Long-term statin safety and efficacy in secondary prevention: can combination therapy improve outcomes?

2003 ◽  
Vol 4 (5) ◽  
pp. 11-16 ◽  
Author(s):  
Thomas C. Wascher
Keyword(s):  
Combination Therapy ◽  
Secondary Prevention ◽  
Safety And Efficacy

Safety and Efficacy of Pioglitazone/Metformin Combination Therapy in Treatment of Type 2 Diabetes: A Rationale for Earlier Use

2009 ◽  
Vol 1 ◽  
pp. CMT.S2370
Author(s):  
Mark Stolar
Keyword(s):  
Risk Factors ◽  
Insulin Resistance ◽  
Glycemic Control ◽  
Combination Therapy ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Safety And Efficacy

Although multiple new agents for the management of diabetes have become available in the past decade, less than 50% of diabetics in the United States have Hgb A-1-C levels below 7.0% and far fewer at the newer more stringent targets of 6.0% to 6.5%. It has become increasingly clear that the course of Type 2 diabetes is marked by progressive loss of beta-cell function in the setting of relatively fixed insulin resistance. However, treatment algorithms are based on initial monotherapy, usually with metformin, and only move to combination or add-on therapy when treatment has failed and disease has progressed. Few therapeutic agents address both insulin resistance and beta cell function, and no monotherapeutic agent fully addresses any physiologic defect. Metformin, a well-established therapy for diabetes is effective in reducing hepatic and to a lesser extent muscle insulin resistance primarily through AMP-kinase activation, but has only modest effects on long-term beta-cell function. Pioglitazone, an agent in the thiazolidinedione (TZD) class has mechanistically distinct effects on hepatic, muscle and adipocyte insulin resistance, primarily through PPAR-gamma activation, as well as having somewhat greater effects on beta-cell function and durability of glycemic control. The combination of the two agents, either as initial therapy, or as very rapid add-on therapy for the patient who does not achieve target glycemia soon after initiation of metformin is a mechanistically favorable and useful approach to early and durable glycemic control of many new-onset diabetic patients. The efficacy of both metformin and pioglitazone as monotherapy has been well-documented in numerous studies, and combination studies have demonstrated superiority in efficacy of combination therapy over monotherapy with either agent as well as superiority in durability of response over non-TZD based combinations such as sulfonylurea/metformin. Safety issues with metformin remain primarily tolerability based on GI side effects with the rare risk of lactic acidosis in patients with declining renal function. The safety of the TZD class, while well-documented, does carry the risks of volume expansion and resultant CHF, as well as weight gain, which while troublesome, uniquely does not impair glycemic control in these patients. A more recent concern has been raised regarding fracture risk and decreased bone density, and although the relative impact appears small it remains relevant. These risks may be somewhat balanced by more recent studies suggesting a favorable effect of pioglitazone on multiple metabolic risk factors for CVD such as lipids, C-reactive protein, and adipocytokines such as adiponectin. Recent mechanistic and outcome studies such as PROACTIVE and PERISCOPE which suggest there may also be modest benefit on plaque progression and CVD outcomes. Metformin has beneficial effects on metabolic CVD risk factors, such as triglycerides, insulin and PAI-1 and there is a persistent signal of favorable CV outcomes in metformin treated patients. This review will address the safety and efficacy of the agents as monotherapy as well as in combination, and explain the physiologic rationale for earlier or initial use of pioglitazone/metformin combination therapy for newly diagnosed diabetes as well as the long term potential benefit for ongoing management of the treated diabetic.

Abstract 3732: Long-Term Safety and Efficacy of ABT-335 (Fenofibric Acid) in Combination with Statin Therapy for the Treatment of Patients with Mixed Dyslipidemia

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Harold E. Bays ◽  
Peter H. Jones ◽  
Syed M. Mohiuddin ◽  
Maureen T. Kelly ◽  
Hsiaoming Sun ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Extension Study ◽  
Integrated Analysis ◽  
Upper Respiratory Tract ◽  
Moderate Dose ◽  
Open Label ◽  
Safety And Efficacy ◽  
Mean Values ◽  
Mixed Dyslipidemia

