Treatment patterns and clinical characteristics of patients with type 2 diabetes mellitus according to body mass index: findings from an electronic medical records database.

OBJECTIVE: This study evaluated relationships between glycaemic control, body mass index (BMI), comorbidities and pharmacological treatment in patients with type 2 diabetes mellitus (T2D). RESEARCH DESIGN AND METHODS: This was a retrospective, cross-sectional analysis of Quintiles electronic medical records research data (study period 1 October 2013-30 September 2014). Eligibility included age ≥18 years, T2D diagnosis, and at least one available BMI measurement. RESULTS: The study included 626 386 patients (mean age, 63.8 year; 51.3% female; 78.5% white; 62.6%, BMI ≥30 kg/m2). A1c data were available for 414 266 patients. The proportion of patients with good glycaemic control (A1c ≤6.5) decreased as BMI category increased, ranging from 40.1% of patients with BMI <30% to 30.1% of patients with BMI ≥40. The proportions of patients with poor glycaemic control (A1c >8% and A1c ≥9%) increased with increasing BMI category. Oral antidiabetic drugs (OAD) were the most frequently used (54.4% of patients with A1c values). Among patients using insulin-based therapy, 50% had an A1c ≥8% and 29% had an A1c ≥9% regardless of concomitant OAD or glucagon-like peptide 1 receptor agonist use. Among patients using three or more OADs, 34.3% and 16.1% had A1c values ≥8% and ≥9%, respectively. There was no common trend observed for changes in the proportion of patients with T2D-related comorbidities according to BMI category. The most notable trend was a 7.6% net increase in the percentage of patients with hypertension from BMI <30 to BMI ≥40. CONCLUSIONS: This large dataset provides evidence that roughly one out of four patients with T2D is not well controlled, and the prevalence of poor glycaemic control increases as BMI increases.

Decreasing incidence of type 2 diabetes mellitus in the United States, 2007-2012: Epidemiologic findings from a large US claims database.

AIMS: To explore epidemiological trends in type 2 diabetes mellitus (T2D) in the US between 2007 and 2012 using a large US claims database, with a particular focus on demographics, prevalence, newly-diagnosed cases, and comorbidities. METHODS: Truven Health MarketScan® Databases were used to identify patients with claims evidence of T2D in the years 2007 and 2012. Newly-diagnosed T2D was characterized by an absence of any T2D claims or related drug claims for 6months preceding the index claim. Demographic and comorbidity characteristics of the prevalent and new-onset T2D groups were compared and analyzed descriptively for trends over time. RESULTS: The overall prevalence of T2D remained stable from 2007 (1.24 million cases/15.07 million enrolled; 8.2%) to 2012 (2.04 million cases/24.52 million enrolled; 8.3%), while the percentage of newly-diagnosed cases fell dramatically from 2007 (152,252 cases; 1.1%) to 2012 (147,011 cases; 0.65%). The mean age of patients with prevalent T2D was similar in 2007 (60.6y) and 2012 (60.0y), while the mean age of newly-diagnosed T2D patients decreased by 3years from 2007 (57.7y) to 2012 (54.8y). Hypertension and hyperlipidemia were the most common comorbidities, evident in 50-75% of T2D patients, and increased markedly from 2007 to 2012 in both prevalent and new-onset T2D populations. Cardiovascular disease decreased slightly in prevalent (-0.9%) and new-onset (-2.8%) cases. CONCLUSIONS: This large US health claims database analysis suggests stabilization in prevalence and declining incidence of T2D over a recent 5-year period, a downward shift in age at T2D diagnosis, but increases in several comorbidities.

Longitudinal Changes in Medical Services and Related Costs in a Single Cohort of Patients Newly Diagnosed With Type 2 Diabetes, 2006 to 2012.

