Effective prevention of cardiovascular disease and diabetes‐related events with atorvastatin in Japanese elderly patients with type 2 diabetes mellitus: Adjusting for treatment changes using a marginal structural proportional hazards model and a rank‐preserving structural failure time model

Abstract

Aim:To assess the preventive effect of atorvastatin on cardiovascular disease and on diabetes-related events in elderly type 2 diabetic patients enrolled in the Japanese Elderly Diabetes Intervention Trial (J-EDIT).Methods: Data were obtained from 1173 patients aged 65-84 years who were enrolled in the J-EDIT. Patients were followed prospectively for 6 years to determine the effects of atorvastatin on serum cholesterol levels, and cardiovascular and diabetes-related events. Because the study protocol allowed atorvastatin to be prescribed according to the clinical needs of each patient, we regarded the J-EDIT data as if they came from a cohort study. We adjusted for clinical characteristics during the study as time-dependent confounders using two methods, inverse-probability-of-treatment (IPT) weighting and g-estimation method. Results: The total follow-up period was 5310.8 person-years (5.7 years of median follow up), during which 202 patients received atorvastatin treatment. Atorvastatin was associated with moderate reductions in cholesterol levels: 24.2 mg/dL for total cholesterol, 22.9 mg/dL for low-density lipoprotein (LDL) cholesterol and 24.3 mg/dL for non-highdensity lipoprotein cholesterol at the first post-treatment year. As a result, the proportion of patients who achieved targeted levels of LDL cholesterol clearly increased after atorvastatin treatment. Eight patients in 476.6 person-years among atorvastatin-treated and 113 untreated patients in 4721.4 person-years had cardiovascular events (the composite endpoint of fatal/non-fatal myocardial infarction, angina pectoris, coronary intervention, and fatal/non-fatal cerebrovascular disease); hazard ratio (HR) = 0.48, 95% confidence interval (CI) = 0.19-1.16, P = 0.10, and HR = 0.32, 95% CI = 0.05-1.87, P = 0.21 from IPT weighting and g-estimation method, respectively. Furthermore, seven in 475.0 person-years among atorvastatin-treated and 149 untreated patients in 4682.4 person-years had diabetes-related events (the composite end-point of sudden death, renal failure death, death as a result of hyperglycemia or hypoglycemia, diabetic gangrene and congestive heart failure in addition to cardiovascular event); HR = 0.30, 95% CI = 0.12-0.77, P = 0.01, and HR = 0.40, 95% CI = 0.09-0.89, P = 0.03 from IPT weighting and g-estimation method, respectively. When cardiovascular events were further differentiated into coronary vascular and cerebrovascular events, atorvastatin especially decreased the cerebrovascular risk. Conclusion:The use of atorvastatin to lower cholesterol levels in elderly Japanese patients with type 2 diabetes mellitus appears to reduce the risk of cardiovascular and diabetes-related events. Geriatr Gerontol Int 2012; 12 (Suppl. 1): 88-102.

Is Atorvastatin Associated with New Onset Diabetes or Deterioration of Glycemic Control? Systematic Review Using Data from 1.9 Million Patients

“…The mean average age of the subjects by study (for which age data were available) ranged between 44 and 74.9 years. Thirteen studies included only patients with type 2 diabetes mellitus [ 2 , 3 , 10 , 11 , 17 – 19 , 21 , 27 – 30 , 33 ], while 3 studies included only patients with type 1 diabetes mellitus [ 13 , 20 , 24 ]. The average time since diagnosis of diabetes ranged between 4 and 26 years.…”

Atorvastatin improves systolic function, but does not prevent the development of dilated cardiomyopathy in streptozotocin-induced diabetic rats

“…This statin also improves leg artery stiffness in type 2 diabetics [Shinohara et al 2005], and appears to reduce the risk of CV and diabetes-related events in elderly Japanese patients with type 2 diabetes [Shinozaki et al 2012]. Atorvastatin does not improve endothelial function, however, in type 2 diabetic patients with average cholesterol levels and no prior CV disease [Tantikosoom et al 2005], and it does not prevent new-onset diastolic dysfunction in a rat model of insulin resistance [Chen et al 2007].…”

Application of causal inference methods in the analyses of randomised controlled trials: a systematic review

“… Concomitant medication What is the effect of use of beta blockers, diuretics, and statins on onset of Type 2 diabetes? MSM with IPW [ 3 ] Use of statins and diuretics found to increase risk of diabetes onset Shinozaki (2012) [ 27 ] Diabetes Effect of intensive (target HbA1c 6.9 or less, BMI < 25, BP < 130/80) vs conventional treatment (no target levels) strategies for type 2 diabetes in elderly patients on risk of morality, cardiovascular events and other diabetes related endpoints Concomitant medication Is there a preventative effect of atorvastatin on cardiovascular disease and on diabetic vascular complications? MSM with IPW, structural nested failure time models with g-estimation [ 3 , 53 ] Atorvastatin estimated to be protective against both cardiovascular events and diabetes related events, though confidence intervals for cardiovascular events were very wide.…”

“…Three of the other studies in cardiovascular disease [ 23 – 25 ] and the mental health application [ 26 ] also used MSMs with IPW. Finally, a study by Sinozaki et al [ 27 ] investigated the effect of atorvostatin on various cardiovascular outcomes (including low-density lipoprotein (LDL) cholesterol, composite cardiovascular event endpoints, diabetes-related endpoints) by using both MSMs with IPW and g-estimation of structural nested models. The authors found that both methods produced relatively similar results for all outcomes examined.…”