Cardiovascular safety of linagliptin in type 2 diabetes: a comprehensive patient-level pooled analysis of prospectively adjudicated cardiovascular events.

BACKGROUND: The cardiovascular (CV) safety of linagliptin was evaluated in subjects with type 2 diabetes (T2DM). METHODS: Pre-specified patient-level pooled analysis of all available double-blind, randomized, controlled trials, ≥ 12 weeks' duration (19 trials, 9459 subjects) of linagliptin versus placebo/active treatment. Primary end point: composite of prospectively adjudicated CV death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for unstable angina (4P-MACE). Hospitalization for congestive heart failure (CHF) was also evaluated; adjudication of CHF was introduced during the phase 3 program (8 trials; 3314 subjects). 4P-MACE was assessed in placebo-controlled trials (subgroup of 18 trials; 7746 subjects). Investigator-reported events suggestive of CHF from 24 placebo-controlled trials (including trials <12 weeks' duration, 8778 subjects) were also analyzed. RESULTS: 5847 patients received linagliptin (5 mg: 5687, 10 mg: 160) and 3612 comparator (glimepiride: 775, voglibose: 162, placebo: 2675); cumulative exposure, 4421.3 and 3254.7 patient-years, respectively. 4P-MACE incidence rates: 13.4 per 1000 patient-years, linagliptin (60 events), 18.9, total comparators (62 events); overall hazard ratio (HR), 0.78 (95% confidence interval [CI], 0.55-1.12). HR for adjudicated hospitalization for CHF (n = 21): 1.04 (0.43-2.47). For placebo-controlled trials, 4P-MACE incidence rates: 14.9 per 1000 patient-years, linagliptin (43 events), 16.4, total comparators (29 events); overall HR, 1.09 (95% CI, 0.68-1.75). Occurrence of investigator-reported events suggestive of CHF was low for linagliptin- (26 events, 0.5%; serious: 16 events, 0.3%) and placebo-treated (8 events, 0.2%; serious: 6 events, 0.2%) patients. CONCLUSIONS: Linagliptin is not associated with increased CV risk versus pooled active comparators or placebo in patients with T2DM.

Efficacy and safety of linagliptin co-administered with low-dose metformin once daily versus high-dose metformin twice daily in treatment-naïve patients with type 2 diabetes: a double-blind randomized trial.

INTRODUCTION: The aim of this study was to investigate the efficacy and safety of linagliptin + low-dose (LD) metformin once daily versus high-dose (HD) metformin twice daily in treatment-naïve patients with type 2 diabetes. METHODS: Patients (n = 689) were randomized (1:1) to double-blind treatment with linagliptin 5 mg + LD metformin (1000 mg) or HD metformin (2000 mg) for 14 weeks. Metformin was initiated at 500 mg/day and up-titrated within 2 weeks; the dose then remained unchanged. The primary endpoint was change in glycated hemoglobin (HbA1c) from baseline to Week 14 in patients who tolerated a daily metformin dose of ≥1000 mg after 2 weeks. RESULTS: At Week 14, HbA1c changed from a mean baseline of 8.0% (64 mmol/mol) by -0.99% (-11 mmol/mol) for linagliptin + LD metformin, and -0.98% (-11 mmol/mol) for HD metformin [treatment difference -0.01% (95% confidence interval -0.13, 0.12) (0 mmol/mol), P = 0.8924]. The proportion of patients who achieved HbA1c <7.0% (53 mmol/mol) without occurrence of moderate or severe gastrointestinal (GI) events (including abdominal pain, nausea, vomiting, diarrhea, and decreased appetite) was the same in both groups (51.3% for both). Although the occurrence of moderate or severe GI events was similar, the linagliptin + LD metformin group had fewer mild GI events (18.5% versus 24.3%). The incidence of hypoglycemia was low in both groups. CONCLUSION: Linagliptin + LD metformin combination showed similar efficacy and safety to HD metformin. This combination may be an alternative treatment option in patients who may have difficulty tolerating metformin doses >1000 mg/day. FUNDING: Boehringer Ingelheim.

Linagliptin improves glycemic control after 1 year as add-on therapy to basal insulin in Asian patients with type 2 diabetes mellitus.

