We report mortality outcomes in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) among people with type 2 diabetes diagnosed within 10 years and no recent ...history of cardiovascular events or cancer.
Overall mortality rates and major causes of death were assessed over an average of 5 years of follow-up. Cause of death was adjudicated centrally by a committee masked to treatment assignment. We examined baseline covariates and the 10-year Framingham Risk Score for associations.
Mortality rate was low (0.59 per 100 participant-years). Participants who died during follow-up were likely to be older, be male, have a history of hypertension, have a history of smoking, and have moderate albuminuria. The two most common underlying causes of death were "cardiovascular-cause" (a composite of underlying causes) (38.6%) and cancer (26.8%). There were no differences by treatment group.
Among people with diabetes of relatively short duration, cause of death was varied. Attention to health risks beyond cardiovascular diseases is warranted.
To describe rescue insulin use and associated factors in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE).
GRADE participants (type 2 diabetes duration <10 ...years, baseline A1C 6.8%-8.5% on metformin monotherapy, N = 5,047) were randomly assigned to insulin glargine U-100, glimepiride, liraglutide, or sitagliptin and followed quarterly for a mean of 5 years. Rescue insulin (glargine or aspart) was to be started within 6 weeks of A1C >7.5%, confirmed. Reasons for delaying rescue insulin were reported by staff-completed survey.
Nearly one-half of GRADE participants (N = 2,387 47.3%) met the threshold for rescue insulin. Among participants assigned to glimepiride, liraglutide, or sitagliptin, rescue glargine was added by 69% (39% within 6 weeks). Rescue aspart was added by 44% of glargine-assigned participants (19% within 6 weeks) and by 30% of non-glargine-assigned participants (14% within 6 weeks). Higher A1C values were associated with adding rescue insulin. Intention to change health behaviors (diet/lifestyle, adherence to current treatment) and not wanting to take insulin were among the most common reasons reported for not adding rescue insulin within 6 weeks.
Proportionately, rescue glargine, when required, was more often used than rescue aspart, and higher A1C values were associated with greater rescue insulin use. Wanting to use noninsulin strategies to improve glycemia was commonly reported, although multiple factors likely contributed to not using rescue insulin. These findings highlight the persistent challenge of intensifying type 2 diabetes treatment with insulin, even in a clinical trial.
To compare the long-term effects of glucose-lowering medications (insulin glargine U-100, glimepiride, liraglutide, and sitagliptin) when added to metformin on insulin sensitivity and β-cell ...function.
In the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) cohort with type 2 diabetes (n = 4,801), HOMA2 was used to estimate insulin sensitivity (HOMA2-%S) and fasting β-cell function (HOMA2-%B) at baseline and 1, 3, and 5 years on treatment. Oral glucose tolerance test β-cell responses (C-peptide index CPI and total C-peptide response incremental C-peptide/incremental glucose over 120 min) were evaluated at the same time points. These responses adjusted for HOMA2-%S in regression analysis provided estimates of β-cell function.
HOMA2-%S increased from baseline to year 1 with glargine and remained stable thereafter, while it did not change from baseline in the other treatment groups. HOMA2-%B and C-peptide responses were increased to variable degrees at year 1 in all groups but then declined progressively over time. At year 5, CPI was similar between liraglutide and sitagliptin, and higher for both than for glargine and glimepiride 0.80, 0.87, 0.74, and 0.64 (nmol/L)/(mg/dL) * 100, respectively; P < 0.001, while the total C-peptide response was greatest with liraglutide, followed in descending order by sitagliptin, glargine, and glimepiride 1.54, 1.25, 1.02, and 0.87 (nmol/L)/(mg/dL) * 100, respectively, P < 0.001. After adjustment for HOMA2-%S to obtain an estimate of β-cell function, the nature of the change in β-cell responses reflected those in β-cell function.
The differential long-term effects on insulin sensitivity and β-cell function of four different glucose-lowering medications when added to metformin highlight the importance of the loss of β-cell function in the progression of type 2 diabetes.
We examined longitudinal associations between emotional distress (specifically, depressive symptoms and diabetes distress) and medication adherence in Glycemia Reduction Approaches in Diabetes: A ...Comparative Effectiveness Study (GRADE), a large randomized controlled trial comparing four glucose-lowering medications added to metformin in adults with relatively recent-onset type 2 diabetes mellitus (T2DM).
The Emotional Distress Substudy assessed medication adherence, depressive symptoms, and diabetes distress in 1,739 GRADE participants via self-completed questionnaires administered biannually up to 3 years. We examined baseline depressive symptoms and diabetes distress as predictors of medication adherence over 36 months. Bidirectional visit-to-visit relationships were also examined. Treatment satisfaction, beliefs about medication, diabetes care self-efficacy, and perceived control over diabetes were evaluated as mediators of longitudinal associations.
