Dapagliflozin or Saxagliptin in Pediatric Type 2 Diabetes.

BACKGROUND: Incidence of type 2 diabetes (T2D) in children and adolescents is increasing, but treatment options are limited. METHODS: This was a 26-week, phase 3 trial with a 26-week extension among patients (10 to 17 years of age) with uncontrolled T2D (A1C 6.5 to 10.5%) receiving metformin, insulin, or both. Participants were randomly assigned 1:1:1 to 5 mg of dapagliflozin (N=81), 2.5 mg of saxagliptin (N=88), or placebo (N=76). Patients in active treatment groups with A1C ≥7% at week 12 were further randomly assigned 1:1 at week 14 to continue the dose or up-titrate to a higher dose (10 mg of dapagliflozin or 5 mg of saxagliptin). The primary end point was change in A1C at week 26. Safety was assessed over 52 weeks. RESULTS: At week 26, the difference versus placebo in adjusted mean change in A1C was −1.03 percentage points (95% confidence interval [CI], −1.57 to −0.49; P<0.001) for dapagliflozin and −0.44 percentage points (95% CI, −0.93 to 0.05; P=0.078) for saxagliptin. Adverse events (AEs) and serious AEs occurred in 72.8% and 8.6% of patients receiving dapagliflozin, 69.3% and 8.0% of patients receiving saxagliptin, and 71.1% and 6.6% of patients receiving placebo. Severe hypoglycemia occurred in 4.9%, 4.5%, and 7.9% of patients in each group, respectively. Over 52 weeks, the most common AE was headache (dapagliflozin 14.8%; placebo 5.3%). Most events were mild and none was considered serious or resulted in discontinuation. CONCLUSIONS: Dapagliflozin, but not saxagliptin, showed significant improvement in A1C compared with placebo. Nonserious headaches were more common in participants treated with dapagliflozin than in those receiving placebo. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT03199053.)

Once-Weekly Exenatide in Youth With Type 2 Diabetes.

OBJECTIVE: Approved treatments for type 2 diabetes in pediatric patients include metformin, liraglutide, and insulin. However, approximately one-half of the youth fail metformin monotherapy within 1 year, insulin therapy is associated with challenges, and liraglutide requires daily injections. Consequently, the efficacy and safety of once-weekly injections of exenatide for the treatment of youth with type 2 diabetes was evaluated. RESEARCH DESIGN AND METHODS: Participants (aged 10 to <18 years) were randomized (5:2) to once-weekly exenatide 2 mg or placebo, respectively. The primary efficacy end point was change in glycated hemoglobin from baseline to week 24. Secondary efficacy end points were also evaluated, and the frequency of adverse events (AEs) was assessed. RESULTS: A total of 83 participants were randomized (exenatide, 59; placebo, 24) and 72 completed 24-week treatment (exenatide, 49; placebo, 23). At 24 weeks, the least squares mean change in glycated hemoglobin was -0.36% for the exenatide and +0.49% for the placebo groups (between-group difference, -0.85%; 95% CI -1.51, -0.19; P = 0.012). Nonsignificant least squares mean differences from baseline to 24 weeks favoring exenatide were observed: fasting glucose -21.6 mg/dL (-49.0, 5.7; P = 0.119), systolic blood pressure -2.8 mmHg (-8.0, 2.4; P = 0.284), and body weight -1.22 kg (-3.59, 1.15; P = 0.307). AEs occurred in 36 (61.0%) and 17 (73.9%) participants in the exenatide and placebo groups, respectively. CONCLUSIONS: In youth with type 2 diabetes suboptimally controlled with current treatments, once-weekly exenatide reduced glycated hemoglobin at 24 weeks and was well tolerated.

Renal effects of atorvastatin and rosuvastatin in patients with diabetes who have progressive renal disease (PLANET I): a randomised clinical trial.

