Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus

In the citing paper

“The same analysis also finds that fibrates reduce the incidence of coronary events, but not death.”

In the citing paper

“The ACCORD, LEADER and VA-COOP trials could not confirm that fibrates reduce the incidence of MACE at a 5% significance level, whilst a significant MACE reduction was observed in the FIELD and VA-HIT trials [91–94].”

In the citing paper

“Studies to date have not demonstrated an overall benefit of fibrates for reduction of cardiovascular or total mortality (165-169).”

In the citing paper

“An a priori analysis demonstrated that a decrease in triglyceride and elevation of HDL cholesterol levels was associated with a decrease in primary events, while at the same time, there was an increase in death in females (169).”

In the citing paper

“Because the four drug classes described above (fibrates, niacin, n-3 fatty acids, and statins) have different underlying mechanisms in reducing triglyceride levels, as well as correcting other associated dyslipidemias, there is a considerable potential for use of drug combinations based on complementary mechanisms (169, 186).”

In the citing paper

“With the exception of the FIELD trial, all these trials involved patients who were receiving statins.”

In the citing paper

“Prior CV outcome studies that administered therapies with TG‐lowering effects (niacin or fenofibrate) on top of statin therapy did not reach their primary endpoints.”

In the citing paper

“Clinical and epidemiological studies have demonstrated that triglyceride (TG) elevation is an independent risk factor for increased cardiovascular (CV) events”

In the citing paper

“Epidemiological, biological, and genetic studies have provided robust evidence of a strong association between elevated TG levels and higher rates of CV events.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11”

In the citing paper

“Finally, any benefits to TG‐lowering therapies may be most pronounced among statin‐treated patients in the higher range of TG elevation (ie, ≥200 mg/dL),4, 5, 6 for whom randomized prospectively designed outcome studies have not been previously conducted prior to the REDUCE‐IT study.”

In the citing paper

“Prespecified subgroup analyses suggested heterogeneity in treatment effects with possible benefit for men with both a triglyceride level $204 mg/dL ($2.3 mmol/L) and an HDL cholesterol level #34 mg/dL (#0.9 mmol/L) (159).”

In the citing paper

“Consistently, creatinine elevations observed in the FIELD [77] and ACCORD-Lipid [80] trials resolved after treatment discontinuation and were not associated with markers of tubular damage.”

In the citing paper

“Although these initial changes in creatinine levels and estimated GFR are true, newer data from well-designed randomised controlled trials (RCTs) show that these changes do not affect the actual kidney function [6,7,8].”

In the citing paper

“Double blinding was reported to have been used in 4 studies (32,35,37,38), with 1 reporting that renal outcomes such as serum creatinine measurements were performed by individuals blinded to study treatment (38).”

In the citing paper

“Fenofibrate caused an acute, sustained plasma creatinine increase in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and Action to Control Cardiovascular Risk in Diabetes (ACCORD) studies.”

In the citing paper

“The ACCORD Lipid trial, which examined patients on a background of statin treatment and high use of renin-angiotensin system blockade, recently confirmed our finding that fenofibrate caused an acute plasma creatinine rise and long-term reduction of micro-and macroalbuminuria, with no adverse effect on end-stage renal disease compared with placebo [1,2].”

In the citing paper

“Fenofibrate induces early and reversible reduction in estimated glomerular filtration rate (eGFR)”

In the citing paper

“Evidence supporting the prescription of fibrates for cardiovascular prevention remains debated.”

In the citing paper

“Clinical trials examining the cardiovascular benefits of FF alone or combined with statins have produced mixed results.”

In the citing paper

“In general, the addition of FF to baseline simvastatin therapy failed to demonstrate an improvement in the prospectively selected primary or secondary cardiovascular endpoints which were prospectively monitored (fatal CV events, nonfatal MI, nonfatal stroke etc.).”

In the citing paper

“Only in pre-specified subgroup analyses was there a suggested heterogeneity in treatment effect according to sex, with a benefit for men (P=0.01 for interaction), and a possible interaction according to lipid subgroup, favoring those patients with both a high baseline TG level and a low baseline level of HLDC (P=0.057 for interaction) [2].”

In the citing paper

“Only in pre-specified subgroup analyses was there a suggested heterogeneity in treatment effect according to sex, with a benefit for men (P=0.01 for interaction), and a possible interaction according to lipid subgroup, favoring those patients with both a high baseline TG level and a low baseline level of HLDC (P=0.057 for interaction) [2].”

In the citing paper

“Similarly, a previous trial of niacin 4 and two previous trials of fenofibrate 5,6 showed no significant decrease in cardiovascular risk, although triglyceride levels were lowered by 26%, 29%, and 26%, respectively.”