Background: The efficacy and safety of ABT-335 + statin combination therapy was demonstrated in three 12-week, controlled studies of patients with mixed dyslipidemia randomized to ABT-335 (135mg) + low or moderate dose rosuvastatin (R), simvastatin (S), or atorvastatin (A), or ABT-335 or statin monotherapy. A subsequent 52-week open label extension study evaluated the long-term safety and efficacy of ABT-335 combined with statins. Methods: Patients who completed 12 weeks of treatment in the 3 controlled studies were eligible to enroll in the 52-week extension study to receive ABT-335 + the moderate dose statin that was used in their initial study: R 20mg, S 40mg, or A 40mg. This was a pre-specified, integrated analysis of patients receiving ABT-335 + statin in the 12- and 52-week studies. Results: Of the 2715 randomized patients, 2316 completed the 12-week studies and 1911 enrolled in the extension study. A total of 2201 patients received at least 1 dose of ABT-335 + statin for a median duration of 364 days; 1139 patients were treated for ≥52 weeks. The incidence of adverse events (AEs) was similar across all 3 combination therapy groups (Table ). The most common AEs were headache, upper respiratory tract infection, nasopharyngitis, and back pain. Rhabdomyolysis was not reported in any group. Patients who were initially randomized to ABT-335 + statin and continued in the extension study (N=979) had sustained improvements in multiple lipids. After 12 and 52 weeks of treatment, combination therapy resulted in mean percent decreases in TG (−45.7% and −47.5%, respectively) and LDL-C (−32.2% and −37.8%), and increases in HDL-C (17.6% and 23.8%). Mean values at 12 and 52 weeks were: TG 141.2 and 136.3 mg/dL; LDL-C 101.6 and 93.5 mg/dL; and HDL-C 45.0 and 47.1 mg/dL, respectively. Conclusions: Long-term ABT-335 + statin combination therapy was generally well tolerated and resulted in comprehensive and sustained improvements in TG, HDL-C, and LDL-C in adults with mixed dyslipidemia. Summary of safety, n/N (%)

scholarly journals Aspirin plus Clopidogrel as Secondary Prevention after Stroke or Transient Ischemic Attack: A Systematic Review and Meta-Analysis

2014 ◽  
Vol 39 (1) ◽  
pp. 13-22 ◽  
Author(s):  
Qinghua Zhang ◽  
Chao Wang ◽  
Maoyong Zheng ◽  
Yanxia Li ◽  
Jincun Li ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Secondary Prevention ◽  
Major Bleeding ◽  
Hemorrhagic Stroke ◽  
Stroke Recurrence ◽  
Short Term ◽  
Bleeding Events ◽  
Vascular Events ◽  
Major Bleeding Events

Background: Antiplatelet agents are the mainstay for secondary prevention of non-cardioembolic stroke. This systematic review examined the safety and efficacy of short-, middle-, and long-term aspirin in combination with clopidogrel as secondary prevention of stroke or transient ischemic attack (TIA) of presumed arterial origin. Methods: PubMed, EmBase, and CENTRAL were searched up to May 2014. Randomized controlled trials (RCTs) that compared aspirin plus clopidogrel versus aspirin or clopidogrel as secondary prevention of stroke or TIA of arterial origin were included. The analyses were stratified into short-term (≤3 months), middle-term (>3 months and <1 year), and long-term (≥1 year). Outcomes were compared using risk ratio (RR) and 95% confidence interval (95% CI). Results: Eight RCTs (20,728 patients) were included in the overall analysis. Compared with aspirin or clopidogrel alone, the complete analysis of all the data indicated that the combination therapy significantly reduced the risk of stroke recurrence (RR, 0.82; 95% CI 0.70-0.96, p = 0.01) and major vascular events (RR, 0.84; 95% CI 0.73-0.96, p < 0.01). But the risk of hemorrhagic stroke (RR, 1.59; 95% CI 1.08-2.33, p = 0.02) and major bleeding (RR, 1.83; 95% CI 1.37-2.45, p < 0.01) was increased. No RCT studied middle-term combination therapy. The analyses were therefore stratified into only two subgroups, short- and long-term treatment. Stratified analysis of short-term treatment showed that relative to monotherapy, the drug combination reduced the risk of stroke recurrence (RR, 0.69; 95% CI 0.59-0.81, p < 0.01) and did not increase the risk of hemorrhagic stroke (RR, 1.23; 95% CI 0.50-3.04, p = 0.65) and major bleeding events (RR, 2.17; 95% CI 0.18-25.71, p = 0.54). Short-term combination therapy was associated with a significantly lower risk of major vascular events (RR, 0.70; 95% CI 0.69 to 0.82, p < 0.01). Stratified analysis of long-term treatment revealed that the combination treatment did not decrease the risk of stroke recurrence (RR, 0.92; 95% CI 0.83-1.03, p = 0.15), but was associated with a significantly higher risk of hemorrhagic stroke (RR, 1.67; 95% CI 1.10-2.56, p = 0.02) and major bleeding events (RR, 1.90; 95% CI 1.46-2.48, p < 0.01). Long-term combination therapy failed to reduce the risk of major vascular events (RR, 0.92; 95% CI 0.84-1.03, p = 0.09). Conclusions: Compared with monotherapy, short-term aspirin in combination with clopidogrel is more effective as secondary prevention of stroke or TIA without increasing the risk of hemorrhagic stroke and major bleeding events. Long-term combination therapy does not reduce the risk of stroke recurrence, and is associated with increased major bleeding events. The clinical applicability of the findings of this systematic review, however, needs to be confirmed in future clinical trials.

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