Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus

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

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

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.

“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].”

Studies to date have not demonstrated an overall benefit of fibrates for reduction of cardiovascular or total mortality.

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

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.

“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).”

Because the four drug classes (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.

“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).”

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

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

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.

“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.”

Triglyceride elevation is an independent risk factor for cardiovascular events.

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

Epidemiological, biological, and genetic studies have provided robust evidence of a strong association between elevated TG levels and higher rates of CV events.

“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”

Any benefits to TG-lowering therapies may be most pronounced among statin-treated patients in the higher range of TG elevation (≥200 mg/dL), for whom randomized prospectively designed outcome studies have not been previously conducted prior to REDUCE-IT.

“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.”

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).

“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 FIELD and ACCORD-Lipid trials, creatinine elevations resolved after treatment discontinuation and were not associated with markers of tubular damage.

“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.”

Initial changes in serum creatinine and estimated GFR with fibrates do not affect actual kidney function.

“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].”

Double blinding was reported in 4 studies, with 1 reporting that renal outcomes such as serum creatinine measurements were performed by individuals blinded to study treatment.

“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).”

Fenofibrate causes an acute, sustained rise in plasma/serum creatinine in patients with type 2 diabetes, as shown in the FIELD and ACCORD trials.

“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.”

The ACCORD Lipid trial confirmed 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.

“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].”

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

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

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

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

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

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

In the ACCORD study, the addition of FF to baseline simvastatin therapy failed to demonstrate an improvement in the prospectively selected primary or secondary cardiovascular endpoints.

“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 pre-specified subgroup analyses of ACCORD, there was a suggested heterogeneity in treatment effect according to sex, with a benefit for men (P=0.01 for interaction).

“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 pre-specified subgroup analyses of ACCORD, there was a possible interaction according to lipid subgroup, favoring patients with both a high baseline TG level and a low baseline level of HDLC (P=0.057 for interaction).

“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].”

Two previous trials of fenofibrate showed no significant decrease in cardiovascular risk despite triglyceride lowering of 29% and 26%.

“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.”

The PROMINENT data further highlight the complexity of lipid mediators of residual risk among patients with insulin resistance who are receiving statin therapy.

“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”

Prior CV outcome studies with niacin or fenofibrate did not prospectively enroll patients with elevated TG levels despite statin therapy.

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

Subgroup analyses suggested possible benefits to TG lowering in patients with dyslipidemia.

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

Randomized data from large outcome studies across broad populations regarding pharmacological TG lowering and effect on CV outcomes have been mixed.

“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”

Subgroup and post hoc analyses of outcome studies suggest possible reductions in major CV events with TG-lowering therapy.

“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”

The subgroup data from ACCORD Lipid, AIM-HIGH, and JELIS trials further support a prospective study of EPA in a broader patient population with hypertriglyceridemia, as a potential add-on to statin therapy to reduce residual CV risk.

“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”

Fibrates effectively lower TG and raise HDL-C.

“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.”

Subgroup analyses of FIELD and ACCORD suggested potential benefit in patients with high TG and low HDL-C.

“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].”

Fibrates' CVD benefit has been inconsistent across trials, especially those with background statin therapy use.

“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.”

FIELD and ACCORD studies did not demonstrate significant reductions in MACE in overall study populations.

“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 ACCORD study, addition of fenofibrate to statin therapy did not result in significant beneficial effects on cardiovascular disease risk.

“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”

A subgroup of patients with atherogenic dyslipidemia may derive cardiovascular benefit from the combination of fenofibrate and simvastatin.

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

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 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 ACCORD study, in people with type 2 diabetes 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 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 later studies (FIELD and ACCORD-Lipid), fenofibrate did not reduce major cardiovascular events in the overall study populations.

“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.”

The FIELD, ACCORD and DAIS trials showed a beneficial effect of fibrates on albuminuria in diabetic patients.

“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.”

Fenofibrate has been shown to decrease albuminuria in a mouse model of type 2 diabetes and in humans.

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

Fenofibrate is not associated with significant differences in onset of ESRD.

“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”

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).

“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].”

TG reduction lowers several inflammatory markers associated with CV risk.

