Long-term Trends in Antidiabetes Drug Usage in the U.S.: Real-world Evidence in Patients Newly Diagnosed With Type 2 Diabetes.

OJBECTIVE: To explore temporal trends in antidiabetes drug (ADD) prescribing and intensification patterns, along with glycemic levels and comorbidities, and possible benefits of novel ADDs in delaying the need for insulin initiation in patients diagnosed with type 2 diabetes. RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes aged 18-80 years, who initiated any ADD, were selected (n = 1,023,340) from the U.S. Centricity Electronic Medical Records. Those who initiated second-line ADD after first-line metformin were identified (subcohort 1, n = 357,482); the third-line therapy choices were further explored. RESULTS: From 2005 to 2016, first-line use increased for metformin (60-77%) and decreased for sulfonylureas (20-8%). During a mean follow-up of 3.4 years post metformin, 48% initiated a second ADD at a mean HbA1c of 8.4%. In subcohort 1, although sulfonylurea usage as second-line treatment decreased (60-46%), it remained the most popular second ADD choice. Use increased for insulin (7-17%) and dipeptidyl peptidase-4 inhibitors (DPP-4i) (0.4-21%). The rates of intensification with insulin and sulfonylureas did not decline over the last 10 years. The restricted mean time to insulin initiation was marginally longer in second-line DPP-4i (7.1 years) and in the glucagon-like peptide 1 receptor agonist group (6.6 years) compared with sulfonylurea (6.3 years, P < 0.05). CONCLUSIONS: Most patients initiate second-line therapy at elevated HbA1c levels, with highly heterogeneous clinical characteristics across ADD classes. Despite the introduction of newer therapies, sulfonylureas remained the most popular second-line agent, and the rates of intensification with sulfonylureas and insulin remained consistent over time. The incretin-based therapies were associated with a small delay in the need for therapy intensification compared with sulfonylureas.

Evaluation of the long-term durability and glycemic control of fasting plasma glucose and glycosylated hemoglobin for pioglitazone in Japanese patients with type 2 diabetes.

BACKGROUND: This study applied a pharmacodynamic model-based approach to evaluate the long-term durability and glycemic control of pioglitazone in comparison with other oral glucose-lowering drugs in Japanese type 2 diabetes mellitus (T2DM) patients. SUBJECTS AND METHODS: Japanese T2DM patients were enrolled in a prospective, randomized, open-label, blinded-end point study and received pioglitazone with or without other oral glucose-lowering drugs (excluding another thiazolidinedione [TZD]) (n=293) or oral glucose-lowering drugs excluding TZD (n=294). Treatment was adjusted to achieve glycosylated hemoglobin (HbA1c) <6.9%, and samples for fasting plasma glucose (FPG) and HbA1c were collected over 2.5-4 years. A simultaneous cascading indirect response model structure was applied to describe the time course of FPG and HbA1c. HbA1c levels were described using both an FPG-dependent and an FPG-independent function. To account for titration, drug effects for both treatment groups were implemented using a time-dependent Emax model. RESULTS: Pioglitazone was superior in both time to maximum effect and the magnitude of reduction achieved in FPG and HbA1c. A greater reduction in median FPG (-21 mg/dL vs. -9 mg/dL) was observed with pioglitazone (P<0.05). Maximum drug effect for FPG was predicted to occur earlier (11 months) for pioglitazone than for the control group (14 months). The simulated additional reduction in FPG and HbA1c achieved with pioglitazone was predicted to be maintained beyond the currently observed study duration. CONCLUSIONS: Pioglitazone was found to result in improved glycemic control and durability compared with control treatment. This model-based approach enabled the quantification of differences in FPG and HbA1c for both treatment groups and simulation to evaluate longer-term durability on FPG and HbA1c.

A model-based approach to analyze the influence of UGT2B15 polymorphism driven pharmacokinetic differences on the pharmacodynamic response of the PPAR agonist sipoglitazar.

The pharmacokinetics of sipoglitazar, a peroxisome proliferator activated receptor agonist, are subject to high inter-individual variability resulting from a polymorphism of the UGT2B15 genotype. The aim of the current analysis was to apply a PK-PD model-based approach to evaluate the influence of UGT2B15 driven pharmacokinetic differences on the clinical response. Efficacy and safety of sipoglitazar compared to placebo were assessed in Type 2 Diabetes Mellitus patients in two Phase II randomized, double-blind studies (sipoglitazar once daily: 8, 16, 32, or 64 mg; sipoglitazar twice daily: 16 or 32 mg; rosiglitazone 8 mg once daily and placebo for 13 weeks; n = 780). Changes in fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c) levels over time were described as a function of individual drug exposure using a simultaneous, cascading indirect response model structure. The effects on FPG and HbA1c could successfully be described for placebo, rosiglitazone, and sipoglitazar treated groups in all three UGT2B15 genotypes. Differences in drug effects between genotypes were fully explained by differences in drug exposure. The current PK-PD analysis confirms that UGT2B15 genotype is a major determinant for differences in FPG and HbA1c response to sipoglitazar treatment between Type 2 Diabetes mellitus patients, due to related differences in drug exposure.