OBJECTIVE: To evaluate the efficacy and long-term safety of linagliptin added to basal insulin in Asian patients with type 2 diabetes mellitus (T2DM) inadequately controlled by basal insulin with/without oral agents. RESEARCH DESIGN AND METHODS: This was a post hoc analysis of Asian patients from a global ≥52 week study in which patients on basal insulin were randomized (1:1) to double-blind treatment with linagliptin 5 mg once daily or placebo (NCT00954447). Basal insulin dose remained stable for 24 weeks, after which adjustments could be made according to the investigator's discretion to improve glycemic control. The primary endpoint was the mean change in glycated hemoglobin (HbA1c) from baseline to 24 weeks. RESULTS: Data were available for 154 Asian patients (80 linagliptin, 74 placebo). Baseline HbA1c (standard deviation [SD]) was 8.6 (0.9)% (70 [10] mmol/mol). The placebo-corrected mean change (standard error [SE]) in HbA1c from baseline was -0.9 (0.1)% (-10 [1] mmol/mol) (95% confidence interval [CI]: -1.2, -0.7; p<0.0001) at Week 24 and -0.9 (0.1)% (-10 [1] mmol/mol) (95% CI: -1.1, -0.6; p<0.0001) at Week 52. The frequency of adverse events (linagliptin 81.3%, placebo 91.9%) and hypoglycemia (Week 24: linagliptin 25.0%, placebo 25.7%; treatment end: linagliptin 28.8%, placebo 35.1%) was similar between groups. By Week 52, changes (SE) in mean body weight were similar in both groups (linagliptin -0.67 [0.26] kg, placebo -0.38 [0.25] kg). CONCLUSIONS: This study was limited by the post hoc nature of the analysis and the small number of patients in the subgroup. However, the results suggest that linagliptin significantly improves glycemic control in Asian patients with T2DM inadequately controlled by basal insulin, without increasing the risk for hypoglycemia or weight gain. ClinicalTrials identifier: NCT00954447.

Safety and Tolerability of Linagliptin in Patients With Type 2 Diabetes: A Comprehensive Pooled Analysis of 22 Placebo-controlled Studies.

PURPOSE: Dipeptidyl peptidase (DPP)-4 inhibitors are an increasingly used antihyperglycemic therapy for patients with type 2 diabetes mellitus (T2DM). Linagliptin, an orally administered DPP-4 inhibitor, has demonstrated favorable efficacy/safety in clinical trials. The aim of this post hoc pooled analysis was to expand current knowledge of the safety of linagliptin. METHODS: Safety data for once-daily linagliptin 5 mg (1 study of linagliptin 2.5 mg twice daily) were analyzed from 22 randomized, double-blind, Phase I-III, placebo-controlled clinical trials of ≤102 weeks' duration. Assessments of pooled data included incidence of patient-reported adverse events (AEs). FINDINGS: Data from 7400 patients (linagliptin, 4810; placebo, 2590) were pooled. Most patients (58.4%) had T2DM diagnosis for >5 years; approximately 75% were receiving ≥1 type of background therapy in addition to linagliptin/placebo. Overall exposure to the study drug was 2412.8 years for linagliptin and 1481.4 years for placebo (mean [SD], 183 [120] days and 209 [150] days, respectively). Overall frequencies of AEs were similar for linagliptin- and placebo-treated patients (57.3% and 61.8%, respectively). The incidence of neoplastic AEs was low (0.6% and 0.9%, respectively); there were no reports of pancreatic neoplasia. Pancreatitis was observed in 2 linagliptin-treated patients (<0.1%) and 1 placebo-treated patient (<0.1%). The occurrence of cardiac disorder AEs was similar in linagliptin- and placebo-treated patients (3.2% [n = 153] and 3.3% [n = 83], respectively); the incidence of heart failure AEs for linagliptin- and placebo-treated patients was 0.2% (n = 11) and 0.3% (n = 7), respectively. Overall, linagliptin was weight neutral. Occurrence of investigator-defined hypoglycemic AEs was low for both linagliptin and placebo (11.5% vs 14.0%). In patients receiving concomitant sulfonylurea therapy, investigator-defined hypoglycemic AEs were more frequent with linagliptin versus placebo (22.1% [238/1079] vs 14.5% [61/421], respectively). Subgroup analyses showed similar frequencies of AEs for linagliptin- and placebo-treated patients across different age groups and renal function levels. IMPLICATIONS: This updated and expanded pooled, post hoc analysis of 22 placebo-controlled trials of linagliptin 5 mg daily supports previous findings of the acceptable overall safety/tolerability profile of linagliptin when administered to a broad range of patients with T2DM. Linagliptin-treated patients demonstrated a low overall risk of hypoglycemia (risk increased by concomitant sulfonylurea therapy). As with all pooled analyses, this study is limited by the use of data from different studies, and the relatively short duration of some included studies, although use of individual patient data from consistently designed trials should minimize methodological differences between trials. Results from ongoing clinical trials will provide additional insight into the long-term safety/tolerability of linagliptin.

