomized, Phase I, II, and III clinical trials plus 6 extension studies. Adverse events (AEs) were assessed descriptively in patients who took ≥1 dose of the study drug. AE incidence rates per 100 patient-years were calculated to adjust for differences in drug exposure across trials. FINDINGS: Total exposure was 3254, 3840, and 5649 patient-years in the placebo, empagliflozin 10 mg, and empagliflozin 25 mg groups, respectively. The incidence of any AEs, AEs leading to treatment discontinuation, severe AEs, and serious AEs was no higher in patients treated with empagliflozin than with placebo. Empagliflozin was not associated with an increased risk of hypoglycemia versus placebo, except in patients on background sulfonylurea and/or insulin. The incidence of events consistent with urinary tract infection was similar across treatment groups (9.4-11.3/100 patient-years); 0.4%, 0.2%, and 0.3% of patients in the placebo, empagliflozin 10 mg, and empagliflozin 25 mg groups, respectively, had urinary tract infections that required or prolonged hospitalization. The incidence of events consistent with genital infection was higher in patients treated with empagliflozin (4.7 and 5.0/100 patient-years for empagliflozin 10 and 25 mg, respectively) than placebo (1.3/100 patient-years), but only 0.1%, 0.1%, and <0.1% in the placebo, empagliflozin 10 mg, and empagliflozin 25 mg groups, respectively, had genital infections that required or prolonged hospitalization. The incidence of AEs consistent with volume depletion was similar with placebo, empagliflozin 10 mg, and empagliflozin 25 mg (1.6, 1.5, and 1.3/100 patient-years, respectively) and was higher with empagliflozin 25 mg than placebo or empagliflozin 10 mg in patients aged >75 years (4.4 vs 2.3 and 2.5/100 patient-years, respectively). The incidences of bone fractures, malignancies, decreased renal function, hepatic injury, venous thromboembolic events, and diabetic ketoacidosis were low and similar across the treatment groups. IMPLICATIONS: In this predefined analysis that was based on >9000 patient-years' exposure to empagliflozin, empagliflozin 10 mg, and empagliflozin 25 mg were well tolerated in patients with T2DM.

Interstitial Lung Disease Associated with mTOR Inhibitors in Solid Organ Transplant Recipients: Results from a Large Phase III Clinical Trial Program of Everolimus and Review of the Literature.

Interstitial lung disease (ILD) has been reported with the use of mammalian target of rapamycin inhibitors (mTORi). The clinical and safety databases of three Phase III trials of everolimus in de novo kidney (A2309), heart (A2310), and liver (H2304) transplant recipients (TxR) were searched using a standardized MedDRA query (SMQ) search for ILD followed by a case-by-case medical evaluation. A literature search was conducted in MEDLINE and EMBASE. Out of the 1,473 de novo TxR receiving everolimus in Phase III trials, everolimus-related ILD was confirmed in six cases (one kidney, four heart, and one liver TxR) representing an incidence of 0.4%. Everolimus was discontinued in three of the four heart TxR, resulting in ILD improvement or resolution. Outcome was fatal in the kidney TxR (in whom everolimus therapy was continued) and in the liver TxR despite everolimus discontinuation. The literature review identified 57 publications on ILD in solid organ TxR receiving everolimus or sirolimus. ILD presented months or years after mTORi initiation and symptoms were nonspecific and insidious. The event was more frequent in patients with a late switch to mTORi. In most cases, ILD was reversed after prompt mTORi discontinuation. ILD induced by mTORi is an uncommon and potentially fatal event warranting early recognition and drug discontinuation.

Partial spleen resection with a radiofrequency needle device--a pilot study.

INTRODUCTION: Total splenectomy leads to an immunocompromised state, with an increased lifetime risk of infection. The lifetime risk of developing overwhelming postsplenectomy infection is 5 %, with a mortality rate of approximately 50 %. In addition to vaccination and antibiotic prophylaxis, partial splenectomy is believed to improve patient safety. METHODS: We performed partial splenectomy in seven patients using a radiofrequency (RF) technique with Habib® needles. In seven patients, an open access partial splenectomy was performed. In three patients, a partial splenectomy was performed simultaneously with intraabdominal tumour resection. In two patients, the upper pole of the spleen was removed due to tumours of the spleen. In one patient, a large symptomatic splenic cyst was resected and in another patient, a partial splenectomy was performed due to trauma. RF was applied using Habib® needles (AngioDynamics, Manchester, GA, 31816, USA). RESULTS: The partial splenectomy procedures were easy and safe in all seven patients. The RF application with the Habib® needles led to primary haemostasis. The blood loss was less than 50 ml in all cases. After a minimum follow-up of 1 year, there were no cases of infections or other adverse events related to the previous partial splenectomy. CONCLUSION: In our experience, partial splenectomy with Habib® needles is easy to perform and safe for the patient. Thus, radiofrequency resection is a good alternative to total splenectomy in many patients and reduces the risk of postsplenectomy infections.