BACKGROUND: The role of lipid-lowering treatments in renoprotection for patients with diabetes is debated. We studied the renal effects of two statins in patients with diabetes who had proteinuria. METHODS: PLANET I was a randomised, double-blind, parallel-group trial done in 147 research centres in Argentina, Brazil, Bulgaria, Canada, Denmark, France, Hungary, Italy, Mexico, Romania, and the USA. We enrolled patients with type 1 or type 2 diabetes aged 18 years or older with proteinuria (urine protein:creatinine ratio [UPCR] 500-5000 mg/g) and taking stable angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or both. We randomly assigned participants to atorvastatin 80 mg, rosuvastatin 10 mg, or rosuvastatin 40 mg for 52 weeks. The primary endpoint was change from baseline to week 52 of mean UPCR in each treatment group. The study is registered with ClinicalTrials.gov, number NCT00296374. FINDINGS: We enrolled 353 patients: 118 were assigned to rosuvastatin 10 mg, 124 to rosuvastatin 40 mg, and 111 to atorvastatin 80 mg; of these, 325 were included in the intention-to-treat population. UPCR baseline:week 52 ratio was 0·87 (95% CI 0·77-0·99; p=0·033) with atorvastatin 80 mg, 1·02 (0·88-1·18; p=0·83) with rosuvastatin 10 mg, and 0·96 (0·83-1·11; p=0·53) with rosuvastatin 40 mg. In a post-hoc analysis to compare statins, we combined data from PLANET I with those from PLANET II (a similar randomised parallel study of 237 patients with proteinuria but without diabetes; registered with ClinicalTrials.gov, NCT00296400). In this analysis, atorvastatin 80 mg lowered UPCR significantly more than did rosuvastatin 10 mg (-15·6%, 95% CI -28·3 to -0·5; p=0·043) and rosuvastatin 40 mg (-18·2%, -30·2 to -4·2; p=0·013). Adverse events occurred in 69 (60%) of 116 patients in the rosuvastatin 10 mg group versus 79 (64%) of 123 patients in the rosuvastatin 40 mg group versus 63 (57%) of 110 patients in the atorvastatin 80 mg group; renal events occurred in nine (7·8%) versus 12 (9·8%) versus five (4·5%). INTERPRETATION: Despite high-dose rosuvastatin lowering plasma lipid concentrations to a greater extent than did high-dose atorvastatin, atorvastatin seems to have more renoprotective effects for the studied chronic kidney disease population. FUNDING: AstraZeneca.

Obesity does not affect treatment outcomes with proton pump inhibitors.

BACKGROUND: Obesity is associated with increased risk of gastroesophageal reflux disease (GERD). GOAL: To evaluate the effect of obesity on symptom resolution in patients with nonerosive reflux disease (NERD) and healing rates in patients with erosive esophagitis (EE). METHODS: Two post hoc analyses were performed. Analyses included pooled data from randomized, double-blind, multicenter studies of proton pump inhibitors (PPIs) in GERD patients. RESULTS: Analysis 1 included 704 patients with NERD receiving esomeprazole 20 mg, esomeprazole 40 mg, or placebo. Analysis 2 included 11,027 patients with EE receiving esomeprazole 40 mg, omeprazole 20 mg, or lansoprazole 30 mg. For NERD patients, no significant association between baseline heartburn severity and body mass index (BMI) was observed. In EE patients, overweight (BMI 25 to <35 kg/m) and obese (BMI ≥35 kg/m) patients had significantly higher rates of Los Angeles (LA) grade C or D EE than patients with BMI <25 kg/m (P<0.0001). Percentages of PPI-treated patients who achieved heartburn resolution or EE healing within a given LA grade were similar across BMI categories. Heartburn resolution was significantly associated with treatment (esomeprazole vs. placebo), increasing age, and for men versus women (all P≤0.0284). EE healing was significantly associated with PPI treatment (esomeprazole and lansoprazole vs. omeprazole), increasing age, race, presence of a hiatal hernia, and lower LA grade at baseline (all P≤0.0183). CONCLUSIONS: In patients with GERD, high BMI was associated with more severe EE at baseline. However, during PPI treatment, BMI is not a significant independent predictor of heartburn resolution or EE healing.

Comparison of lipid-modifying efficacy of rosuvastatin versus atorvastatin in patients with acute coronary syndrome (from the LUNAR study).