Assessment of AACE/ACE recommendations for initial dual antihyperglycemic therapy using the fixed-dose combination of sitagliptin and metformin versus metformin.

OBJECTIVE: The American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) diabetes algorithm recommends a stratified approach to initial therapy to achieve a glycated hemoglobin (HbA1c) goal of ≤6.5% in patients with type 2 diabetes mellitus (T2DM) who have inadequate glycemic control. Data from a double-blind study in drug-naïve T2DM patients comparing initial monotherapy with metformin (MET) with initial dual therapy with a fixed-dose combination of sitagliptin and MET (SITA/MET FDC) was used to determine AACE/ACE HbA1c goal attainment in these treatment groups. METHODS: A total of 1,250 patients (mean baseline HbA1c = 9.9%) were randomized 1:1 to SITA/MET FDC 50/500 mg twice daily (b.i.d.) or MET 500 mg b.i.d. for 18 weeks. SITA/MET FDC and MET were uptitrated over 4 weeks to 50/1,000 mg b.i.d. and 1,000 mg b.i.d., respectively. RESULTS: At week 18, a higher percentage of patients receiving SITA/MET FDC had HbA1c levels ≤6.5% and <7% than those receiving MET alone within each of the 3 AACE/ACE HbA1c categories (6.5-7.5%, >7.5-9.0%, and >9.0%). Of patients with a baseline HbA1c >7.5-9.0% who initiated SITA/MET FDC, 48.6% achieved an HbA1c ≤6.5% at week 18 compared with 23.1% of patients who initiated MET monotherapy (P<.001). In patients with a baseline HbA1c >9.0%, 24.0% on SITA/MET FDC achieved an HbA1c ≤6.5% compared with 12.8% on MET alone (P<.001). CONCLUSION: In T2DM patients with a baseline HbA1c >7.5-9.0%, substantially more achieved the HbA1c goal of ≤6.5% with initial dual therapy (SITA/MET FDC) than with initial monotherapy (MET), which is in agreement with the AACE/ACE diabetes algorithm.

Time to initiation of oral antihyperglycemic and statin therapy in previously untreated patients with type 2 diabetes in the United States.

OBJECTIVE: To assess the time from the first observed diagnosis of type 2 diabetes (T2DM) to initiation of an oral antihyperglycemic agent (OAHA) and statin. METHODS: In a retrospective US cohort study using the GE electronic medical record database, patients ≥18 years were included if they had a T2DM diagnosis between January 1, 2004 and December 31, 2005 (index period), had a last pre-index HbA1c value ≥7%, and had not received antihyperglycemic agents within one year prior to diagnosis (index date). Patients were eligible for statin therapy but not on a statin within one year before the index date. Patients had medical records for one year prior to (baseline) and two years after (follow up) diagnosis. RESULTS: Of the 2254 eligible patients, 58% were male, mean age was 58 years, mean HbA1c was 8.5%, and mean LDL cholesterol was 115 mg/dL (2.97 mmol/L) at baseline. Additionally, 21% of patients had pre-existing overt cardiovascular disease, 40% had dyslipidemia, 37% were obese, and 11% were smokers. During follow-up, 66.1% and 41.9% of patients initiated an OAHA and a statin, respectively. Among the treated patients, median time from the first observed diabetes diagnosis to therapy initiation was 3 months (interquartile range: 1, 9) for OAHAs and 6 months (2, 13) for statins. LIMITATIONS: Treatment initiation with injectable antihyperglycemic agents and/or non-statin lipid-modifying therapies as well as contraindications to OAHAs or statins were not assessed, therefore their impact on our study results cannot be determined. Laboratory measurements were not available for every patient and thus many patients were excluded from the analysis. CONCLUSION: Treatment initiation with OAHAs and/or statins was suboptimal in patients with T2DM who were treatment eligible and previously untreated with OAHAs and statins. Of those treated, patients initiated treatment with an OAHA more often and earlier than with a statin.

Lower risk of hypoglycemia with sitagliptin compared to glipizide when either is added to metformin therapy: a pre-specified analysis adjusting for the most recently measured HbA(1c) value.

