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.
Patients with type 2 diabetes aged 18-80 years, who initiated any ADD, were selected (
= 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,
= 357,482); the third-line therapy choices were further explored.
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 HbA
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,
< 0.05).
Most patients initiate second-line therapy at elevated HbA
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.
The aim of this study was to evaluate the temporal pattern of amputations in patients with type 2 diabetes mellitus (T2DM), the risk of amputations by new and older anti-diabetic drugs (ADDs), and ...the interplay of peripheral artery disease (PAD) with therapy and amputation risk.
Using Centricity Electronic Medical Records from USA, 3 293 983 patients with T2DM were identified: 169 739 received sodium-glucose cotransporter type-2 inhibitors (SGLT-2i; no exposure to incretins); 149 826 received glucagon-like peptide 1 receptor agonists GLP-1RA, no SGLT-2i or dipeptidyl peptidase-4 inhibitor (DPP-4i) exposure; 448 225 received DPP-4i (no exposure to GLP-1RA or SGLT-2i); and 1 954 353 received other ADDs. The proportion of incident amputations per 10 000 adults ranged between 4.7 and 6.8 during 2000-08 and significantly increased to 12.3 in 2017. Over 17 211 719 person-years follow-up post T2DM diagnosis, the rates per 1000 person-years of any and lower limb amputations (LLAs) were similar between SGLT-2i and incretins 95% confidence interval (CI) range: 1.06-1.67, and significantly higher in other groups (95% CI range: 1.96-2.29). In propensity score-adjusted pairwise analyses, the risk of LLA was not higher in SGLT-2i vs. GLP1-RA hazard ratio (HR) (95% CI): 0.88 (0.73, 1.05), and lower in SGLT-2i vs. DPP-4i/other ADD HR (95% CI): 0.65 (0.56, 0.75)/0.43 (0.37, 0.49). The rate of LLA was similar in patients treated with canagliflozin, empagliflozin, or dapagliflozin. Patients with PAD had more than four-fold higher LLA risk (range of 95% CI of HR: 3.6-6.0).
The risk of amputation in patients treated with SGLT-2i and incretins was not higher compared with other ADDs. Pre-existing PAD was the greatest driver of amputation risk.
Hypoglycemia has been associated with an increased risk of cardiovascular (CV) events and all-cause mortality. This study assessed whether, in a nationally representative population, there is an ...association between hypoglycemia, the risk of CV events, and all-cause mortality among insulin-treated people with type 1 diabetes or type 2 diabetes.
This retrospective cohort study used data from the Clinical Practice Research Datalink database and included all insulin-treated patients (≥30 years of age) with a diagnosis of diabetes.
In patients who experienced hypoglycemia, hazard ratios (HRs) for CV events in people with type 1 diabetes were 1.51 (95% CI 0.83, 2.75; P = ns) and 1.61 (1.17, 2.22), respectively, for those with and without a history of CV disease (CVD) before the index date. In people with type 2 diabetes, the HRs for patients with and without a history of CVD were 1.60 (1.21, 2.12) and 1.49 (1.23, 1.82), respectively. For all-cause mortality, HRs in people with type 1 diabetes were 1.98 (1.25, 3.17), and 2.03 (1.66, 2.47), respectively, for those with and without a history of CVD. Among people with type 2 diabetes, HRs were 1.74 (1.39, 2.18) and 2.48 (2.21, 2.79), respectively, for those with and without a history of CVD. The median time (interquartile range) from first hypoglycemia event to first CV event was 1.5 years (0.5, 3.5 years) and 1.5 years (0.5, 3.0 years), respectively, for people with type 1 and type 2 diabetes.
Hypoglycemia is associated with an increased risk of CV events and all-cause mortality in insulin-treated patients with diabetes. The relationship between hypoglycemia and CV outcomes and mortality exists over a long period.