PURPOSE: Documenting diabetes treatment patterns and associated costs over time is an important step in gauging the medical and economic impact of current treatment guidelines in a real-world setting. This study was designed to assess changes in medication treatment patterns, health care costs, and comorbidities over a 6-year period after a new diagnosis of type 2 diabetes mellitus (T2DM). This analysis is the first of its kind to observe, over time, a single US cohort of patients newly diagnosed with T2DM. METHODS: This study was a longitudinal assessment of changes in medical services and comorbidities for a single cohort (N = 35,017) of adults newly diagnosed with T2DM in 2006 using claims data from Truven Health Analytics MarketScan(®) databases. Prevalence of diabetes-related comorbidities and utilization/costs of inpatient/outpatient services and medications were analyzed annually for the index (diagnosis) year (Y1) through year 6 (Y6) postindex. Costs were adjusted to 2012 dollars. FINDINGS: From Y1 to Y6, increased prevalence was noted for several T2DM-associated comorbidities: cerebrovascular disease (13%-21%), peripheral vascular disease (3%-10%), nephropathy (3%-13%), and retinopathy (4%-14%). All-cause costs of inpatient and outpatient services and medications were analyzed for the index year (Y1) through Y6 postindex (adjusted to 2012 dollars). Total health care utilization costs (services plus drugs) increased by 33.3% from Y1 ($329.8 million) to Y6 ($439.5 million). Inpatient costs across the entire cohort increased 19.3% from Y1 ($49.8 million; $1421/patient) to Y6 ($59.4 million; $1695/patient) but increased 46.6% among utilizers, despite a decline in inpatient utilizers (7.3% to 5.9% of patients). The percentage of outpatient services utilizers remained stable (Y1, 98.2%; Y6, 97.2%), but total visits increased by 9.1%. Costs of outpatient services increased by 32.5%, from $145 million (Y1) to $192 million (Y6). Total drug costs increased from $101.5 million (Y1) to $114.7 million (Y6) but accounted for a smaller percentage of all health care costs in Y6 versus Y1 (26.1% vs 30.7%). Antidiabetes drugs accounted for a small percentage of overall costs in both Y1 (3.6%) and Y6 (5.3%). IMPLICATIONS: Overall, we found evidence of increasing comorbidities paralleled by large increases in costs for medical services but less for prescriptions. These findings confirm a need for aggressive diabetes management to slow disease progression and minimize comorbidity and economic burdens of the disease.

Effects of Age on Glycemic Control in Patients With Type 2 Diabetes Treated with Insulin Detemir: A Post-Hoc Analysis of the PREDICTIVE™ 303 Study.

BACKGROUND: This post-hoc sub-analysis investigated whether age (<65 years vs ≥65 years) affects glycemic control or hypoglycemic risk in patients with type 2 diabetes mellitus (T2DM) treated with once-daily insulin detemir. METHODS: This was a 26-week, randomized, open-label, phase IV trial involving 2812 patients at 1083 predominantly primary care sites throughout the United States, of which 541 were designated for investigator-led insulin titration. The main efficacy measure was change in HbA1c (A1C) from baseline to Week 26. Patients were stratified by age in the sites designated for the investigator-led titration of insulin detemir. Safety measures included adverse events and change in hypoglycemic event rates from baseline to Week 26. RESULTS: At Week 26, mean A1C and fasting plasma glucose decreased in both groups, but mean differences in change from baseline were not significant between groups. Within the group ≥65 years, significant reductions occurred for all daytime hypoglycemia, but there was no significant change from baseline in the other categories. In the group <65 years, reductions from baseline were significant for all hypoglycemic event categories. Changes in hypoglycemia rates from baseline were not significantly different between the age groups and there was no weight increase in either age group. CONCLUSIONS: This analysis demonstrates that insulin detemir has similar efficacy and safety profiles for patients with T2DM ≥65 years compared with <65 years when treated via an investigator-led algorithm.

Coverage of insulin delivery devices and basal insulin analogs by US managed care organizations.