At baseline, mean ± SD age of participants (56% of whom were White, 17% Hispanic/Latino, 18% Black, and 66% male) was 58.0 ± 10.2 years, diabetes duration 4.2 ± 2.8 years, HbA1c 7.5% ± 0.5%, and medication adherence 89.9% ± 11.1%. Higher baseline depressive symptoms and diabetes distress were independently associated with lower adherence over 36 months (P < 0.001). Higher depressive symptoms and diabetes distress at one visit predicted lower adherence at the subsequent 6-month visit (P < 0.0001) but not vice versa. Treatment assignment did not moderate relationships. Patient-reported concerns about diabetes medications mediated the largest percentage (11.9%-15.5%) of the longitudinal link between emotional distress and adherence.
Depressive symptoms and diabetes distress both predict lower adherence to glucose-lowering medications over time among adults with T2DM. Addressing emotional distress and concerns about anticipated negative effects of taking these treatments may be important to support diabetes treatment adherence.
BACKGROUND:Stroke is a morbid and potentially mortal complication among patients hospitalized with acute medical illness. The potential of extended-duration thromboprophylaxis with the factor Xa ...inhibitor betrixaban to reduce the risk of stroke compared with standard-dose enoxaparin in this population was assessed in this retrospective APEX trial substudy (Acute Medically Ill Venous Thromboembolism Prevention With Extended Duration Betrixaban).
METHODS:Hospitalized acutely medically ill subjects (n=7513) were randomized in a double-dummy double-blind fashion to either extended-duration oral betrixaban (80 mg once daily for 35–42 days) or standard-dose subcutaneous enoxaparin (40 mg once daily for 10±4 days) for venous thromboprophylaxis. Stroke events were adjudicated by an independent, blinded event adjudication committee.
RESULTS:The mean age of study participants was 76 years; 45% were male; 13% had had a stroke; and 45% had congestive heart failure. There were fewer all-cause strokes (0.54% versus 0.97%; relative risk RR=0.56; 95% confidence interval, 0.32–0.96; P=0.032; adjusted RR=0.43%; number needed to treat=233) and ischemic strokes (0.48% versus 0.91%; RR=0.53; 95% confidence interval, 0.30–0.94; P=0.026; adjusted RR=0.43%; number needed to treat=233) among patients treated with betrixaban versus enoxaparin through 77 days of follow-up. Among high-risk subjects, those with congestive heart failure or ischemic stroke as their index event, betrixaban reduced the risk of all-cause stroke (0.72% versus 1.48%; RR=0.49; 95% confidence interval, 0.26–0.90; P=0.019; adjusted RR=0.76%; number needed to treat=132) and ischemic stroke (0.63% versus 1.38%; RR=0.45; 95% confidence interval, 0.24–0.87; P=0.014; adjusted RR=0.75%; number needed to treat=134) compared with enoxaparin.
CONCLUSIONS:Among hospitalized medically ill patients, extended-duration betrixaban significantly reduced all-cause stroke and ischemic stroke through 77 days of follow-up
CLINICAL TRIAL REGISTRATION:URLhttp://www.clinicaltrials.gov. Unique identifierNCT01583218.
Background The Acute Medically Ill VTE (Venous Thromboembolism) Prevention with Extended Duration Betrixaban (APEX) trial assessed the safety and efficacy of extended-duration thromboprophylaxis ...using betrixaban versus standard dosing of enoxaparin among acutely ill medical patients. The 80 mg betrixaban dose was halved to 40 mg among subjects with severe renal insufficiency and those receiving a concomitant strong P-glycoprotein (P-gp) inhibitor. Methods This analysis assessed the pharmacokinetics, efficacy and safety of full (80 mg) and reduced dose (40 mg) betrixaban relative to enoxaparin in the APEX trial. Results The median concentration of betrixaban among subjects administered the 80 mg dose was higher than that of the 40 mg dose (19 ng/ml vs 11 ng/ml, P < .001). In the primary analysis Cohort 1 (D-dimer ≥2X ULN), the primary efficacy outcome (PEO) (asymptomatic proximal DVT, symptomatic proximal or distal DVT, symptomatic nonfatal PE, or VTE-related death) was significantly reduced among subjects treated with 80 mg of extended dose betrixaban vs enoxaparin 6.27% (95/1516) vs 8.39% (130/1549), RRR = 0.26 (0.04–0.42), P = .023; and similarly in the entire PEO population 4.87% (122/2506) vs 7.06% (181/2562), RRR = 0.30 (0.13–0.44), P = .001. There was no difference in the primary outcome for subjects treated with 40 mg betrixaban dose vs enoxaparin across Cohorts. Additionally, there was no excess of major bleeding associated with either betrixaban dose compared with enoxaparin. Conclusions The 80 mg betrixaban dose achieves higher serum concentrations than the 40 mg dose and is associated with improved efficacy across all cohorts relative to standard dose enoxaparin, without an excess risk of major bleeding in the management of medically ill patients.
