Dietmar Neubacher

Durable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials

BACKGROUND Treatment options for HIV-1 infected individuals who have received extensive previous antiretroviral therapy are limited. We compared efficacy and safety of the novel non-peptidic protease inhibitor tipranavir co-administered with ritonavir plus an optimised background regimen with that of an investigator-selected ritonavir-boosted comparator protease inhibitor (CPI-ritonavir) in such patients. METHODS We did a combined analysis of 48-week data from two ongoing, randomised, open-label, multinational, phase III, RESIST studies. HIV-1-infected adults with 3 months or longer previous triple antiretroviral class experience, two or more previous protease inhibitor regimens, HIV-1 RNA 1000 copies per mL or greater, and genotypically demonstrated primary resistance to protease inhibitor, were eligible. Primary endpoints were proportion of treatment responders (with reduction in viral load of 1 log(10) copies per mL or greater below baseline without treatment change) at 48 weeks and time to treatment failure through 48 weeks (intention-to-treat analysis). The RESIST studies are registered with ClinicalTrials.gov, numbers NCT00054717 (RESIST-1) and NCT00144170 (RESIST-2). FINDINGS 3324 patients were screened; 746 received tipranavir-ritonavir and 737 CPI-ritonavir. 486 (65.1%) patients on tipranavir-ritonavir and 192 (26.1%) on CPI-ritonavir remained on assigned treatment until week 48. At week 48, more patients achieved and maintained treatment response in the tipranavir-ritonavir group than in the CPI-ritonavir group (251 [33.6%] vs 113 [15.3%]; p<0.0001). Median time to treatment failure was significantly longer in the tipranavir-ritonavir group than in the CPI-ritonavir group (113 days vs 0 days; p<0.0001). Gastrointestinal system disorders and raised transaminase, cholesterol, and triglycerides were more frequent in the tipranavir-ritonavir group than in the CPI-ritonavir group. INTERPRETATION Compared with CPI-ritonavir, tipranavir-ritonavir with an optimised background regimen provides better virological and immunological responses over 48 weeks in patients who have received extensive previous antiretroviral treatment.

Cardiovascular safety with linagliptin in patients with type 2 diabetes mellitus: a pre-specified, prospective, and adjudicated meta-analysis of a phase 3 programme.

BackgroundThis study investigated the cardiovascular (CV) safety profile of the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin versus comparator treatments.MethodsThis was a pre-specified meta-analysis of CV events in linagliptin or comparator-treated patients with type 2 diabetes mellitus (T2DM) from eight Phase 3 studies. All suspected CV events were prospectively adjudicated by a blinded independent expert committee. The primary endpoint was a composite of CV death, stroke, myocardial infarction, and hospitalization for unstable angina. Three secondary composite endpoints derived from the adjudicated CV events were also pre-specified. Risk estimates were calculated using several statistical methods including Cox regression analysis.ResultsOf 5239 treated patients (mean ± SD HbA1c 65 ± 10 mmol/mol [8.0 ± 0.9%], age 58 ± 10 years, BMI 29 ± 5 kg/m2), 3319 received linagliptin once daily (5 mg, 3159; 10 mg, 160) and 1920 received comparators (placebo, 977; glimepiride 1-4 mg, 781; voglibose 0.6 mg, 162). Cumulative exposure (patient-years) was 2060 for linagliptin and 1372 for comparators. Primary CV events occurred in 11 (0.3%) patients receiving linagliptin and 23 (1.2%) receiving comparators. The hazard ratio (HR) for the primary endpoint showed significantly lower risk with linagliptin than comparators (HR 0.34 [95% confidence interval (CI) 0.16-0.70]) as did estimates for all secondary endpoints (HR ranging from 0.34 to 0.55 [all upper 95% CIs < 1.0]).ConclusionsThese results from a large Phase 3 programme support the hypothesis that linagliptin may have CV benefits in patients with T2DM.