Depression and diabetes commonly co-exist, however the temporal trends in the bidirectional association of both diseases in different sociodemographic setting has not been explored. We investigated ...the trends in prevalence and likelihood of having either depression or type 2 diabetes (T2DM) in African American (AA, or black) and White Caucasians (WC, or white).
In this nationwide population-based study, the US Centricity Electronic Medical Records was used to establish cohorts of >2.5 million adults diagnosed with either T2DM or depression between 2006 and 2017. Logistic regression models were used to investigate ethnic differences in: (a) subsequent probability of depression in individuals with T2DM; and (b) subsequent probability of T2DM in individuals with depression; stratified by age and sex.
A total of 920,771 (15 % black) adults were identified with T2DM and 1,801,679 (10 % black) with depression. AA diagnosed with T2DM were much younger (56 vs. 60 years) and had significantly lower prevalence of depression (17 vs. 28 %). AA diagnosed with depression were slightly younger (46 vs. 48 years) and had significantly higher prevalence of T2DM (21 % vs. 14 %). The prevalence of depression in T2DM increased from 12 % (11, 14) to 23 % (20, 23) in black and 26 (25, 26) to 32 (32, 33) in white.
Depressive AA above 50 years recorded the highest adjusted probability of T2DM (men: 6.3 % (5.8, 7.0), women: 6.3 % (5.9, 6.7)), while diabetic white women below 50 years had the highest probability of depression (20.2 % (18.6, 22.0)). No significant ethnic difference in diabetes was observed for younger adults diagnosed with depression: black 3.1 % (2.7, 3.7); white 2.5 % (2.2, 2.7).
We have observed significant difference in depression between AA and WC recently diagnosed with diabetes consistent across different demographics. Depression in people with diabetes is increasing with significantly higher values among white women younger than 50 years.
•Depression in people with diabetes is increasing significantly.•Ethnic difference in depression among people with T2DM is mostly driven by gender gap.•Ethnic difference in T2DM in people with depression is mostly associated with age.•Younger white women with diabetes are the most likely to develop depression.•Older blacks with depression are the most likely to develop T2DM.
This trial was conducted to determine whether the reduction in microvascular risk and improved glycemic control that had been observed with medical therapy, as compared with conventional dietary ...treatment, in patients with newly diagnosed type 2 diabetes was sustained during 10 years of follow-up. Despite an early loss of glycemic differences, continued microvascular risk reduction and emergent risk reductions for myocardial infarction and death from any cause were observed.
Despite an early loss of glycemic differences, continued microvascular risk reduction and emergent risk reductions for myocardial infarction and death from any cause were observed.
The United Kingdom Prospective Diabetes Study (UKPDS), a randomized, prospective, multicenter trial, showed that intensive glucose therapy in patients with newly diagnosed type 2 diabetes mellitus was associated with a reduced risk of clinically evident microvascular complications and a nonsignificant reduction of 16% in the relative risk of myocardial infarction (P=0.052).
1
In patients whose body weight was more than 120% of their ideal weight
2
and who primarily received metformin, reductions in the risk of myocardial infarction of 39% (P=0.01) and of death from any cause of 36% (P=0.01) were observed. The results of the UKPDS, which were published in 1998, . . .
