Kidney Biomarkers and Decline in eGFR in Patients with Type 2 Diabetes.

BACKGROUND AND OBJECTIVES: Biomarkers may improve identification of individuals at risk of eGFR decline who may benefit from intervention or dialysis planning. However, available biomarkers remain incompletely validated for risk stratification and prediction modeling. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We examined serum cystatin C, urinary kidney injury molecule-1 (uKIM-1), and urinary neutrophil gelatinase-associated lipocalin (UNGAL) in 5367 individuals with type 2 diabetes mellitus and recent acute coronary syndromes enrolled in the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) trial. Baseline concentrations and 6-month changes in biomarkers were also evaluated. Cox proportional regression was used to assess associations with a 50% decrease in eGFR, stage 5 CKD (eGFR<15 ml/min per 1.73 m2), or dialysis. RESULTS: eGFR decline occurred in 98 patients (1.8%) over a median of 1.5 years. All biomarkers individually were associated with higher risk of eGFR decline (P<0.001). However, when adjusting for baseline eGFR, proteinuria, and clinical factors, only baseline cystatin C (adjusted hazard ratio per 1 SD change, 1.66; 95% confidence interval, 1.41 to 1.96; P<0.001) and 6-month change in urinary neutrophil gelatinase-associated lipocalin (adjusted hazard ratio per 1 SD change, 1.07; 95% confidence interval, 1.02 to 1.12; P=0.004) independently associated with CKD progression. A base model for predicting kidney function decline with nine standard risk factors had strong discriminative ability (C-statistic 0.93). The addition of baseline cystatin C improved discrimination (C-statistic 0.94), but it failed to reclassify risk categories of individuals with and without eGFR decline. CONCLUSIONS: The addition of cystatin C or biomarkers of tubular injury did not meaningfully improve the prediction of eGFR decline beyond common clinical factors and routine laboratory data in a large cohort of patients with type 2 diabetes and recent acute coronary syndrome. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_01_16_CJASNPodcast_18_3_G.mp3.

Relationship of glycated haemoglobin and reported hypoglycaemia to cardiovascular outcomes in patients with type 2 diabetes and recent acute coronary syndrome events: The EXAMINE trial.

AIMS: To investigate relationships between glycated haemoglobin (HbA1c) and reported hypoglycaemia and risk of major adverse cardiovascular events (MACE). METHODS: The EXAMINE trial randomized 5380 patients with type 2 diabetes (T2DM) and a recent acute coronary syndrome (ACS) event, in 49 countries, to double-blind treatment with alogliptin or placebo in addition to standard of care. We used Cox proportional hazards models to analyse relationships among MACE, HbA1c levels and hypoglycaemic events. RESULTS: Patients randomized to alogliptin achieved lower HbA1c levels than the placebo group in all baseline HbA1c categories without differences in hypoglycaemia rates. No systematic change was found in MACE rates according to baseline HbA1c (Pinteraction = 0.971) or HbA1c category at 1 month. Patients in the combined treatment groups (n = 5380) who experienced serious hypoglycaemia (n = 34) had higher MACE rates than those who did not (35.3% vs 11.4%, adjusted hazard ratio [HR] 2.42, 95% confidence interval [CI] 1.27-4.60; P = .007), although the association was less strong when analysing only events after the hypoglycaemic event (adjusted HR 1.60, 95% CI 0.80, 3.20). CONCLUSIONS: There were no relationships between baseline HbA1c levels or HbA1c levels after 1 month of treatment and the risk of MACE. Alogliptin improved glycaemic control without increasing hypoglycaemia. Reported events of hypoglycaemia and serious hypoglycaemia were associated with MACE. These data underscore the safety of alogliptin in improving glycaemic control in T2DM post-ACS. Further study of hypoglycaemia as an independent risk factor for MACE in patients with T2DM and coronary disease is needed.

Angiotensin-Converting Enzyme Inhibitor Use and Major Cardiovascular Outcomes in Type 2 Diabetes Mellitus Treated With the Dipeptidyl Peptidase 4 Inhibitor Alogliptin.