Ritonavir-boosted tipranavir demonstrates superior efficacy to ritonavir-boosted protease inhibitors in treatment-experienced HIV-infected patients: 24-Week results of the RESIST-2 trial

BACKGROUND Tipranavir, a novel protease inhibitor, has demonstrated antiviral activity against protease inhibitor-resistant human immunodeficiency virus type 1 (HIV-1) isolates. The Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST-2) trial is an ongoing, open-label, phase III trial comparing ritonavir-boosted tipranavir (TPV/r) plus an optimized background regimen with an individually optimized, ritonavir-boosted protease inhibitor in treatment-experienced, HIV-1-infected patients. METHODS Patients at 171 sites in Europe and Latin America who had received > or = 2 previous protease inhibitor regimens, had triple-antiretroviral class experience, had an HIV-1 RNA level > or = 1000 copies/mL, and had genotypically demonstrated primary protease inhibitor resistance were eligible. After genotypic resistance tests were performed, a protease inhibitor and optimized background regimen were selected before randomization. Patients were randomized to receive either TPV/r or comparator protease inhibitor-ritonavir (CPI/r) and were stratified on the basis of preselected protease inhibitor and enfuvirtide use. Treatment response was defined as a confirmed HIV-1 load reduction > or = 1 log10 less than the baseline value without a treatment change at week 24. RESULTS A total of 863 patients were randomized and treated. At baseline, the mean HIV-1 load was 4.73 log10 copies/mL, and the mean CD4+ cell count was 218 cells/mm3. The preplanned 24-week efficacy analyses of 539 patients demonstrated treatment response rates of 41% in the TPV/r arm and 14.9% in the CPI/r arm (intent-to-treat analysis; P<.0001). The mean CD4+ cell count increased by 51 cells/mm3 in the TPV/r arm and by 18 cells/mm3 in the CPI/r arm. The most common adverse events were mild-to-moderate diarrhea, nausea, and headache. Grade 3 or greater elevations in serum transaminase, cholesterol, and triglyceride levels were more frequent in the TPV/r arm. CONCLUSIONS TPV/r had superior antiviral activity and increased immunologic benefits, compared with CPI/r, at week 24 among treatment-experienced patients infected with multidrug-resistant HIV-1.

Long-term efficacy and safety of tipranavir boosted with ritonavir in HIV-1-infected patients failing multiple protease inhibitor regimens: 80-week data from a phase 2 study.

Background:BI 1182.2, an open-label, randomized, multicenter, phase 2 study, evaluated efficacy and tolerability of the protease inhibitor (PI) tipranavir (TPV; 500 mg twice daily or 1000 mg twice daily) administered with ritonavir (100 mg twice daily) in combination with 1 nucleoside reverse transcriptase inhibitor and 1 nonnucleoside reverse transcriptase inhibitor in multiple PI-experienced HIV-1-infected patients. Methods:Forty-one patients were evaluated in 2 arms: low-dose (19 patients) or high-dose (22 patients) ritonavir-boosted tipranavir (TPV/r). Primary endpoints were change from baseline in HIV-1 RNA concentrations at weeks 16, 24, 48, and 80 and percentage of patients with plasma HIV-1 RNA levels lower than the limit of quantitation. Safety was evaluated by adverse events (AEs), grade 3/4 abnormalities, and serious AEs. Results:Of all patients, 59% were still receiving TPV/r (14 in low-dose arm and 10 in high-dose arm) at week 80. Patients in both arms had a median >2.0-log10 reduction in plasma viral load. Intent-to-treat analysis demonstrated that a similar proportion of patients in the high-dose and low-dose groups achieved plasma HIV-1 RNA levels <50 copies/mL at week 80 (43% vs. 32%; P = 0.527). The most frequently observed AEs were diarrhea, headache, and nausea. Conclusion:TPV/r combined with other active antiretroviral agents can provide a durable treatment response for highly treatment-experienced patients.

Efficacy and Cardiovascular Safety of Linagliptin as an Add-On to Insulin in Type 2 Diabetes: A Pooled Comprehensive Post Hoc Analysis.