Evaluation of the impact of UGT polymorphism on the pharmacokinetics and pharmacodynamics of the novel PPAR agonist sipoglitazar.

Sipoglitazar is a peroxisome proliferator-activated receptor α, δ, and γ agonist. During phase I, a wide distribution of clearance between individuals was observed. Hypothesized to result from a polymorphism in the uridine 5'-diphospate-glucuronosyltransferase (UGT)2B15 enzyme, pharmacogenetic samples were collected from each individual for genotyping UGT2B15 in a subsequent phase I trial in healthy subjects (n = 524) and in 2 phase II trials in type 2 diabetes subjects (n = 627), total genotype frequency was as follows: *1/*1 (22%), *1/*2 (51%), and *2/*2 (27%). The impact of genotype on exposure was assessed using a pharmacokinetic modeling approach; the influence of genotype on efficacy was evaluated using 12-week HbA1c change from baseline. Model analysis demonstrated UGT2B15 genotype accounted significantly for the variability in sipoglitazar clearance; however, a small fraction of subjects had a clearance that could not be explained entirely by genotype. HbA1c drop increased with daily drug dose. When stratified by both dose and genotype, HbA1c drop was larger in the UGT2B15*2/*2 compared with UGT2B15*1/*1 and UGT2B15*1/*2 genotypes (P < .05). In summary, UGT2B15 genotype is a strong predictor for sipoglitazar clearance; a greater clinical response observed in the UGT2B15*2/*2 genotype appears to confirm this. However, overlap in individual rates of clearance across genotypes remains after accounting for genotype.

The effect of genetic polymorphisms in UGT2B15 on the pharmacokinetic profile of sipoglitazar, a novel anti-diabetic agent.

PURPOSE: Sipoglitazar was a novel, azolealkanoic acid derivative that possesses selective activity for the peroxisome proliferator-activated receptors (PPAR) PPARγ, PPARα, and PPARδ. The compound undergoes phase II biotransformation by conjugation catalyzed by UDP-glucuronosyltransferase (UGT). The aim of this analysis was to explore the influence of genetic polymorphism in UGT on the pharmacokinetics of sipoglitazar. METHODS: Three preliminary phase I clinical pharmacology studies were conducted in tandem in healthy human subjects. Genotyping was undertaken in a total of 82 subjects in the phase I program for the purpose of genotyping UGT polymorphisms. Plasma samples were collected for up to 48 h post-dose to characterize the pharmacokinetic profile following a single oral dose of the drug. RESULTS: Plasma concentrations of sipoglitazar and the distribution of dose-normalized individual values for area under the plasma concentration-time curve from time 0 to infinity (AUC(0-∞)) before any stratification were considerably skewed with a multi-modal distribution. The proportion of variability in AUC(0-∞) explained by UGT2B15 was 66.7 % (P < 0.0001); the addition of other genetic or demographic factors was not statistically significant. Subjects homozygous for the UGT2B15 D85Y variant (UGT2B15*2/*2) were exposed to greater plasma concentrations of sipoglitazar than subjects homozygous for the wild-type allele UGT2B15*1/*1 (3.26-fold higher) or heterozygous allele UGT2B15*1/*2 (2.16-fold higher). CONCLUSIONS: These results indicate that sipoglitazar clearance is substantially modified by UGT2B15 enzyme variants, with higher exposure observed in the UGT2B15*2/*2 genotype group.

Comparison of normal and reversed-phase solid phase extraction methods for extraction of beta-blockers from plasma using molecularly imprinted polymers.

A molecularly imprinted polymer (MIP) prepared using propranolol as template, methacrylic acid (MA) and ethylene glycol dimethacrylate (EGDMA) was used to develop SPE methods in "reversed-" and normal phase mode for an analogue of propranolol (M47070) with another analogue (M45655) used as an internal standard. The compounds were also extracted in reversed-phase mode onto a non-imprinted polymer. It was necessary to employ a protein precipitation step ahead of MIP-SPE in order to facilitate downstream analysis. High extraction efficiencies and linear calibration ranges were achieved using both reversed-phase (RP) and normal phase (NP) MIP-based methods. Extraction efficiencies were lower on the non-imprinted polymer indicating stronger retention by the MIP. This stronger retention was attributed to selective imprint-based binding by the MIP that was not available for the non-imprinted polymer. Although clean extracts were obtained in both RP and NP modes, low level interference from template-related impurities or degradation products compromised detection of M47070 at low concentrations for the MIP-based methods. This interference made accuracy of the MIP-based methods poorer at low concentrations. The reversed-phase method showed marginally better accuracy and precision than the normal phase method.