Activation of the sympathetic nervous system when there is dipeptidyl peptidase 4 inhibition in the presence of high-dose angiotensin-converting enzyme (ACE) inhibition has led to concerns of potential increases in cardiovascular events when the 2 classes of drugs are coadministered. We evaluated cardiovascular outcomes from the EXAMINE (Examination of Cardiovascular Outcomes With Alogliptin versus Standard of Care) trial according to ACE inhibitor use. Patients with type 2 diabetes mellitus and a recent acute coronary syndrome were randomly assigned to receive the dipeptidyl peptidase 4 inhibitor alogliptin or placebo added to existing antihyperglycemic and cardiovascular prophylactic therapies. Risks of adjudicated cardiovascular death, nonfatal myocardial infarction and stroke, and hospitalized heart failure were analyzed using a Cox proportional hazards model in patients according to ACE inhibitor use and dose. There were 3323 (62%) EXAMINE patients treated with an ACE inhibitor (1681 on alogliptin and 1642 on placebo). The composite rates of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke were comparable for alogliptin and placebo with ACE inhibitor (11.4% versus 11.8%; hazard ratio, 0.97; 95% confidence interval, 0.79-1.19; P=0.76) and without ACE inhibitor use (11.2% versus 11.9%; hazard ratio, 0.94; 95% confidence interval, 0.73-1.21; P=0.62). Composite rates for cardiovascular death and heart failure in patients on ACE inhibitor occurred in 6.8% of patients on alogliptin versus 7.2% on placebo (hazard ratio, 0.93; 95% confidence interval, 0.72-1.2; P=0.57). There were no differences for these end points nor for blood pressure or heart rate in patients on higher doses of ACE inhibitor. Cardiovascular outcomes were similar for alogliptin and placebo in patients with type 2 diabetes mellitus and coronary disease treated with ACE inhibitors.

Cardiovascular Mortality in Patients With Type 2 Diabetes and Recent Acute Coronary Syndromes From the EXAMINE Trial.

OBJECTIVE: We evaluated the risk of cardiovascular (CV) death in all Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) study participants and in those who experienced an on-study, major nonfatal CV event. RESEARCH DESIGN AND METHODS: The study randomly assigned 5,380 patients with type 2 diabetes to alogliptin or placebo within 15 to 90 days of an acute coronary syndrome (ACS). Deaths and nonfatal CV events (myocardial infarction [MI], stroke, hospitalized heart failure [HHF], and hospitalization for unstable angina [UA]) were adjudicated. Patients were monitored until censoring or death, regardless of a prior postrandomized nonfatal CV event. Time-updated multivariable Cox models were used to estimate the risk of death in the absence of or after each nonfatal event. RESULTS: Rates of CV death were 4.1% for alogliptin and 4.9% for placebo (hazard ratio [HR] 0.85; 95% CI 0.66, 1.10). A total of 736 patients (13.7%) experienced a first nonfatal CV event (5.9% MI, 1.1% stroke, 3.0% HHF, and 3.8% UA). Compared with patients not experiencing a nonfatal event, the adjusted HR (95% CI) for death was 3.12 after MI (2.13, 4.58; P < 0.0001) 4.96 after HHF (3.29, 7.47; P < 0.0001), 3.08 after stroke (1.29, 7.37; P = 0.011), and 1.66 after UA (0.81, 3.37; P = 0.164). Mortality rates after a nonfatal event were comparable for alogliptin and placebo. CONCLUSIONS: In patients with type 2 diabetes and a recent ACS, the risk of CV death was higher after a postrandomization, nonfatal CV event, particularly heart failure, compared with those who did not experience a CV event. The risk of CV death was similar between alogliptin and placebo.

Initial combination therapy with alogliptin and pioglitazone in drug-naïve patients with type 2 diabetes.

OBJECTIVE: To assess the efficacy and tolerability of alogliptin plus pioglitazone for initial combination therapy in drug-naïve type 2 diabetic patients. RESEARCH DESIGN AND METHODS: This 26-week, double-blind, parallel-group study randomized 655 patients with inadequately controlled type 2 diabetes to four arms: 25 mg alogliptin (A25) q.d. monotherapy, 30 mg pioglitazone (P30) q.d. monotherapy, or 12.5 (A12.5) or 25 mg alogliptin q.d. plus pioglitazone (P30) q.d. combination therapy. Primary efficacy was A1C change from baseline with the high-dose combination (A25+P30) versus each monotherapy. RESULTS: Combination therapy with A25+P30 resulted in greater reductions in A1C (-1.7±0.1% from an 8.8% mean baseline) vs. A25 (-1.0±0.1%, P<0.001) or P30 (-1.2±0.1%, P<0.001) and in fasting plasma glucose (-2.8±0.2 mmol/l) vs. A25 (-1.4±0.2 mmol/l, P<0.001) or P30 (-2.1±0.2 mmol/l, P=0.006). The A25+P30 safety profile was consistent with those of its component monotherapies. CONCLUSIONS: Alogliptin plus pioglitazone combination treatment appears to be an efficacious initial therapeutic option for type 2 diabetes.

Alogliptin use in elderly people: a pooled analysis from phase 2 and 3 studies.