OBJECTIVE: The perception in the US is that insulin formulations prescribed for type 1 and type 2 diabetes and delivered via insulin pens are more costly to patients than the same or similar products provided in vials, and that basal insulin analogs offered either in pens or vials are likewise more costly to patients than human insulin formulations. This study compares levels of coverage and copays by private and Medicare Part D plans for insulin pens and vials containing basal insulin analogs and for NPH formulations in vials. METHODS: A commercially available formulary database (Access Point, Pinsonault Associates; updated quarterly) was analyzed as of January 2010 for private insurance plans and as of March 2010 for Medicare Part D plans. Analyses were performed for Tier-level coverage and copays per prescription for basal insulin analogs in pens and vials, and NPH in vials. RESULTS: Basal insulin analogs in pens were covered by >91% of private and Part D plans. NPH coverage was reported by >92% of private plans and 69-95% of Part D plans, depending on brand. Irrespective of delivery mode, copays in the majority of private plans for basal insulin analogs and NPH were in the >$10-35 range. Copays were higher in Part D plans, with the majority of plans and subscribers in a >$35-50 range. Prior authorization was required by <10% of insurance plans for insulin analog pen prescriptions, and <3% of plans for insulin analog or NPH prescriptions in vials. LIMITATIONS: This analysis was descriptive, copay stratification was not based on a statistical model but on copay ranges typically used by the plans, and there were no direct correlations performed on the numbers of subscribers per plan vs copay or Tier level. CONCLUSION: These results counter the widely held perception that insurance coverage is less extensive for insulin pens vs vials. Medicare Part D plans often had higher copay requirements than private plans for the same product at the same copay Tier.

Small intestinal cannabinoid receptor changes following a single colonic insult with oil of mustard in mice.

Cannabinoids are known to be clinically beneficial for control of appetite disorders and nausea/vomiting, with emerging data that they can impact other GI disorders, such as inflammation. Post-inflammatory irritable bowel syndrome (PI-IBS) is a condition of perturbed intestinal function that occurs subsequent to earlier periods of intestinal inflammation. Cannabinoid 1 receptor (CB1R) and CB2R alterations in GI inflammation have been demonstrated in both animal models and clinically, but their continuing role in the post-inflammatory period has only been implicated to date. Therefore, to provide direct evidence for CBR involvement in altered GI functions in the absence of overt inflammation, we used a model of enhanced upper GI transit that persists for up to 4 weeks after a single insult by intracolonic 0.5% oil of mustard (OM) in mice. In mice administered OM, CB1R immunostaining in the myenteric plexus was reduced at day 7, when colonic inflammation is subsiding, and then increased at 28 days, compared to tissue from age-matched vehicle-treated mice. In the lamina propria CB2R immunostaining density was also increased at day 28. In mice tested 28 day after OM, either a CB1R-selective agonist, ACEA (1 and 3 mg/kg, s.c.) or a CB2R-selective agonist, JWH-133 (3 and 10 mg/kg, s.c.) reduced the enhanced small intestinal transit in a dose-related manner. Doses of ACEA and JWH-133 (1 mg/kg), alone or combined, reduced small intestinal transit of OM-treated mice to a greater extent than control mice. Thus, in this post-colonic inflammation model, both CBR subtypes are up-regulated and there is increased efficacy of both CB1R and CB2R agonists. We conclude that CBR remodeling occurs not only during GI inflammation but continues during the recovery phase. Thus, either CB1R- or CB2-selective agonists could be efficacious for modulating GI motility in individuals experiencing diarrhea-predominant PI-IBS.

Synthesis and SAR of pyridazinone-substituted phenylalanine amide alpha4 integrin antagonists.

Structural modification and cellular adhesion inhibition activities of pyridazinone-substituted phenylalanine amide alpha(4) integrin antagonists are described. Functionality requirements for the arylamide moiety and the carboxylic acid group were demonstrated. The study also revealed novel structure-activity relationships (SAR) for arylated pyridazinones. A correlation between bioavailability and permeability was also explored. A selected compound showed effectiveness in a mouse leukocytosis study.