Patients with acute coronary syndrome are recommended for early aggressive low-density lipoprotein (LDL) cholesterol-lowering therapy. The LUNAR study compared the efficacy of rosuvastatin with that of atorvastatin in decreasing LDL cholesterol in patients with acute coronary syndrome. Adult patients with coronary artery disease who were hospitalized for an acute coronary syndrome within 48 hours of first symptoms were randomized (n = 825) to an open-label, once-daily treatment with rosuvastatin 20 mg (RSV20), rosuvastatin 40 mg (RSV40), or atorvastatin 80 mg (ATV80) for 12 weeks. Patients were evaluated at weeks 2, 6, and 12. The primary end point was treatment efficacy in lowering LDL cholesterol averaged over 6 to 12 weeks. Changes in other lipoproteins, including high-density lipoprotein (HDL) cholesterol, and safety were evaluated. Analysis of covariance was used to compare least squares mean differences between each rosuvastatin treatment arm and the atorvastatin arm. The efficacy of RSV40 in lowering LDL cholesterol was significantly greater than that of ATV80 (46.8% vs 42.7% decrease, p = 0.02). LDL cholesterol lowering by RSV20 was similar to that by ATV80. Increases in HDL cholesterol were significantly greater with RSV40 (11.9%, p <0.001) and RSV20 (9.7%, p <0.01) than with ATV80 (5.6%). RSV40 was also significantly more effective than ATV80 in improving most other secondary efficacy variables, whereas the effects of RSV20 on these parameters were generally similar to those of ATV80. All 3 treatments were generally well tolerated over 12 weeks. In conclusion, results from the LUNAR study show that RSV40 more effectively decreased LDL cholesterol, increased HDL cholesterol, and improved other blood lipid parameters than ATV80 in patients with acute coronary syndrome.

Longitudinal assessment of estimated glomerular filtration rate in apparently healthy adults: a post hoc analysis from the JUPITER study (justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin).

BACKGROUND: Serum creatinine-based estimates of glomerular filtration rate (eGFR) are frequently used to identify patients with chronic kidney disease and assess cardiovascular risk both in clinical trials and in clinical practice. Although change in eGFR may be useful to assess change in renal function in patients with chronic kidney disease, the utility of serum creatinine-based eGFR is uncertain, particularly among individuals with normal or only mildly impaired renal function. OBJECTIVE: The goal of this study was to examine the relationship between baseline serum creatinine and eGFR, as well as changes in these parameters, in apparently healthy adults in a post hoc analysis of data obtained in participants in the JUPITER study (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin). METHODS: JUPITER was a randomized study of rosuvastatin 20 mg versus placebo in apparently healthy adults with high-sensitivity C-reactive protein levels ≥ 2.0 mg/L, LDL-C <130 mg/dL, and serum creatinine ≤ 2.0 mg/dL. Changes from baseline in serum creatinine and eGFR, based on the Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations, were assessed in the entire population and in subsets classified according to baseline eGFR status. RESULTS: Baseline characteristics of the 16,279 JUPITER study participants (mean age, 66 years; 62% men; 72% white; and 58% with a history of hypertension) who had both a baseline and ≥ 1 postbaseline serum creatinine measurement were similar to the entire population of 17,802 patients who entered the trial. The mean age of the study population was 66 years, 62% were men, 72% were white, and 58% had a history of hypertension. Mean (SD) serum creatinine increased from baseline by 0.08 (0.16) mg/dL and 0.09 (0.14) mg/dL in the rosuvastatin and placebo groups, respectively (P = 0.001) at year 1 and by 0.09 (0.18) and 0.10 (0.16) mg/dL (P = 0.0045) at the final visit. Reductions in MDRD and CKD-EPI eGFR were ∼ 0.5 mL/min/1.73 m(2) greater with placebo than with rosuvastatin (P < 0.004) at year 1 and the final visit. The magnitude of eGFR change was closely related to baseline eGFR, with greater reductions among subjects with eGFR ≥ 60 mL/min/1.73 m(2) in both the rosuvastatin and placebo groups. Among those with an eGFR ≥ 90 mL/min/1.73 m(2) , mean changes at year 1 and final visit ranged from -16 to -23 mL/min/1.73 m(2) with MDRD and CKD-EPI, respectively; in contrast, mean changes were <1 mL/min/1.73 m(2) in subjects with eGFR <60 mL/min/1.73 m(2) . CONCLUSIONS: In JUPITER, reductions in MDRD or CKD-EPI eGFR levels were greater in study participants with higher baseline eGFR levels but less in the rosuvastatin than in the placebo group. Future studies are required to assess the reliability of serum creatinine-based estimates of GFR to assess change in renal function, particularly among individuals with normal serum creatinine levels.