Long-term outcome of ATG vs. Basiliximab induction.

BACKGROUND: An evaluation of the long-term efficacy and incidence of adverse events after induction therapy with antithymocyte globulin (ATG) vs. Basiliximab in renal transplant patients. METHODS: Sixty recipients receiving ATG induction and a dual immunosuppression with Tacrolimus and steroids were compared retrospectively with 60 patients treated with Basiliximab. The following characteristics were evaluated: concomitant immunosuppression, recipient age, donor age, time on dialysis, cold ischemia time, year of transplantation and HLA mismatches. RESULTS: The 6-year patient survival in the ATG group was 91·7% compared to 85% in the Basiliximab group (not significant, n.s.). Graft survival at 6 years was 89·7% and. 83·6% in the ATG and the Basiliximab group (n.s.), respectively. Incidence of biopsy proven acute rejection episodes (33·3% vs. 26·7%) and delayed graft function (30% vs. 33·3%) were similar in both groups. Kidney function was not significantly different at 1 and 6 years. CMV infections were more prevalent in the ATG arm (22% vs. 5%; P = 0·05), and a significantly higher rate of haematological complications was observed following ATG induction. CONCLUSIONS: ATG induction was associated with an improved (but n.s.) trend in patient and graft survival. Patients induced with ATG had a higher rate of CMV infections and haematological complications.

Symptomatic lymphoceles after kidney transplantation - multivariate analysis of risk factors and outcome after laparoscopic fenestration.

Lymphocele formation is a common complication after kidney transplantation, and laparoscopic surgery has become a widely accepted treatment option. The aim of this retrospective study was to analyze the risk factors of lymphocele development and to assess the treatment outcome after laparoscopic fenestration. We analyzed 426 renal allograft recipients operated between 2002 and 2006 receiving triple immunosuppression with calcineurin inhibitors. The incidence of lymphocele was 9.9%, while 24 (5.6%) patients with symptomatic lymphoceles required laparoscopic surgery. Serum creatinine at diagnosis was significantly higher in patients with lymphoceles treated surgically (3.2 +/- 0.7 vs. 1.7 +/- 0.6 mg/dL; p < 0.001). After successful laparoscopic intervention, creatinine concentrations recovered until discharge and were comparable to other patients (1.6 +/- 0.5 vs. 1.5 +/- 0.5 mg/dL; p = NS). While we observed a significant association of lymphocele formation with diabetes, tacrolimus therapy, and acute rejection in univariate testing, only diabetes remained a significant factor after multivariate analysis. Laparoscopic fenestration proved to be a safe and efficient method without any associated mortality and a low recurrence rate of 8.3% (n = 2). We conclude that diabetes is an independent risk factor for lymphocele development, and laparoscopic fenestration should be the treatment of choice for larger and symptomatic lymphoceles, as it is safe and offers a low recurrence rate.

Aspergillus spondylodiscitis after multivisceral transplantation.

BACKGROUND: Although spondylodiscitis is rare, it is increasingly described in patients with compromised immunity due to malignancy, chemotherapy or immunosuppression. Typical pathogens are staphylococcus aureus and enterobacteria; fungal spondylodiscitis is uncommon. CASE REPORT: We present a case of aspergillus spondylodiscitis following pulmonary aspergillosis in a patient with multivisceral and kidney transplantation. Due to irreversible disc destruction, surgical restoration by autologous iliac crest graft was required in addition to intravenous antifungal therapy, which consisted of voriconazole, caspofungin and liposomal amphotericin B. CONCLUSIONS: Aspergillus spondylodiscitis is a diagnostic and therapeutic challenge, a combination of surgical debridement and antifungal therapy is inevitable to prevent rapid progression of invasive aspergillosis and neurological damage.

Management of biliary complications following living donor liver transplantation--a single center experience.

PURPOSE: Biliary complications (BC) after living donor liver transplantation (LDLT) are reported in up to 32%. We retrospectively reviewed the biliary reconstruction after 95 LDLT. METHODS: Eighty-one right hemiliver grafts and 14 left lateral section grafts were transplanted. Bile duct anastomoses were performed as duct-to-duct (DD) or bilioenteric anastomosis (RYHJ); multiple bile ducts were anastomosed using a ductoplasty or multiple direct bile duct anastomoses. RESULTS: After right hemiliver LDLT, a total of 45.5% of BC was observed, with an incidence of 27.7% in case of DD anastomosis and 18.8% in case of RYHJ. After DD anastomosis, strictures were successfully treated endoscopically in 50%; insufficiencies mainly required reoperations. CONCLUSION: BC still account for a high percentage of morbidity and mortality after LDLT. DD anastomoses are performed more frequently and are feasible in cases with simple biliary anatomy; RYHJ is the gold standard for the reconstruction of multiple bile ducts.

Donor brain death significantly interferes with tolerance induction protocols.

