Aspirin in type 2 diabetes: a survey of prescribing habits and investigation of effects on inflammation, oxidative stress, insulin resistance and endothelial function
Student thesis: Doctoral Thesis
a) Summary of observational study results Aims: Aspirin is recommended in secondary prevention (SP) in diabetes and macrovascular disease. Recommendation in primary prevention (PP) remains controversial as does the dose of aspirin prescribed. To ascertain whether these controversies are reflected in clinical practice, we conducted a survey of healthcare professionals' views on aspirin prescribing in diabetes. Methods: An anonymous online survey consisting of 26 questions (Likert scale) covering demographic characteristics and aspirin prescribing habits in primary prevention and secondary prevention was circulated via email. Results: 152 people responded with variable response rates: Primary care (96/152, 63%) - mixture of doctors/Diabetes Specialist Nurses; Secondary care were predominantly diabetes specialists (56/152, 37%). Primary prevention (PP): 39/103(37%) did not routinely prescribe aspirin whilst 16/121(13.2%) would consider using aspirin in all diabetes patients as primary prevention. Using Chi-square contingency tables showed that there were differences when prescribing aspirin with regards to hypertension as a risk factor in primary prevention between primary care (20/68[29.4%] opting for aspirin) and secondary care (24/49 [48.98%], p-value-0.03) and doctors and nurses (38/60 vs 16/58, p=0.0009) and also with microalbuminuria - primary care vs secondary care (15/67vs 21/48, p=0.015), and doctors versus nurses (26/60 vs 11/59, p=0.004). Nurses were less likely to prescribe aspirin as primary prevention in smokers (11/57[19.2%] vs 22/60 [36%]; OR-0.41 [0.16-1.03], p=0.042). Secondary prevention (SP): Despite no contraindications 8/125(6.4%) would not give aspirin. 75mg/day or 300mg/day preferred doses in various settings. There were no statistically significant differences between primary and secondary care (62/73 vs 47/52 or 84.9% vs 90.4%, p=0.36) but doctors prescribed aspirin more often compared to nurses (59/67 vs 51/85 or 60% vs 88.1%, p=0.006).In patients with history of peptic ulceration respondents recommended a) use of PPI cover in PP-37/103(35.9%) and SP-60/103(58.3%), b) enteric coated aspirin PP- 13/103(12.6%) and SP-11/103(10.7%), c) not use any anti-platelet agents in PP-53/103(51.5%) and SP-8/103(7.8%). Enteric coated aspirin recommended by respondents as follows: Always-8/109(7.3%), sometimes-16.5%, occasionally-37.6%, and never-35.8%. 89/103(86.5%) had stated their patients had raised issues with them regards aspirin use. 27/103(26.2%) would definitely take aspirin themselves if they had diabetes. The differences were not significant either in a primary prevention setting or a secondary prevention setting when primary care was compared to secondary care but doctors were more likely to prescribe aspirin with PPI cover or in the enteric coated form compared to nurses (48/57[84.2%] vs 23/46 [50%]; OR=0.188 (0.067-0.511), p<0.001). Conclusions: This survey confirmed that the controversy with regards to aspirin use particularly in primary prevention was reflected in a heterogeneous prescribing of aspirin in patients with diabetes. Further clarification and guidance on the optimum dose of aspirin in diabetes is required. b) Summary of Interventional Results Aims: To study the effects of aspirin at different doses on markers of oxidative stress, insulin resistance, dysglycaemia, endothelial function, and vascular inflammation in the primary prevention setting in a population with type 2 diabetes and high risk of cardiovascular disease. Methodology: Following baseline assessment subjects had aspirin (75mg, 300mg, 3.6 gm) or placebo (with minimum 2 week washout) and pre-intervention and post-intervention assessment of markers for metabolic indices (Blood pressure, weight, BMI, Fructosamine, Lipids, Creatinine),oxidative stress (TAOS, FRAP, & Glutathione assays), insulin resistance (HOMA), vascular inflammation (HsCRP, sVCAM-1), and endothelial function (photoplethysmography). Results: (reported in Mean±1SD or Median and Interquartile ranges) (See Table 28, P114) 17 Caucasians, 12 males, 5 females with age range between 40 and 75 years, completed the study. Mean age of the cohort was 57.4±9.1yrs (mean±1SD), with baseline characteristics summarized in Table-6 & Appendix B. Briefly HbA1c was 7.9±1.2%, blood pressure systolic- 130.8±11.5 mmHg & diastolic-73.95±6.97 mmHg, total cholesterol-4.57±1.01 mmol/l, and HDL-C-1.13±0.46 mmol/l. At baseline TAOS concentration was 59.3±9.7 (ascorbate equivalent antioxidant concentration micromolar or AEAC (μM)), total glutathione-302.2±183.3μM, FRAP- 0.86±0.23 (mM Fe II), HOMA-IR-1.41±1.04 Units, HOMA-S–76.27±45.20 %, Fructosamine- 282.9±50.6 μM/l, RI-GTN- 7.17% (3.17-12.83), RI-Salbutamol- 18.5% (13-21.5), Hs-CRP (15 subjects)=0.66 mg/L (0.41 to 2.06 mg/L, Median & IQR), and sVCAM-1 (15 subjects)=487.04 ng/ml (IQR = 450.4 to 572.3). There was a trend towards significance for the TAOS assay with an increase in antioxidant capacity but it did not reach significance. Reduced glutathione (GSH): p=0.12, oxidised glutathione (GSSG): p=0.38, or Glutathione ratio (GSH:GSSG): p=0.367 were not significantly different following any of the interventions. Differences in FRAP were nonsignificant following any of the interventions. Measurements of insulin resistance (HOMA-IR), and insulin sensitivity (HOMA-S) seemed to improve with aspirin 75mgs/day & 300mgs/day but did not reach significance (see figure 18, 19). Neither the different doses of aspirin nor placebo had a significant impact upon glycaemic control (Fructosamine, P=0.39), endothelial function (photoplethysmography, RI-GTN-p=0.36, RI-Salb-p=0.46), Vascular inflammation (Hs-CRPp> 0.05, sVCAM-1>0.05), fasting glucose, BMI, blood pressure, or lipid parameters. Multiple regression analyses showed a good correspondence between the metabolic factors at baseline but were not repeated with different doses as there were no significant differences demonstrated with any of the parameters. Conclusions: Aspirin at the doses studied and over the 2 week duration caused no significant changes in any of the markers studied. Good metabolic control (blood pressure, glycaemia, lipids), and widespread use of statins may be responsible for the lack of effect demonstrated.
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