Cardiovascular event reduction and adverse events among subjects attaining low-density lipoprotein cholesterol <50 mg/dl with rosuvastatin. The JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin).

OBJECTIVES: The purpose of this study was to assess the impact on cardiovascular and adverse events of attaining low-density lipoprotein cholesterol (LDL-C) levels <50 mg/dl with rosuvastatin in apparently healthy adults in the JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) trial. BACKGROUND: The safety and magnitude of cardiovascular risk reduction conferred by treatment to LDL-C levels below current recommended targets remain uncertain. METHODS: A cohort of 17,802 apparently healthy men and women with high-sensitivity C-reactive protein ≥2 mg/l and LDL-C <130 mg/dl were randomly allocated to rosuvastatin 20 mg daily or placebo, and followed up for all-cause mortality, major cardiovascular events, and adverse events. In a post-hoc analysis, participants allocated to rosuvastatin were categorized as to whether or not they had a follow-up LDL-C level <50 mg/dl. RESULTS: During a median follow-up of 2 years (range up to 5 years), rates of the primary trial endpoint were 1.18, 0.86, and 0.44 per 100 person-years in the placebo group (n = 8,150) and rosuvastatin groups without LDL-C <50 mg/dl (n = 4,000) or with LDL-C <50 mg/dl (n = 4,154), respectively (fully-adjusted hazard ratio: 0.76; 95% confidence interval: 0.57 to 1.00 for subjects with no LDL-C <50 mg/dl vs. placebo and 0.35, 95% confidence interval: 0.25 to 0.49 for subjects attaining LDL-C <50 mg/dl; p for trend <0.0001). For all-cause mortality, corresponding event rates were 0.67, 0.65, and 0.39 (p for trend = 0.004). Rates of myalgia, muscle weakness, neuropsychiatric conditions, cancer, and diabetes mellitus were not significantly different among rosuvastatin-allocated participants with and without LDL-C <50 mg/dl. CONCLUSIONS: Among adults with LDL-C <130 mg/dl and high-sensitivity C-reactive protein ≥2 mg/l, rosuvastatin-allocated participants attaining LDL-C <50 mg/dl had a lower risk of cardiovascular events without a systematic increase in reported adverse events.

Intravenous esomeprazole pharmacodynamics in critically ill patients.

OBJECTIVE: A widely held belief contends that food-induced proton pump activation is important for optimal proton pump inhibitor-induced inhibition of gastric acid secretion. This study was undertaken to assess intragastric acid control with intravenous (IV) esomeprazole in critically ill patients. RESEARCH DESIGN AND METHODS: This open-label, single-arm, exploratory trial was conducted at five university or regional hospital intensive care units in the US. Adult patients admitted to an intensive care unit who required mechanical ventilation and had at least one additional risk factor for stress-induced ulcer received twice-daily IV esomeprazole 40 mg for 48 hours and could continue for another 24 hours if no prepyloric enteral feedings were planned. CLINICAL TRIAL REGISTRATION: D9612L00107; ClinicalTrials.gov Identifier NCT00428701. MAIN OUTCOME MEASURES: The primary efficacy variable was the linear-interpolated percentage of time intragastric pH was > or =4 during 24-48 hours. Secondary efficacy variables included the interpolated percentage of time intragastric pH was > or =4 during 0-24, 0-48, and 48-72 hours, the percentage of gastric aspirates collected with pH > or =4 during 0-24, 24-48, 0-48, and 48-72 hours, and time to stable pH > or =4. Safety was assessed based on adverse events (AEs), physical examinations, vital signs, laboratory tests, and electrocardiograms. RESULTS: Forty-five patients were enrolled (one was excluded because of previous partial gastrectomy). Interpolated mean percentage time pH > or =4 was 88.8%, 80.7%, and 83.5% for 24-48, 0-24, and 0-48 hours, respectively. For 0-72 hours, > or =78% of gastric aspirates had pH > or =4. Median time to stable pH was 1 hour (95% confidence interval: 0.67, 2.00). Treatment was well tolerated, with no evidence of gastrointestinal bleeding. A total of 75 AEs occurred in 34 patients, none considered treatment related. CONCLUSIONS: In this noncontrolled exploratory study, twice-daily IV esomeprazole 40 mg rapidly decreased intragastric acidity and effectively maintained pH >/=4 during 0-72 hours in fasting, critically ill, mechanically ventilated patients at high risk for stress ulcers.