Studies in rodents showed that antibodies are able to induce tolerance of allografts. As clinical results are unsatisfactory and deceased donors are still the main source of organ transplants, we investigated whether donor brain-death impacts on tolerance induction after experimental kidney transplantation. Anti-CD4 monoclonal antibodies (RIB 5/2; 2.5 mg/kg x 5 days) treated and untreated recipients of brain-dead donor grafts were compared with RIB 5/2 treated and untreated recipients of living donor grafts (F344-to-Lewis). All recipients received low-dose CsA (1.5 mg/kg x 10 days). Kidneys were recovered 4, 16 and 40 weeks after transplantation and examined by morphology, immunohistology and flow cytometry. Renal function was monitored monthly. RIB 5/2 treatment significantly decreased proteinuria in recipients of living donor allografts when compared with living donor controls. After 40 weeks, inflammatory cell infiltration and MHC class II expression were reduced while morphologic alterations were minimal. In contrast, treatment of brain-dead graft recipients had no impact on graft function. Structural changes and graft infiltration were comparable to brain-dead donor controls at all time points. RIB 5/2 treatment significantly improved graft function in recipients of living donor grafts; however, it was not effective in recipients of brain-dead donor organs.

Present status and future perspectives of intestinal transplantation.

Intestinal transplantation (ITx) is the only definitive therapy for irreversible intestinal failure. Owing to the limited short- and long-term graft survival over the years, ITx has been a complementary treatment to home parenteral nutrition. However, the development of intestinal and multivisceral transplantation has been significant over the past 15-20 years owing to the progress in immunosuppressive therapy, refinement of surgical techniques, post-transplant care, intestinal immunology, and immunological as well as anti-infectious monitoring. The improvement of patient- and graft survival over the last few years together with data on the cost effectiveness of ITx, following 2 years after transplantation, may require a redefinition of the indication for ITx.

Graft versus host disease after liver transplantation - a single center experience and review of literature.

Graft versus host disease (GvHD) after liver transplantation has an incidence of 0.1-1%. It is an infrequent but severe and mostly lethal complication. Approximately, 80 cases have been reported in literature so far. A single center experience is reported retrospectively. We performed a retrospective analysis of 1815 liver transplants in our center, transplanted over a period of 17 years. Five patients (5/1815 = 0.28%) with histologically diagnosed GvHD were included in the analysis. Onset of GvHD was between postoperative day (POD) 20 and 60. All patients developed skin rash, being the first symptom in four cases; one patient had joint pain as initial symptom. Macrochimerism was confirmed in all patients. Treatment consisted of augmentation of baseline immunosuppression (n = 4), methylprednisolone (n = 4), and T-cell depleting antibodies (n = 3). One patient received no specific therapy because of her deleterious condition. All patients died because of either haemorrhage or uncontrollable infections. In our experience, GvHD has been an extremely rare, albeit deleterious clinical condition, which was resistant to classical immunosuppressive rescue regimens.

Effects of ketogenic diet on epileptiform activity in children with therapy resistant epilepsy.

PURPOSE: The purpose was to quantify changes of epileptiform activity during ketogenic diet (KD) treatment in children with therapy resistant epilepsy, and evaluate how these changes are related to activity stage and to clinical effects on seizure frequency, seizure severity, attentional behaviour, quality of life (QOL), and beta-hydroxybutyrate (betaOHb). METHODS: Eighteen children were investigated with 24h ambulatory EEG monitoring 1 week prior to KD initiation and, after 3 months of KD treatment. Epileptiform activity was evaluated by automated spike detection. This data was compared with data presented in a previous study published in Epilepsia 2006, on sleep structure and different activity stages, clinical data on seizure frequency, seizure severity, QOL and attentional behaviour on the same children [Hallbook, T., Lundgren, J., Rosén, I., 2007. Ketogenic diet improves sleep quality in children with therapy resistant epilepsy. Epilepsia 48, 59-65]. RESULTS: After 3 months of KD treatment the number of interictal epileptiform discharges (IEDs) was significantly reduced (p<0.001). When considering the four activity stages separately, the reduction was significant during non-rapid eye movement sleep stage 2, slow wave sleep (SWS) and rapid eye movement (REM) sleep (p=0.001, 0.001, 0.002), and not significantly so during awake (p=0.07). Beta-hydroxybutyrate was significantly increased (p<0.001). There was a significant correlation between the reduction in IEDs and clinical seizures (Spearman r=0.6, p=0.005) and between improvement in attentional behaviour and the increase in betaOHb (Spearman r=0.5, p=0.03). There was no significant correlation between changes in attentional behaviour and IEDs or clinical seizures. CONCLUSION: This study shows that KD reduces the number of IEDs, especially during sleep. It shows a correlation between reduction in epileptiform activity and clinical seizures. There were no correlations between reduction in epileptiform activity and clinical seizures and improvement in QOL or attention. The increase in betaOHb correlated with improvement in attention.