Linda A. Jaber

Evolution of Peroxisome Proliferator-Activated Receptor Agonists:

OBJECTIVE: To discuss the evolution of peroxisome proliferator-activated receptor (PPAR) agonists from single site to multiple subtype or partial agonists for the treatment of type 2 diabetes, dyslipidemia, obesity, and the metabolic syndrome. DATA SOURCES: Information was obtained from MEDLINE (1966-March 2007) using search terms peroxisome proliferator-activated receptor agonist, PPAR dual agonist, PPAR α/γ agonist, PPAR pan agonist, partial PPAR, and the specific compound names. Other sources included pharmaceutical companies, the Internet, and the American Diabetes Association 64th-66th Scientific Sessions abstract books. STUDY SELECTION AND DATA EXTRACTION: Animal data, abstracts, clinical trials, and review articles were reviewed and summarized. DATA SYNTHESIS: PPAR α, γ, and δ receptors play an important role in lipid metabolism, regulation of adipocyte proliferation and differentiation, and insulin sensitivity. The PPAR dual agonists were developed to combine the triglyceride lowering and high-density lipoprotein cholesterol elevation from the PPAR-α agonists (fibrates) with the insulin sensitivity improvement from the PPAR-γ agonists (thiazolidinediones). Although the dual agonists reduced hemoglobin A1C(A1C) and improved the lipid profile, adverse effects led to discontinued development. Currently, PPAR-γ agonists (GW501516 in Phase I trials), partial PPAR-γ agonists (metaglidasen in Phase II and III trials), and pan agonists (α, γ, δ netoglitazone in Phase II and III trials) with improved cell and tissue selectivity are undergoing investigation to address multiple aspects of the metabolic syndrome with a single medication. By decreasing both A1C and triglycerides, metaglidasen did improve multiple aspects of the metabolic syndrome with fewer adverse effects than compared with placebo. Metaglidasen is now being compared with pioglitazone. CONCLUSIONS: Influencing the various PPARs results in improved glucose, lipid, and weight management, with effects dependent on full or partial agonist activity at single or multiple receptors. Although the dual PPAR compounds have been associated with unacceptable toxicities, new PPAR agonist medications continue to be developed and investigated to discover a safe drug with benefits in multiple disease states.

Antidiabetic prescribing trends and predictors of thiazolidinedione discontinuation following the 2007 rosiglitazone safety alert

This study aimed to examine the change in antidiabetic medication prescribing trends and predictors of thiazolidinedione (TZD) discontinuation six months after the 2007 rosiglitazone safety alert. We performed a retrospective cohort analysis. Patients with two prescriptions for a TZD between 1 January and 21 May 2007, including one covering 21 May 2007, and continuous enrolment during 2006-2007 were identified from the MarketScan database. Multivariate logistic regression analysis was used to compare characteristics between patients who continued and discontinued each TZD. We identified 40,836 and 37,183 individuals with a current prescription for rosiglitazone and pioglitazone, respectively. Significantly more rosiglitazone (53.5%) compared to pioglitazone users (21.4%) discontinued initial therapy six months after the alert (p<0.001). Approximately 23% of patients who discontinued rosiglitazone were switched to pioglitazone, while <1% was switched from pioglitazone to rosiglitazone. Notably, 19.4% of patients who discontinued rosiglitazone and 36.1% of those who discontinued pioglitazone did not have evidence of any antidiabetic drug at follow-up. There was a significant decrease in metformin and an increase in sitagliptin prescribing in patients who discontinued TZDs. Age, sex, region, cardiovascular comorbidities and physician specialty predicted TZD discontinuation. These findings suggest that FDA advisories may be associated with substantial changes in medication use.

Pioglitazone: Effect on CYP3A4 Activity

Clinical studies demonstrate CYP3A4 enzyme induction with troglitazone, a thiazolidinedione derivative structurally related to pioglitazone. The objective of this prospective, open‐label study conducted in healthy volunteers was to evaluate the influence of multiple‐dose pioglitazone therapy on the urinary excretion ratio of 6‐β‐hydroxycortisol to cortisol, an endogenous marker of CYP3A4 activity. Twelve subjects were given pioglitazone hydrochloride 45 mg daily for 14 days. Urine was collected over a 24‐hour period before pioglitazone and after administration of the last tablet. Baseline and posttreatment CYP3A4 activity was assessed with the urinary 6‐β‐hydroxycortisol/cortisol ratio. The mean ± SD 6‐β hydroxycortisol/cortisol ratios before and after treatment were 8.3 ± 4.4 and 9.4 ± 4.0, respectively (p = 0.29). The mean change from baseline was a nonsignificant 20.2%. Nine subjects had a small increase and 3 subjects had a reduction in the ratio. Using the ratio as a marker of CYP3A4 activity, the data support a lack of inductive effect on CYP3A4 by multiple‐dose pioglitazone therapy. Thus, administration of pioglitazone should not result in clinically significant effects on the pharmacokinetics of other CYP3A4 substrates.