Aim: Complex associations between T2DM, CKD and HF challenge treatment strategies and results in significant life years loss. Risk of CKD and HF in young- and usual-onset T2DM among White Caucasian ...(WC) and African American (AA) were explored. Methods: From nationally representative EMRs of USA, 1491672 WC and 31133 AA diagnosed with T2DM from 2000-2018 within age 18-39 /40-49/50-59/ 60-69 yrs were identified. The restricted mean time (RMT) to CKD and HF in AA and WC were compared, adjusting for anthropometric and time-varying disease confounders. Results: At T2DM Dx, 10 /12% and 2 /4% of WC /AA had existing CKD and HF; 48 /57% and 39 /32% had hypertension and dyslipidaemia. With mean 5 yrs follow-up, 95% CIs of CKD+HF incidence rates/1000PY were: (23-24) /(37-38) /(53-54) /(82-83) in 18-39 /40-49 /50-59/ 60-69 yrs grps for WC and (30-31) /(47-49) /(66-68) /(93-95) for AA. Compared to WC, AA had significantly higher risk of CKD and HF across all age groups (HR CI range: 1.1-2.4). In AA/WC aged 18-39 yrs, RMT (CI) in yrs to CKD 8.3 (7.8-8.7) /8.9 (8.5-9.2) and HF 9.4 (8.6-10.3) /11.4 (9.8-12.9) was on average only 3.2 /3.2 yrs and 2.7 /3.3 longer compared to those aged 60-69 yrs at Dx (Fig). Conclusion: Developing cardio-renal complications within 10 yrs of young-onset T2DM and significant higher risk among AA compared to WC call for more intense prevention strategies in young-onset population, particularly in AA.
The directional flexibility of proteins is an equilibrium molecular property which is accessible to both experiment and computation. Single molecule force spectroscopy (SMFS) experiments report ...effective directional spring constants to describe the collective anisotropic response of a protein structure to mechanical pulling forces applied along selected axes. On the other hand, computational methods have thus far employed either indirect force based nonequilibrium simulations or coarse-grained elastic network models (ENM) to predict protein directional spring constants. Here, we examine the ability of equilibrium atomistic Molecular Dynamics (MD) simulations to estimate the directional flexibility and mechanical anisotropy of proteins. MD-derived effective directional spring constants are found to correlate well with SMFS spring constants (ρ2 = 0.97–0.99; Adj R 2 = 0.92–0.99) and unfolding forces (ρ2 = 0.85–0.97; Adj R 2 = 0.63–0.91) for five different globular proteins. Specifically, the computed spring constants reproduce the mechanical anisotropy reported by SMFS along five different directions of green fluorescence protein (GFP) and six directions of the immunoglobulin-binding B1 domain of streptococcal protein G (GB1). Further, protein dynamics as captured in MD can be translated into spring constants which can distinguish the N–C directional flexibility of ubiquitin (Ub) from two structurally homologous small ubiquitin-like modifier (SUMO1 and SUMO2) isoforms. We apply our computational framework to study the mechanical anisotropy of Ub along the seven lysine–C-term directions which are functionally relevant. We show that Ub possesses two distinct flexibility scales along these directions which roughly differ by an order of magnitude. Further, our studies reveal that the mechanical anisotropy of Ub is modified in contrasting ways by the binding of two partner proteins (UBCH5A and UEV) which attach and recognize these biomolecular tag proteins. On the basis of equilibrium MD benchmarks for flexibility along 2485 bond vectors in Ub, we propose and validate a new covariance-propagation scheme to extract spring constants from ENM normal modes. We also critically examine the ability of ENM to predict directional flexibility of proteins and suggest modifications to improve these intuitive and scalable descriptions.
Individualized treatment of patients with diabetes requires detailed evaluation of risk factor dynamics at the population level. This study evaluated the persistent glycemic and cardiovascular (CV) ...risk factor burden over 2 years after treatment intensification (TI).
From U.S. Centricity Electronic Medical Records, 276,884 patients with incident type 2 diabetes who intensified metformin were selected. Systolic blood pressure (SBP) ≥130/140 mmHg and LDL ≥70/100 mg/dL were defined as uncontrolled for those with/without a history of CV disease at TI. Triglycerides ≥150 mg/dL and HbA
≥7.5% (58 mmol/mol) were defined as uncontrolled. Longitudinal measures over 2 years after TI were used to define risk factor burden.