BACKGROUND: In a previously-published study, adding sitagliptin or glipizide to ongoing metformin therapy provided similar HbA(1c) improvement (both groups, -0.7%) after 52 weeks in patients with type 2 diabetes (T2DM). Significantly fewer patients experienced symptomatic hypoglycemia with sitagliptin (5% of 588 patients) compared to glipizide (32% of 584 patients). Glycemic efficacy and patient characteristics may influence hypoglycemic events. The present analysis evaluated the risk of hypoglycemia with sitagliptin or glipizide after adjusting for the most recently measured HbA(1c) value. METHODS: Data for this analysis were from the aforementioned 52-week, randomized, double-blind, active-controlled study. The primary endpoint was confirmed hypoglycemia (i.e., symptomatic hypoglycemia confirmed with a concurrent fingerstick glucose ≤70 mg/dL [3.9 mmol/L]); the secondary endpoint was severe hypoglycemia (requiring medical or non-medical assistance or symptoms of neuroglycopenia). Complementary log-log regression random effects models with terms for treatment, most recently measured HbA(1c) value, time (i.e., days since randomization), gender, and age (< or ≥65 years) were used to assess adjusted subject-specific treatment effects. RESULTS: Over the full range of HbA(1c) levels and follow-up time, the risk of confirmed hypoglycemic events was lower with sitagliptin compared with glipizide (31 vs. 448 events; adjusted hazard ratio [HR] = 0.05 [95% CI: 0.03, 0.09], p < 0.001). The risk was also lower with sitagliptin in the younger (HR = 0.06 [95% CI: 0.03, 0.12], p < 0.001) and older (HR = 0.02 [0.01, 0.08], p < 0.001) age groups compared with glipizide. For severe hypoglycemia events (2 vs. 22), the risk was lower with sitagliptin (HR = 0.08 [95% CI: 0.01, 0.47]; p = 0.005). LIMITATIONS: The actual time between the HbA(1c) measurement and the hypoglycemic event was variable and not controlled for in the analysis. CONCLUSION: In pre-specified analyses adjusting for the most recently measured HbA(1c) value, there was a substantial reduction in risk for confirmed hypoglycemia with sitagliptin compared to glipizide when added to ongoing metformin therapy in patients with T2DM. The risk of confirmed hypoglycemia was very low in younger and older patients treated with sitagliptin.

Compliance and persistence with concomitant statin and oral antihyperglycemic therapy.

OBJECTIVES: To compare compliance and persistence with statin and oral antihyperglycemic therapies in patients with type 2 diabetes who received concomitant therapy. STUDY DESIGN: Retrospective cohort study using a large US commercial claims database. METHODS: Patients with type 2 diabetes and dispensed prescriptions for both statin and oral antihyperglycemic therapies on the same date in 2006 (index date = first date of such dispensing) were included in the analysis (N = 52,414). Patients were required to have continuous enrollment in the database for 1 year prior to (baseline) and 2 years after (follow-up) index date. The 2-year medication possession ratio (MPR) was compared between statin and oral antihyperglycemic therapy. For the persistence analysis, treatment discontinuation was defined by a gap >30 days between the last date of supply from previous dispensing and subsequent refill. The likelihood of discontinuation of statin versus oral antihyperglycemic therapy was estimated by fitting a robust Cox proportional hazards regression model, adjusted for baseline variables. RESULTS: The 2-year MPR was 70% for statin and 78% for oral antihyperglycemic therapy (P <.0001). The proportion of patients with a 2-year MPR >80% was 52% for statin and 63% for oral antihyperglycemic therapy (P <.0001). The median time to discontinuation of statin was significantly shorter compared with oral antihyperglycemic therapy (284 vs 495 days, P <.001). There was a greater risk to discontinue statin than oral antihyperglycemic therapy (adjusted hazard ratio: 1.47 [95% confidence interval 1.45-1.48]). CONCLUSIONS: Compliance and persistence with statin therapy significantly lagged behind oral antihyperglycemic therapy in patients with type 2 diabetes who were treated concomitantly with both therapies.

Sitagliptin more effectively achieves a composite endpoint for A1C reduction, lack of hypoglycemia and no body weight gain compared with glipizide.

Sitagliptin and glipizide added to metformin provided similar degrees of glycemic efficacy in patients with type 2 diabetes with inadequate glycemic control on metformin monotherapy at 1 year; however, significantly more patients in the sitagliptin group achieved an A1C reduction of >0.5% without hypoglycemia and without an increase in body weight.

Underutilization of statins in patients with type 2 diabetes in US clinical practice: a retrospective cohort study.