In the citing paper

“Thus, our data further highlight the complexity of lipid mediators of residual risk among patients with insulin resistance who are receiving statin therapy. 6,23-25”

In the citing paper

“Nonetheless, these studies also did not prospectively enroll patients with elevated TG levels despite statin therapy,6, 12, 13, 14, 15”

In the citing paper

“subgroup analyses suggested possible benefits to TG lowering in patients with dyslipidemia.5, 6”

In the citing paper

“However, randomized data from large outcome studies across broad populations regarding pharmacological TG lowering and effect on CV outcomes have been mixed (Table 4).1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24”

In the citing paper

“Furthermore, TG reduction lowers several inflammatory markers associated with CV risk, and subgroup and post hoc analyses of outcome studies suggest possible reductions in major CV events with TG‐lowering therapy.3, 4, 5, 6, 7, 8, 9, 10, 11”

In the citing paper

“The subgroup data (Table 5) from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid,6 Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes (AIM‐HIGH),5 and JELIS4 trials further support a prospective study of EPA in a broader patient population with hypertriglyceridemia, as exemplified in REDUCE‐IT, as a potent”

In the citing paper

“While these agents effectively lower TG and raise HDL-C, their CVD benefit has been inconsistent across trials, especially those with background statin therapy use.”

In the citing paper

“For example, the FIELD and ACCORD studies did not demonstrate significant reductions in major adverse CVD events (MACE) in the overall study populations, though subgroup analyses suggested potential benefit in patients with high TG and low HDL-C [61, 62].”

In the citing paper

“While these agents effectively lower TG and raise HDL-C, their CVD benefit has been inconsistent across trials, especially those with background statin therapy use.”

In the citing paper

“For example, the FIELD and ACCORD studies did not demonstrate significant reductions in major adverse CVD events (MACE) in the overall study populations, though subgroup analyses suggested potential benefit in patients with high TG and low HDL-C [61, 62].”

In the citing paper

“In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, addition of fenofibrate to statin therapy did not result in significant beneficial effects on CVD risk”

In the citing paper

“a subgroup of patients with atherogenic dyslipidemia may have derive CV benefit from the combination of fenofibrate and simvastatin”

In the citing paper

“In the ACCORD study, in people with type 2 diabetes who were at high risk for ASCVD, the combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal MI, or nonfatal stroke compared with simvastatin alone.”

In the citing paper

“In the ACCORD study, in people with type 2 diabetes who were at high risk for ASCVD, the combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal MI, or nonfatal stroke compared with simvastatin alone (153).”

In the citing paper

“In contrast, later studies conducted largely in patients receiving statin therapy, such as FIELD [77] and ACCORD-Lipid [80], did not demonstrate a reduction in major cardiovascular events with fenofibrate in the overall study populations.”

In the citing paper

“In fact, the FIELD [6], the ACCORD [7] and the DAIS [8] trials showed a beneficial effect of fibrates on albuminuria in diabetic patients; an established marker of early microvascular disease and a predictor of adverse CVD outcomes and kidney disease progression.”

In the citing paper

“Fenofibrate has been shown to decrease albuminuria in a mouse model of type 2 diabetes [10] and in humans [1,2,11].”

In the citing paper

“Data from the ACCORD trial previously demonstrated that fenofibrate induced early and reversible reduction in kidney function without significant differences in onset of ESRD.13, 14”

In the citing paper

“A meta-analysis pooling outcomes from these trials found that fibrates significantly reduce the risk of MACE by −10% (95% CI − 0 to − 18, p = 0.048) [94, 95].”

In the citing paper

“Furthermore, TG reduction lowers several inflammatory markers associated with CV risk, and subgroup and post hoc analyses of outcome studies suggest possible reductions in major CV events with TG‐lowering therapy.3, 4, 5, 6, 7, 8, 9, 10, 11”

In the citing paper

“Overall, 4 trials had a Jadad score of 4 (24,25,32,35), 1 scored 3 (33), 2 scored 2 (29,31), and 1 scored 1 (30).”

In the citing paper

“But when used in combination with statins no further risk reduction was observed,46”

In the citing paper

“However, SBP >140 mmHg or <120 mmHg were related to higher risk of adverse renal outcomes in patients with diabetes when compared with those without diabetes and with high CV risk.”

In the citing paper

“Potential use of fibrates to reduce TG levels is quite limited, due to the risk of myopathy if given with statins and the little benefit demonstrated in RCTs, aside from sub-group analysis including subjects with very high TG levels.200,270,271”

In the citing paper

“In most cases of myopathy or rhabdomyolysis, there are drug interactions with a higher-than-standard dose of statin or combination with gemfibrozil.200”

In the citing paper

“However, fibrates were demonstrated to cause side effects such as liver dysfunction and increase in creatinine levels, and thus large-scale clinical trials of fibrates have shown negative results for prevention of ASCVD.”