With 3.7 years' mean follow-up, patients were 59 years; 70% were obese; 22% had a history of CV disease; 60, 30, 50, and 48% had uncontrolled HbA
, SBP, LDL, and triglycerides, respectively, at TI; and 81% and 69% were receiving antihypertensive and lipid-modifying therapies, respectively. The proportion of patients with consistently uncontrolled HbA
increased from 31% in 2005 to 41% in 2014. Among those on lipid-modifying drugs, 41% and 37% had consistently high LDL and triglycerides over 2 years, respectively. Being on antihypertensive therapies, 29% had consistently uncontrolled SBP. Among patients receiving cardioprotective therapies, 63% failed to achieve control in HbA
+ LDL, 57% in HbA
+ SBP, 55% in LDL + SBP, and 63% in HbA
+ triglycerides over 2 years after TI.
Among patients on multiple therapies for risk factor control, more than one-third had uncontrolled HbA
, lipid, and SBP levels, and more than one-half had two CV risk factors that were simultaneously uncontrolled after TI.
Background. Morbidity and mortality for critically ill patients with infections remains a global healthcare problem. We aimed to determine whether β-lactam antibiotic dosing in critically ill ...patients achieves concentrations associated with maximal activity and whether antibiotic concentrations affect patient outcome. Methods. This was a prospective, multinational pharmacokinetic point-prevalence study including 8 β-lactam antibiotics. Two blood samples were taken from each patient during a single dosing interval. The primary pharmacokinetic/pharmacodynamic targets were free antibiotic concentrations above the minimum inhibitory concentration (MIC) of the pathogen at both 50% (50% f T> MIC ) and 100% (100% f T> MIC ) of the dosing interval. We used skewed logistic regression to describe the effect of antibiotic exposure on patient outcome. Results. We included 384 patients (361 evaluable patients) across 68 hospitals. The median age was 61 (interquartile range IQR, 48–73) years, the median Acute Physiology and Chronic Health Evaluation II score was 18 (IQR, 14–24), and 65% of patients were male. Of the 248 patients treated for infection, 16% did not achieve 50% f T> MIC and these patients were 32% less likely to have a positive clinical outcome (odds ratio OR, 0.68; P=.009). Positive clinical outcome was associated with increasing 50% f T>MIC and 100% f T> MIC ratios (OR, 1.02 and 1.56, respectively; P<.03), with significant interaction with sickness severity status. Conclusions. Infected critically ill patients may have adverse outcomes as a result of inadeqaute antibiotic exposure; a paradigm change to more personalized antibiotic dosing may be necessary to improve outcomes for these most seriously ill patients.
•A unique decision-modeling framework is developed for the ready-made garment industry in Bangladesh.•The framework integrates Delphi method and the fuzzy analytic hierarchy process.•Key supply chain ...disruption factors and drivers are identified.•Supply chain disruption factors and drivers are analyzed thoroughly.•A sensitivity analysis is also conducted to confirm the validity of the framework.
The purpose of this paper is to develop a framework to identify, analyze, and to assess supply chain disruption factors and drivers. Based on an empirical analysis, four disruption factor categories including natural, human-made, system accidents, and financials with a total of sixteen disruption drivers are identified and examined in a real-world industrial setting. This research utilizes an integrated approach comprising both the Delphi method and the fuzzy analytic hierarchy process (FAHP). To test this integrated method, one of the well-known examples in industrial contexts of developing countries, the ready-made garment industry in Bangladesh is considered. To evaluate this industrial example, a sensitivity analysis is conducted to ensure the robustness and viability of the framework in practical settings. This study not only expands the literature scope of supply chain disruption risk assessment but through its application in any context or industry will reduce the impact of such disruptions and enhance the overall supply chain resilience. Consequently, these enhanced capabilities arm managers the ability to formulate relevant mitigation strategies that are robust and computationally efficient. These strategies will allow managers to take calculated decisions proactively. Finally, the results reveal that political and regulatory instability, cyclones, labor strikes, flooding, heavy rain, and factory fires are the top six disruption drivers causing disruptions to the ready-made garment industry in Bangladesh.
PDF