Background and purpose: Although its incidence is not high, adolescent hypertension may predict hypertension and increased cardiovascular risk in adulthood. Therefore, the aim of the present study ...was to assess whether cerebrovascular reactivity is altered in adolescent white coat and sustained hypertensive patients compared to healthy teenagers.
Methods: Fifty‐nine normotensive, 47 white coat hypertensive (WCH), and 73 sustained hypertensive (SH) adolescents were studied. WCH and SH were differentiated by ambulatory blood pressure monitoring. Cerebrovascular reactivity was assessed by transcranial Doppler breath‐holding test and was expressed in percent (%) change to the resting cerebral blood flow velocity value.
Results: The percent increase in middle cerebral artery mean blood flow velocity after 30 s of breath holding was lower in both WCH (5.3 ± 3.1%) and SH (9.5 ± 2.6%) groups indicating lower vasodilatory reactivity compared to healthy adolescents (12.1 ± 2.2%). Additionally, serum nitric oxide (NOx) concentrations were lower in both WCH (30.6 ± 11 μM) and SH (30.7 ± 22.4 μM) groups compared to controls (38.8 ± 7.6 μM).
Conclusions: Both white coat and sustained hypertension result in decreased vasodilatory reaction to CO2 in adolescents, suggesting involvement of the cerebral arterioles. The present study underlines the importance of early recognition and proper treatment of adolescent hypertension in order to prevent long‐term cardiovascular complications.
Acrylic acids and alanines substituted with heteroaryl groups at the β‐position were synthesized and spectroscopically characterized (UV, HRMS, 1H NMR, and 13C NMR spectroscopy). The heteroaryl ...groups were furanyl, thiophenyl, benzofuranyl, and benzothiophenyl and contained the alanyl side chains either at the 2‐ or 3‐positions. While the former are good substrates for phenylalanine ammonia‐lyase (PAL), the latter compounds are inhibitors. Exceptions are thiophen‐3‐yl‐alanine, a moderate substrate and furan‐3‐yl‐alanine, which is inert. Possible reasons for these exceptions are discussed. Starting from racemic heteroaryl‐2‐alanines their D‐enantiomers were prepared by using a stereodestructive procedure. From the heteroaryl‐2‐acrylates, the L‐enantiomers of the heteroaryl‐2‐alanines were prepared at high ammonia concentration. These results can be best explained by a Friedel–Crafts‐type electrophilic attack at the aromatic part of the substrates as the initial step of the PAL reaction.
Go organic! Novel substrates and inhibitors of phenylalanine ammonia‐lyase (PAL) from parsley reveal an astonishing broad substrate specificity and support the Friedel–Crafts‐type mechanism (MIO=5‐methylene‐3,5‐dihydroimidazol‐4‐one).
OBJECTIVE
Differences in type 2 diabetes phenotype by age are described, but it is not known whether these differences are seen in a more uniformly defined adult population at a common early stage of ...care. We sought to characterize age-related clinical and metabolic characteristics of adults with type 2 diabetes on metformin monotherapy, prior to treatment intensification.
RESEARCH DESIGN AND METHODS
In the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE), participants were enrolled who had type 2 diabetes duration <10 years, had HbA1c 6.8–8.5%, and were on metformin monotherapy. Participants were randomly assigned to one of four additional glucose-lowering medications. We compared baseline clinical and metabolic characteristics across age categories (<45, 45 to <55, 55 to <65, and ≥65 years) using ANOVA and Pearson χ2 tests.
RESULTS
Within the GRADE cohort (n = 5,047), we observed significant differences by age, with younger adults having greater racial diversity, fewer medications for common comorbidities, lower prevalence of CVD, higher weight and BMI, and more pronounced hyperglycemia and diabetic dyslipidemia and with metabolic profile indicating lower insulin sensitivity (inverse fasting insulin 1/(fasting insulin), HOMA of steady-state insulin sensitivity, Matsuda index) and inadequate β-cell response (oral disposition index) (P < 0.05 across age categories).
CONCLUSIONS
Clinical and metabolic characteristics of type 2 diabetes differ by age within the GRADE cohort. Younger adults exhibit more prominent obesity-related characteristics, including higher obesity levels and lower insulin sensitivity and β-cell compensation. Given the increasing burden of type 2 diabetes and complications, particularly among younger populations, these age-related distinctions may inform risk factor management approaches and treatment priorities. Further study will determine whether age-related differences impact response to therapy.
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