In the citing paper

“Furthermore, in subsequent trials, including Benzafibrate Infarction Prevention (BIP) study (using bezafibrate alone) [7], Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study (using fenofibrate alone) [8], and the Action to Control Cardiovascular Risk in Diabetes (ACCORD)-lipid study (using fenofibrate on top of simvastatin) [9], primary endpoints were statistically negative and”

In the citing paper

“Of note, when data from several fibrate trials were stratified by lipid profiles, it appeared that individuals with hypertriglyceridemia and low high-density lipoprotein cholesterol levels may have a reduction in cardiovascular risk with the addition of fibrates to background statin therapy.130,133–135”

In the citing paper

“Combinations of statins with fibrates, niacin, or fish oil have thus far generally failed to demonstrate cardiovascular benefits beyond that achieved with statins alone.128–132”

In the citing paper

“Both studies had relatively short follow-up periods and the evidence from statin trials indicates that the clinical benefits of LDL-lowering may only emerge after about 1 year [51], so these trials may have underestimated the potential impact of longer-term treatment [120,290].”

In the citing paper

“Early preliminary data from phase III trials suggests a reduction of CV events in line with the LDL-C reduction achieved [286,290,291].”

In the citing paper

“Several outcome trials assessing the effects of adding a PCSK9 inhibitor to high-intensity statin therapy have now been reported, with similar proportional reductions in major vascular events in women and men [120,286,290].”

In the citing paper

“This fibrate is easy to take, and has shown an excellent safety record in the Action to Control Cardiovascular Risk in Diabetes and Fenofibrate Intervention and Event Lowering in Diabetes trials, although additional CVD benefit has not been demonstrated, and serum creatinine was reversibly increased during treatment.46,47”

In the citing paper

“In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, 141 in patients with type 2 diabetes the combination therapy of fenofibrate with simvastatin did not reduce the rates of CVD as compared with simvastatin alone when all the patients were analysed together.”

In the citing paper

“However, the HDL-raising effect has been markedly less (,5%) in the long-term intervention trials in people with type 2 diabetes 127,141”

In the citing paper

“However, patients who had both TG levels in the higher third (≥2.3 mmol/L or ≥204 mg/ dL) and an HDL-C level below the lower third (≤0.88 mmol/L or ≤34 mg/dL)-representing 17% of all participants-appeared to benefit from the combination therapy.”

In the citing paper

“The ACCORD trial has confirmed this: patients who had both TG levels in the higher third (≥2.3 mmol/L, ≥204 mg/dL) and an HDL-C level below the lower third (≤0.88 mmol/L, ≤34 mg/ dL)-representing 17% of all participants-appeared to benefit from adding fenofibrate to simvastatin.141”

In the citing paper

“Although the Helsinki Heart Study reported a significant reduction in CVD outcomes with gemfibrozil, neither the FIELD nor the ACCORD study showed a reduction in total CVD outcomes.”

In the citing paper

“However, the HDL-raising effect has been markedly less ( ≏ 5%) in the long-term intervention trials in people with type 2 diabetes 261,262”

In the citing paper

“Although the Helsinki Heart Study reported a significant reduction in CVDoutcomeswith gemfibrozil, neither the FIELD nor the ACCORD study showed a reduction in total CVD outcomes. 261,262,265”

In the citing paper

“The ACCORD trial confirmed this: patients who had both TG levels in the higher third [ ≥ 2.3 mmol/L (204 mg/dL)] and an HDL-C level in the lower third [ ≤ 0.88 mmol/L (34 mg/dL)], representing 17% of all participants, appeared to benefit from adding fenofibrate to simvastatin. 262”

In the citing paper

“For instance, lipid‐modifying agents such as fenofibrate and pemafibrate primarily lower triglycerides but have shown limited cardiovascular benefit, with only a non‐significant trend toward risk reduction in large outcome trials [43, 44].”

In the citing paper

“Although the Helsinki Heart Study reported a significant reduction in CVD outcomes with gemfibrozil, neither the FIELD nor the ACCORD study showed a reduction in total CVD outcomes.”

In the citing paper

“The ACCORD trial confirmed this: patients who had both TG levels in the higher third [!2.3 mmol/L (204 mg/dL)] and an HDL-C level in the lower third [ 0.88 mmol/L (34 mg/ dL)], representing 17% of all participants, appeared to benefit from adding fenofibrate to simvastatin.262”

In the citing paper

“In this study, gemfibrozil significantly suppressed the incidence of CAD by 34% in middle-aged men in primary prevention; these men had non-HDL-C levels of 200 mg/dL or higher.”

In the citing paper

“The SHARP study695), although the design of which does not fit into this “CQ22”, showed that combination therapy using statin and ezetimibe in patients with CKD (including those for both primary prevention and secondary prevention) suppressed ASCVD incidence compared to placebo.”

In the citing paper

“In a meta-analysis including CARDS804), LDL-C-lowering therapy using statins greatly decreases CAD-related mortality, CVD, and cerebral infarction in diabetic patients.”

In the citing paper

“The ACCORD lipid trial found no benefit of adding fenofibrate to statin therapy43”

In the citing paper

“For patients with diabetes mellitus and statin therapy, fibrates have not been shown to provide any further reduction of risk [87–89].”

In the citing paper

“Moreover, combination therapy with statin plus EPA in this high-risk subgroup reduced CVD risk by 53% compared with statin monotherapy, 503 even though the dose of EPA (up to 1.8 g/d) translated into minimal triglyceride reduction (5% between groups).”