OBJECTIVES: To estimate the proportion of patients with type 2 diabetes who were eligible for statin treatment per American Diabetes Association (ADA) recommendations and the proportion who were actually prescribed a statin in US clinical practice. Factors associated with receiving a statin prescription were also determined. METHODS: Patients ≥ 25 years diagnosed with type 2 diabetes or had received prescriptions for antihyperglycemic agents between 7/2006 and 6/2008 were identified within a large electronic medical record database. Eligibility for statin therapy was determined according to 2008 ADA recommendations. Statin use was assessed based on prescription records during a 12-month follow-up period. An adjusted logistic regression analysis was performed to estimate the likelihood of statin use in relation to selected baseline characteristics. RESULTS: Of the 125,464 patients identified, 98.5% were eligible for statin therapy. Only 62.9% received a statin prescription during follow-up period. In an adjusted logistic regression, factors associated with increased likelihood of statin use were older age, male gender, smoking, history of cardiovascular conditions, and receiving an antihyperglycemic, antihypertensive, or anticoagulant prescription at baseline (all p < 0.05). LIMITATIONS: Of the patients who did not receive statin during follow-up, 13% of them were previously on a statin during the baseline period. The reasons for discontinuing therapy are not known. It cannot be excluded that some of these patients were intolerant or had contraindications to statin. The data on prescription dispensing and compliance were not recorded. CONCLUSIONS: Nearly all patients with type 2 diabetes were eligible for statin therapy, but less than two-thirds received statin therapy in US clinical practice. Efforts to minimize this gap are warranted.

The delta e13 isoform of the calcitonin receptor forms a six-transmembrane domain receptor with dominant-negative effects on receptor surface expression and signaling.

The CTRdelta e13 splice variant of the rabbit calcitonin receptor, which lacks the 14 amino acids of the seventh transmembrane domain (TMD) that are encoded by exon 13, is poorly expressed on the cell surface, fails to mobilize intracellular calcium or activate Erk, and inhibits the cell surface expression of the full-length C1a isoform. Nuclear magnetic resonance- and fluorescence-activated cell sorter-based experiments showed that the residual seventh TMD of CTRdelta e13 fails to partition into the lipid bilayer, resulting in an extracellular C terminus. Truncating the receptor after residue 397 to delete the cytoplasmic tail resulted in reduced cell surface expression and an inability to mobilize intracellular calcium or activate Erk, but the truncated receptor did not inhibit C1a cell surface expression. In contrast, when the receptor was truncated after residue 374 to eliminate the entire seventh TMD domain and the C-terminal domain, the resulting receptor reduced the cell surface expression of C1a in a manner similar to that of CTRdelta e13. Thus, normal cell surface expression, mobilization of intracellular calcium, and Erk activation requires the cytoplasmic C-terminal tail of the CTR, whereas the absence of the seventh TMD in the transmembrane helical bundle causes the dominant-negative effect on the surface expression of C1a.

The alternatively spliced deltae13 transcript of the rabbit calcitonin receptor dimerizes with the C1a isoform and inhibits its surface expression.

Numerous alternatively spliced transcripts are generated from the gene for the G protein-coupled calcitonin receptor, and some of the splice variants show differences in receptor-mediated signaling events. This study showed that the deltae13 splice variant of the rabbit calcitonin receptor is expressed together with the more common C1a in osteoclast-like cells. Since other G protein-coupled receptors form homo- or heterodimers, we examined whether heterodimerization of the calcitonin receptor splice variants occurs and, if so, whether it affects the function of the receptor. Homodimers of both isoforms and deltae13/C1a heterodimers were detected by co-immunoprecipitation and fluorescence resonance energy transfer analysis. In contrast to the C1a isoform, the deltae13 isoform was not efficiently transported to the cell surface. When co-expressed with the C1a splice variant, the deltae13 isoform colocalized with the C1a isoform within the cell but not at the cell surface. Furthermore, the overexpression of the deltae13 variant led to a significant reduction of the C1a surface expression and consequently a reduction of the cAMP response and Erk phosphorylation after ligand stimulation. We therefore suggest that the deltae13 variant of the rabbit calcitonin receptor acts to regulate the surface expression of the C1a isoform.

Binding of filamin to the C-terminal tail of the calcitonin receptor controls recycling.

Many G protein-coupled receptors undergo endocytosis, but the mechanisms involved in endocytic sorting and recycling remain to be fully elucidated. We found that the G protein-coupled calcitonin receptor (CTR) undergoes tonic internalization and accumulates within the cell. Using a fluorescence loss in photobleaching assay, we classified these vesicles functionally as recycling vesicles. In a two-hybrid screening, we found that the actin-binding protein filamin interacted with the C-terminal tail of the CTR. The degradation of the receptor was profoundly increased in the absence of filamin or the CTR-filamin interaction. The absence of filamin was also associated with a marked decrease in recycling of the receptor from the endosomes to the cell surface. In contrast, calcitonin-induced inhibition of spontaneous filamin proteolysis was associated with increased recycling of the receptor to the cell surface and decreased degradation of the CTR, suggesting an important role for filamin in the endocytic sorting and recycling of the internalized CTR.