“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”

Overall, 4 trials had a Jadad score of 4, 1 scored 3, 2 scored 2, and 1 scored 1.

“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).”

When fibrates are used in combination with statins, no further risk reduction was observed.

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

Systolic blood pressure >140 mmHg or <120 mmHg was related to higher risk of adverse renal outcomes in patients with diabetes when compared with those without diabetes and with high cardiovascular risk.

“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.”

Potential use of fibrates to reduce triglyceride levels is quite limited, due to the risk of myopathy if given with statins and the little benefit demonstrated in randomized controlled trials, aside from sub-group analysis including subjects with very high triglyceride levels.

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

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

Large-scale clinical trials of fibrates have shown negative results for prevention of ASCVD.

“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 BIP, FIELD, and ACCORD-lipid trials, primary endpoints were statistically negative and the clinical efficacy of fibrates on CV events was questioned.

“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”

When fibrate trial data were stratified by lipid profile, patients with hypertriglyceridemia and low HDL cholesterol appeared to have lower cardiovascular risk when fibrates were added to background statin therapy.

“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”

Combining statins with fibrates, niacin, or fish oil has generally not shown cardiovascular benefits beyond statins alone.

“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”

Because both PCSK9 outcome trials had relatively short follow-up and statin trials indicate clinical benefits of LDL-lowering may emerge only after about 1 year, these trials may have underestimated the impact of longer-term treatment.

“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].”

Early preliminary phase III data suggest a reduction in cardiovascular events in line with the achieved LDL-C reduction.

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

Several outcome trials of adding a PCSK9 inhibitor to high-intensity statin reported similar proportional reductions in major vascular events in women and men.

“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].”

Fenofibrate is easy to take, and has shown an excellent safety record in the ACCORD and FIELD trials, although additional CVD benefit has not been demonstrated, and serum creatinine was reversibly increased during treatment.

“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 ACCORD, fenofibrate plus simvastatin did not reduce cardiovascular event rates compared with simvastatin alone in the overall type 2 diabetes population.

“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 long-term trials of people with type 2 diabetes, fibrates raised HDL-C by markedly less than 5%.

“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 ACCORD, the 17% of participants with triglycerides in the upper third (≥2.3 mmol/L or ≥204 mg/dL) and HDL-C in the lower third (≤0.88 mmol/L or ≤34 mg/dL) appeared to benefit from combination therapy.

“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 ACCORD, patients with TG in the highest third (at least 2.3 mmol/L, at least 204 mg/dL) and HDL-C in the lowest third (at most 0.88 mmol/L, at most 34 mg/dL), representing 17% of participants, appeared to benefit from adding fenofibrate to simvastatin.

“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”

The Helsinki Heart Study reported significant reduction in CVD outcomes with gemfibrozil, but FIELD and ACCORD did not show reduction in total CVD outcomes.

“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 long-term intervention trials involving people with type 2 diabetes, fibrates raise HDL-C by only about 5%.

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

The Helsinki Heart Study reported a significant reduction in CVD outcomes with gemfibrozil, whereas FIELD and ACCORD did not show a reduction in total CVD outcomes.

“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”

The ACCORD trial confirmed that patients with triglycerides in the higher third and HDL-C in the lower third, representing 17% of participants, appeared to benefit from adding fenofibrate to simvastatin.

“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”

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.

“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].”

The FIELD and ACCORD studies showed no reduction in total cardiovascular disease outcomes.

“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.”

The ACCORD trial confirmed that patients with triglycerides in the higher third and HDL-C in the lower third, representing 17% of participants, appeared to benefit from adding fenofibrate to simvastatin.

“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”

Gemfibrozil significantly suppressed the incidence of CAD by 34% in middle-aged men in primary prevention with non-HDL-C levels of 200 mg/dL or higher in the Helsinki Heart Study.

“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.”

The SHARP study showed that combination therapy using a statin and ezetimibe in patients with chronic kidney disease suppressed ASCVD incidence compared with placebo.

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

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

The ACCORD lipid trial found no benefit of adding fenofibrate to statin therapy.

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

For patients with diabetes mellitus and statin therapy, fibrates have not been shown to provide any further reduction of risk.

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

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

“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).”