OBJECTIVES: To compare the efficacy and safety of alogliptin, a dipeptidyl peptidase-4 (DPP-4) enzyme inhibitor, in elderly (> or =65) and younger (<65) patients with type 2 diabetes mellitus. DESIGN: Pooled analysis of six randomized, double-blind, placebo-controlled studies of alogliptin. PARTICIPANTS: Patients aged 18 to 80 with type 2 diabetes mellitus and inadequate glycemic control. INTERVENTIONS: Elderly (mean age 70.0; n=455) and younger (mean age 51.8; n=1,911) patients received alogliptin 12.5 mg (n=922), alogliptin 25 mg (n=910), or placebo (n=534) for 26 weeks (12 weeks in a Phase 2 study). The studies evaluated alogliptin as monotherapy and coadministered with pioglitazone, glyburide, metformin, or insulin. MEASUREMENTS: Efficacy endpoints included change from baseline in glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), weight, and lipid values. Safety variables included hypoglycemic events, adverse events, and blood pressure. RESULTS: Least-squares mean HbA1c decreased from baseline by 0.7% and 0.8% in elderly patients receiving alogliptin 12.5 and 25 mg, respectively, and 0.5% and 0.6%, respectively, in younger patients (P<.001 for both alogliptin doses vs placebo for both age groups P=.70 for 12.5 mg and .68 for 25 mg for differences between age groups). Results were similar for FPG. Incidence of hypoglycemia was 8.3% or less in all alogliptin groups (< or =10.5% for placebo), with no apparent difference between elderly and younger patients. Changes in weight were negligible in all treatment groups in both age categories. The safety profiles of alogliptin were similar in the age and dose groups. CONCLUSION: Alogliptin was effective and well tolerated in the elderly patients enrolled in these studies. Improvements in HbA1c were similar to those seen in younger patients, and no increase in the risk of hypoglycemia, weight gain, or other adverse events was apparent in elderly patients.

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin added to pioglitazone in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study.

OBJECTIVES: To evaluate the efficacy and safety of alogliptin in patients with type 2 diabetes inadequately controlled by therapy with a thiazolidinedione (TZD). RESEARCH DESIGN AND METHODS: In a multicenter, double-blind, placebo-controlled clinical study, 493 patients 18-80 years old with inadequate glycemic control after stabilization (i.e., glycosylated hemoglobin [HbA(1c)] 7.0-10.0%) despite ongoing treatment with a TZD were randomly assigned (2:2:1) to treatment with pioglitazone plus alogliptin 12.5 mg, alogliptin 25 mg or placebo once daily. Concomitant therapy with metformin or sulfonylurea at prestudy doses was permitted. MAIN OUTCOME MEASURES: The primary efficacy endpoint was change in HbA(1c) from baseline to Week 26. Secondary endpoints included changes in fasting plasma glucose (FPG) and body weight, and incidences of marked hyperglycemia (FPG > or = 200 mg/dL [11.10 mmol/L]) and rescue for hyperglycemia. RESULTS: Least squares (LS) mean change in HbA(1c) was significantly (p < 0.001) greater for alogliptin 12.5 mg (-0.66%) or 25 mg (-0.80%) than for placebo (-0.19%). A significantly (p < or = 0.016) larger proportion of patients achieved HbA(1c) < or = 7% with alogliptin 12.5 mg (44.2%) or 25 mg (49.2%) than with placebo (34.0%). LS mean decreases in FPG were significantly (p = 0.003) greater with alogliptin 12.5 mg (-19.7 mg/dL [-1.09 mmol/L]) or 25 mg (-19.9 mg/dL [-1.10 mmol/L]) than with placebo (-5.7 mg/dL [-0.32 mmol/L]). The percentage of patients with marked hyperglycemia was significantly (p < 0.001) lower for alogliptin (< or =25.0%) than placebo (44.3%). The incidences of overall adverse events and hypoglycemia were similar across treatment groups, but cardiac events occurred more often with active treatment than placebo. CONCLUSIONS: Addition of alogliptin to pioglitazone therapy significantly improved glycemic control in patients with type 2 diabetes and was generally well tolerated. The study did not evaluate the effect of combination therapy on long-term clinical outcomes and safety. CLINICAL TRIAL REGISTRATION: NCT00286494, clinicaltrials.gov.

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes and inadequate glycemic control: a randomized, double-blind, placebo-controlled study.

OBJECTIVE: To evaluate the dipeptidyl peptidase-4 (DPP-4) inhibitor alogliptin in drug-naïve patients with inadequately controlled type 2 diabetes. RESEARCH DESIGN AND METHODS: This double-blind, placebo-controlled, multicenter study included 329 patients with poorly controlled diabetes randomized to once-daily treatment with 12.5 mg alogliptin (n = 133), 25 mg alogliptin (n = 131), or placebo (n = 65) for 26 weeks. Primary efficacy end point was mean change from baseline in A1C at the final visit. RESULTS: At week 26, mean change in A1C was significantly greater (P < 0.001) for 12.5 mg (-0.56%) and 25 mg (-0.59%) alogliptin than placebo (-0.02%). Reductions in fasting plasma glucose were also greater (P < 0.001) in alogliptin-treated patients than in those receiving placebo. Overall, incidences of adverse events (67.4-70.3%) and hypoglycemia (1.5-3.0%) were similar across treatment groups. CONCLUSIONS: Alogliptin monotherapy was well tolerated and significantly improved glycemic control in patients with type 2 diabetes, without raising the incidence of hypoglycemia.