Synthesis and biological evaluation of novel pyridazinone-based alpha4 integrin receptor antagonists.

A novel series of pyridazinone-functionalized phenylalanine analogues was prepared and evaluated for inhibition of cellular adhesion mediated by alpha4beta1/VCAM-1 and alpha4beta7/MAdCAM-1 interactions. Concise syntheses were developed and applied for exploration of structure-activity relationships pertaining to the pyridazinone ring as well as the N-acyl phenylalanine scaffold. Potent dual antagonists of alpha4beta1 and alpha4beta7 were generated from an amide subseries; antagonists selective for alpha4beta7 were identified from urea and carbamate-based subseries. The pharmacokinetic properties of selected members of the series have been determined in rats and demonstrate that the use of ester prodrugs and alterations to the amide linkage can lead to improved oral bioavailability in this series. An alpha4beta7-selective member of the carbamate subseries (36c), upon oral administration, demonstrated in vivo efficacy in the mouse DSS colitis model.

Agonists of cannabinoid receptor 1 and 2 inhibit experimental colitis induced by oil of mustard and by dextran sulfate sodium.

Oil of mustard (OM) is a potent neuronal activator that is known to elicit visceral hyperalgesia when given intracolonically, but the full extent to which OM is also proinflammatory in the gastrointestinal tract is not known. We have previously shown that male CD-1 mice given a single administration of 0.5% OM develop a severe colitis that is maximum at day 3 and that gradually lessens until essentially absent by day 14. OM-induced neuronal stimulation is reported to be reduced by cannabinoid agonists, and cannabinoid receptor 1 (CB1R)-/- mice have exacerbated experimental colitis. Therefore, we examined the role of cannabinoids in this OM-induced 3-day model of colitis in CD-1 mice and in a 7-day dextran sulfate sodium (DSS) colitis model in BALB/c mice. In OM colitis, the CB1R-selective agonist ACEA and the CB2R-selective agonist JWH-133 reduced (P < 0.05) colon weight gain (means +/- SE; 82 +/- 13% and 47 +/- 15% inhibition, respectively), colon shrinkage (98 +/- 24% and 42 +/- 12%, respectively), colon inflammatory damage score (49 +/- 11% and 40 +/- 12%, respectively), and diarrhea (58 +/- 12% and 43 +/- 11%, respectively). Histological damage was similarly reduced by these treatments. Likewise, CBR agonists attenuated DSS colitis, albeit at higher doses; ACEA at 10 mg/kg, twice daily, inhibited (P < 0.05) macroscopic and microscopic scores (46 +/- 9% and 63 +/- 7%, respectively); whereas 20 mg/kg, twice daily, of JWH-133 was required to diminish (P < 0.05) macroscopic and microscopic scores (29 +/- 7% and 43 +/- 5%, respectively). CB1R and CB2R immunostaining of colon sections revealed that CB1R in enteric neurons was more intense in colitic vs. control mice; however, CB1R was also increased in the endothelial layer in OM colitis only. CB2R immunostaining was more marked in infiltrated immune cells in OM colitis. These findings validate the OM colitis model with respect to the DSS model and provide strong support to the emerging idea that cannabinoid receptor activation mediates protective mechanisms in experimental colitis. The demonstration of CB1R agonist effects in colitis support the neurogenic nature of the OM-induced colitis model and reinforce the importance of neuronal activation in intestinal inflammation.

Aza-bicyclic amino acid carboxamides as alpha4beta1/alpha4beta7 integrin receptor antagonists.