Effect of Administration Time of Exenatide on Satiety Responses, Blood Glucose, and Adverse Events in Healthy Volunteers

The objective was to investigate whether varying administration time of exenatide affects the magnitude of satiety responses, blood glucose, and adverse events in healthy volunteers. In this randomized, single‐blind, placebo‐controlled, 4‐period crossover, single‐dose study, the authors measured satiety responses, blood glucose, and adverse events in 20 participants receiving exenatide (10 μg) at either −60 minutes, −30 minutes, or −15 minutes or placebo at −30 minutes relative to a standardized test meal. Compared with placebo, exenatide reduced caloric intake (P = .0059), food intake (P = .0032), and glucose concentrations at 60 (P < .001) and 120 minutes after meals (P = .015). Nausea (63% vs 20%), reduced appetite (43% vs 10%), and vomiting (18% vs 0%) occurred more frequently in exenatide‐treated subjects compared with placebo (P < .05). Significant differences were noted in caloric intake (P = .0149) and food intake (P = .0205) based on the administration time of exenatide, with doses given further from meals producing reduced feeding responses. No such difference was found in postprandial glucose concentrations or adverse events based on timing of exenatide administration. Single‐dose exenatide administered further from mealtime had an increased magnitude on satiety responses in healthy volunteers. Postprandial glucose concentrations and the frequency of adverse events did not differ by the administration time of exenatide.

Aspirin Dose for Prevention of Cardiovascular Disease in Diabetics

OBJECTIVE To determine whether a specific dose of aspirin can be recommended for prevention of cardiovascular disease in patients with diabetes. DATA SOURCE Biomedical literature was accessed through MEDLINE (1990–February 2002). Key terms included diabetes, cardiovascular protection, and aspirin. DATA SYNTHESIS Pharmacologic and clinical studies focusing on the dose–response relationship of aspirin therapy were reviewed. Evidence supports the benefit of low-dose aspirin therapy in reducing vascular events in secondary and primary prevention trials in various patient populations; however, some studies suggest larger doses of aspirin may be needed in certain patients. CONCLUSIONS Review of the evidence does not support a particular dose of aspirin for cardiovascular protection in diabetic patients. Clinical guidelines recommend aspirin therapy in the range of 81–325 mg/d. However, due to an increased prevalence of cardiovascular morbidity and disturbances in coagulation in diabetic patients, the dose of aspirin for prevention of cardiovascular disease in these individuals may be different from that in other populations and requires further evaluation.

Safety and Efficacy of Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors in Type 1 Diabetes: A Systematic Review and Meta-Analysis

AIMS Sodium-glucose cotransporter 2 (SGLT2) inhibitors are currently FDA approved for the management of type 2 diabetes. Our objective was to review the available evidence of the effects of SGLT2 inhibitors on HbA1c, body weight, and total daily insulin dose, as well as their safety profile in patients with type 1 diabetes. METHODS Four randomized controlled trials (RCTs) were identified by conducting a systematic search of PubMed, Embase, Web of Science, Scopus and Cochrane library databases through August 2017. Data on study design, sample size, mean ± standard deviation of HbA1c, body weight, and total daily insulin dose, as well as reported adverse events were extracted. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated using a random-effects model. RESULTS Relative to placebo, therapy with SGLT2 inhibitors led to significant reductions in HbA1c (WMD 0.39; 95% CI 0.27, 0.51), body weight (WMD 2.76; 95% CI 1.11, 4.40), and total daily insulin dose (WMD 5.03; 95% CI 1.83, 8.23). In addition, there was no significant difference in the rate of adverse events. CONCLUSIONS The current study lends supports for the development of SGLT2 inhibitors in combination with insulin as a treatment option for patients with type 1 diabetes.

Diagnostic performance of HbA1c for diabetes in Arab vs. European populations: a systematic review and meta-analysis.

To examine differences in the performance of HbA1c for diagnosing diabetes in Arabs compared with Europeans.

Does Dapagliflozin Affect Energy Intake and Appetite? A Randomized, Controlled Exploratory Study in Healthy Subjects

The primary aims of this study were to assess the effects of dapagliflozin versus placebo on energy intake and appetite ratings in healthy individuals. This was a randomized, single‐blind, placebo‐controlled, 2‐period crossover study. In each period, healthy individuals received either dapagliflozin or placebo for 2 weeks. On assessment days, participants were asked to consume a standard preload breakfast. Appetite ratings were measured with 100‐mm visual analog scales immediately before and during the 4.25‐hour period after breakfast. Energy intake was measured at an ad libitum lunch. Energy intake and appetite responses were assessed at the end of each 2‐week treatment period by mixed‐design analysis of variance. Eighteen individuals completed all assessments (44% female; mean age, 22.8 years; 44% Caucasian; mean BMI, 25.2 kg/m2). There was no difference in energy intake on dapagliflozin compared to placebo (mean difference, −19.8 kcal; P = .516). Mean differences in prebreakfast desire for salty foods (11.3 mm, P = .094) and postbreakfast desire for sweet foods (8.1 mm, P = .054) trended higher with dapagliflozin relative to placebo. Our data do not support an effect of dapagliflozin on energy intake or appetite measures in young, healthy subjects. Although not statistically significant, the size of the mean differences in prebreakfast desire for salty foods and postbreakfast desire for sweet foods on dapagliflozin were larger than placebo and reflect the drugs natriuretic and glucuretic effects. These findings should be further evaluated in patients with type 2 diabetes.