OBJECTIVE With the expanding armamentarium of noninsulin therapies for type 2 diabetes mellitus, the use of insulin with various oral agents is becoming more common. In this study, we assessed the efficacy and cardiovascular (CV) safety of the dipeptidyl peptidase-4 inhibitor linagliptin as add-on to insulin in patients with type 2 diabetes. METHODS In this post hoc analysis, data for patients receiving basal or basal-bolus insulin were pooled from 4 randomized, double-blind, phase 3 clinical trials of linagliptin 5 mg once daily or placebo given as add-on to background glucose-lowering treatment. Changes in glycated hemoglobin (A1C) and CV risk factors were assessed from baseline to end of trial. The primary CV endpoint was a composite of CV death, nonfatal myocardial infarction, nonfatal stroke and hospitalization due to unstable angina. RESULTS The number of patients receiving basal or basal-bolus insulin as background therapy was 1613 (linagliptin: n=811; placebo: n=802). The placebo-adjusted mean (SE) change from baseline in A1C was -0.41 (0.05)% (95% CI -0.50, -0.32; p<0.0001). Treatment with linagliptin provided a relative weight benefit and reduced insulin requirements without affecting blood pressure, heart rate or lipids. The incidence of hypoglycemia with linagliptin was similar to that for placebo (38.7% vs. 39.4%, respectively). The hazard ratio (HR) for the primary endpoint showed that treatment with linagliptin was not associated with an increased CV risk (HR 1.07 [95% CI 0.62, 1.85]). CONCLUSIONS Linagliptin, when added to ongoing insulin treatment in patients with type 2 diabetes, improves glycemic control and has a neutral impact on major adverse CV events.

Linagliptin added to sulphonylurea in uncontrolled type 2 diabetes patients with moderate-to-severe renal impairment

Glucose-lowering treatment options are limited for uncontrolled type 2 diabetes mellitus (T2DM) patients with advanced stages of renal impairment (RI). This retrospective analysis evaluated glycaemic efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor linagliptin added to sulphonylurea. Three randomized phase 3 studies (n = 619) including T2DM subjects with moderate or severe RI [estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2] were analysed; only sulphonylurea-treated subjects who received additional linagliptin (n = 58) or placebo (n = 33) were evaluated. Linagliptin provided meaningful placebo-adjusted HbA1c reductions of −0.68% (95% confidence interval: −1.19, −0.17), −1.08% (−2.02, −0.14) and −0.62% (−1.25, 0.01) after 24, 18 and 12 weeks, respectively. There was a similar incidence of overall adverse events (linagliptin: 79.3%, placebo: 75.8%) and hypoglycaemia (linagliptin: 37.9%, placebo: 39.4%). Severe hypoglycaemia was more common with placebo (linagliptin: 1.7%, placebo: 6.1%). These data suggest that linagliptin is a safe and effective glucose-lowering treatment in T2DM patients with moderate-to-severe RI for whom sulphonylurea treatment is no longer sufficient.

Glucose Exposure and Variability with Empagliflozin as Adjunct to Insulin in Patients with Type 1 Diabetes: Continuous Glucose Monitoring Data from a 4-Week, Randomized, Placebo-Controlled Trial (EASE-1)

BACKGROUND We evaluated the effect of empagliflozin as adjunct to insulin on 24-h glucose exposure and variability in patients with type 1 diabetes. METHODS Patients (N = 75) with HbA1c ≥7.5% to ≤10.5% were randomized to receive empagliflozin 2.5 mg, empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily as adjunct to insulin for 4 weeks. Insulin dose was to be kept as stable as possible during week 1 of treatment and was freely adjustable thereafter. Markers of glucose exposure and variability were assessed from 7-day blinded continuous glucose monitoring intervals. This study is completed ( ClinicalTrials.gov NCT01969747). RESULTS Empagliflozin reduced hourly mean glucose area under the median curve over 24 h versus placebo within week 1 (adjusted mean differences: -12.2 mg/dL·h [95% confidence interval -23.9 to -0.5], -30.2 mg/dL·h [-42.2 to -18.2], and -33.0 mg/dL·h [-44.8 to -21.1] with empagliflozin 2.5, 10, and 25 mg, respectively; all P < 0.05) and increased time in glucose target range (>70 to ≤180 mg/dL). Results were sustained to week 4 with empagliflozin 25 mg. All empagliflozin doses significantly reduced glucose variability (interquartile range and mean amplitude of glucose excursions) versus placebo at weeks 1 and 4. Except for small increases in hours per day with glucose ≤70 mg/dL during the stable insulin period, empagliflozin did not increase time in hypoglycemia compared with placebo. CONCLUSIONS In patients with type 1 diabetes, empagliflozin as adjunct to insulin decreased glucose exposure and variability and increased time in glucose target range.