A series of N-carboxy, N-alkyl, and N-carboxamido azabicyclo[2.2.2]octane carboxamides were prepared and assayed for inhibition of alpha4beta1-VCAM-1 and alpha4beta7-MAdCAM-1 interactions. Potency and alpha4beta1/alpha4beta7 selectivity were sensitive to the substituent R1-R3 in the structures 6, 7, and 8. Several compounds demonstrated low nanomolar balanced alpha4beta1/alpha4beta7 in vitro activity. Two compounds were selected for in vivo leukocytosis studies and demonstrated increases in circulating lymphocytes up to 250% over control.

Acute colitis induction by oil of mustard results in later development of an IBS-like accelerated upper GI transit in mice.

Oil of mustard (OM) is a potent neuronal activator that promotes allodynia and hyperalgesia within minutes of application. In this study, OM was used to induce an acute colitis. We also investigated whether intracolonic OM-induced inflammation alters gastrointestinal (GI) function over a longer time frame as a model of postinflammatory irritable bowel syndrome (PI-IBS). Mice given a single administration of 0.5% OM developed a severe colitis that peaked at day 3, was reduced at day 7, and was absent by day 14. At the peak response, there was body weight loss, colon shrinkage, thickening and weight increases, distension of the proximal colon, and diarrhea. Macroscopic inspection of the distal colon revealed a discontinuous pattern of inflammatory damage and occasional transmural ulceration. Histological examination showed loss of epithelium, an inflammatory infiltrate, destruction of mucosal architecture, edema, and loss of circular smooth muscle architecture. OM administration increased transit of a carmine dye bolus from 58% of the total length of the upper GI tract in untreated age-matched controls to as high as 74% when tested at day 28 post-OM. Mice in the latter group demonstrated a significantly more sensitive response to inhibition of upper GI transit by the mu-opioid receptor agonist loperamide compared with normal mice. OM induces a rapid, acute, and transient colitis and, in the longer term, functional changes in motility that are observed when there is no gross inflammation and thereby is a model of functional bowel disorders that mimic aspects of PI-IBS in humans.

Rationale, design, and synthesis of novel phenyl imidazoles as opioid receptor agonists for gastrointestinal disorders.

A small series of novel, imidazoles 4 have been prepared that exhibit very good binding affinities for the delta and mu opioid receptors (ORs), as well as demonstrate potent agonist functional activity at the delta OR. Representative imidazole 4a (K(i) delta = 0.9 nM; K(i) mu = 55 nM; K(i) kappa = 124 nM; EC(50) delta =13-25 nM) was further profiled for OR related in vivo effects. Compound 4a reduced gastrointestinal (GI) propulsive motility in a dose-dependent and naloxone-reversible manner, based on the results of the mouse glass bead expulsion test (3, 5, and 10 mg/kg, ip) and the mouse fecal pellet output test (1 and 3 mg/kg, ip). Compound 4a showed no analgesic activity as measured by the mouse abdominal irritant test (MAIT) when dosed at 100 mg/kg, sc, but did show significant MAIT activity at doses of both 10 microg (40% inhibition) and 100 microg (100% inhibition) when dosed intracerebroventricularly (icv). Taken together, these in vivo results suggest that 4a acts peripherally when dosed systemically, and that these prototypical compounds may prove promising as medicinal leads for GI indications.

Aza-bicyclic amino acid sulfonamides as alpha(4)beta(1)/alpha(4)beta(7) integrin antagonists.

The design, synthesis, and biological activity of novel alpha(4)beta(1) and alpha(4)beta(7) integrin antagonists, containing a bridged azabicyclic nucleus, are reported. Conformational analysis of targets containing an azabicyclo[2.2.2]octane carboxylic acid and known integrin antagonists indicated that this azabicycle would be a suitable molecular scaffold. Variation of substituents on the pendant arylsulfonamide and phenylalanine groups resulted in potent alpha(4)beta(1)-selective and dual alpha(4)beta(1)/alpha(4)beta(7) antagonists. Potent compounds 11i, 11h, and 14 were effective in the antigen-sensitized sheep model of asthma.