Predictors of heartburn resolution and erosive esophagitis in patients with GERD.

OBJECTIVES: The primary objective was to assess gastroesophageal reflux disease (GERD) symptom resolution rates with esomeprazole by erosive esophagitis (EE) status, and the secondary objective was to evaluate potential predictors of the presence of EE and heartburn resolution. BACKGROUND: Patients with GERD who have EE have higher reported symptom resolution rates than those with nonerosive reflux disease (NERD) when treated with proton pump inhibitors (PPIs). STUDY: This open-label multicenter study included adults with GERD symptoms. Patients were stratified by EE status after endoscopy and received once-daily esomeprazole 40 mg for 4 weeks. Questionnaires determined symptom response rates, and baseline predictors of EE or heartburn resolution were evaluated. Potential predictors, including years with GERD, history of EE, and time to relief with antacids, were examined. RESULTS: Heartburn resolution rates at 4 weeks were higher for patients with EE than NERD (69% [124/179] vs. 48% [85/177]; p < 0.0001). Multivariate models had moderate predictive ability for EE (c-index, 0.76) and poor predictive ability (c-index, 0.57) for heartburn resolution. However, faster heartburn relief with antacid use, particularly within 15 min, was predictive of EE and heartburn resolution. CONCLUSIONS: Patients with EE have higher heartburn resolution rates than patients with NERD after treatment, although recall bias may be possible. Fast relief with antacid use is predictive of EE and heartburn resolution with a PPI and suggests that a history of antacid relief may provide corroborative evidence to empiric PPI therapy in determining whether patients with heartburn have acid reflux disease. ClinicalTrials.Gov IDENTIFIER: NCT00242736.

Effects of esomeprazole on acid output in patients with Zollinger-Ellison syndrome or idiopathic gastric acid hypersecretion.

OBJECTIVES: To evaluate the efficacy and safety of oral esomeprazole in the control of gastric acid hypersecretion in patients with hypersecretory states. METHODS: In this 12-month, open-label, multicenter study, acid output (AO) was evaluated at baseline, day 10, and months 3, 6, and 12. The starting dose of esomeprazole was 40 mg or 80 mg twice daily. On day 10, patients with controlled AO were maintained on the same dose, while those with uncontrolled AO had their doses increased (maximum dose 240 mg/day) until control was attained. Esophagogastroduodenoscopy (EGD) was performed at baseline and at 6 and 12 months. Safety and tolerability were assessed throughout the study by EGD, gastric analysis, and adverse events. RESULTS: Twenty-one patients (19 with Zollinger-Ellison syndrome [ZES], 2 with idiopathic gastric acid hypersecretion [IGH]) completed the study. Of the 20 patients with controlled AO at day 10, 18 (90%) had sustained AO control for the rest of the study. At 12 months, AO was controlled in 14 of 16 patients receiving esomeprazole 40 mg twice daily, in all 4 patients receiving esomeprazole 80 mg twice daily, and in the 1 patient receiving esomeprazole 80 mg 3 times daily. At 6 and 12 months, no patient had endoscopic evidence of mucosal disease. Esomeprazole was well tolerated; 1 patient had a serious adverse event (hypomagnesemia) attributed to treatment that resolved with magnesium supplementation during continued treatment. CONCLUSION: Esomeprazole in appropriately titrated doses controls AO over 12 months in patients with hypersecretory states and is well tolerated.