Randomized, double-blind, placebo-controlled dose-finding study of the dipeptidyl peptidase-4 inhibitor linagliptin in pediatric patients with type 2 diabetes

To identify the dose of the dipeptidyl peptidase‐4 (DPP‐4) inhibitor linagliptin in pediatric patients with type 2 diabetes (T2D).

Empagliflozin as Adjunctive to Insulin Therapy in Type 1 Diabetes: The EASE Trials

OBJECTIVE To evaluate the safety and efficacy of empagliflozin 10- and 25-mg doses plus a unique lower dose (2.5 mg) as adjunct to intensified insulin in patients with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS The EASE (Empagliflozin as Adjunctive to inSulin thErapy) program (N = 1,707) included two double-blind, placebo-controlled phase 3 trials: EASE-2 with empagliflozin 10 mg (n = 243), 25 mg (n = 244), and placebo (n = 243), 52-week treatment; and EASE-3 with empagliflozin 2.5 mg (n = 241), 10 mg (n = 248), 25 mg (n = 245), and placebo (n = 241), 26-week treatment. Together they evaluated empagliflozin 10 mg and 25 mg, doses currently approved in treatment of type 2 diabetes, and additionally 2.5 mg on 26-week change in glycated hemoglobin (primary end point) and weight, glucose time-in-range (>70 to ≤180 mg/dL), insulin dose, blood pressure, and hypoglycemia. RESULTS The observed largest mean placebo-subtracted glycated hemoglobin reductions were −0.28% (95% CI −0.42, −0.15) for 2.5 mg, −0.54% (−0.65, −0.42) for 10 mg, and −0.53% (−0.65, −0.42) for 25 mg (all P < 0.0001). Empagliflozin 2.5/10/25 mg doses, respectively, reduced mean weight by −1.8/−3.0/−3.4 kg (all P < 0.0001); increased glucose time-in-range by +1.0/+2.9/+3.1 h/day (P < 0.0001 for 10 and 25 mg); lowered total daily insulin dose by −6.4/−13.3/−12.7% (all P < 0.0001); and decreased systolic blood pressure by −2.1/−3.9/−3.7 mmHg (all P < 0.05). Genital infections occurred more frequently on empagliflozin. Adjudicated diabetic ketoacidosis occurred more with empagliflozin 10 mg (4.3%) and 25 mg (3.3%) but was comparable between empagliflozin 2.5 mg (0.8%) and placebo (1.2%). Severe hypoglycemia was rare and frequency was similar between empagliflozin and placebo. CONCLUSIONS Empagliflozin improved glycemic control and weight in T1D without increasing hypoglycemia. Ketoacidosis rate was comparable between empagliflozin 2.5 mg and placebo but increased with 10 mg and 25 mg. Ketone monitoring for early ketoacidosis detection and intervention and lower empagliflozin doses may help to reduce this risk.

2.3 Cardiovascular (CV) Safety of Linagliptin in Patients with Type 2 Diabetes (T2D): A Pooled Comprehensive Analysis of Prospectively Adjudicated CV Events in Phase 3 Studies (376-OR)

SamenvattingIncidence of CV events is increased in T2D, but the potential for CV risk modulation with glucose lowering therapies is debated. We compared the incidence of CV events and CV mortality in patients with T2D treated with linagliptin (lina), a once daily DPP-4 inhibitor, with non-lina comparators (comp) in 19 double-blind RCTs (duration ≥ 12 weeks).