<< Algorithm Module C

Q2. Pharmacotherapy: Combination Therapy

objective

Achieve lipid goals through the use of combination pharmacologic agents.

background

Occasionally, a statin alone is insufficient to reach a patient's LDL goal.  When this occurs, a more potent statin or higher dosage may be prescribed, or other lipid lowering agents may be added to the regimen.  If the choice is to combine agents, the achieved reduction in LDL will be the sum of the lowering provided by each drug.

To date, there have been no large, published clinical endpoint trials evaluating the benefits of combination pharmacologic therapies for dyslipidemia.  There are, however, angiographic and LDL-C lowering trials demonstrating benefit with certain drug combinations.  As a result of the lack of clinical outcome data to support an advantage of combination drug therapy over monotherapy with statins, careful consideration must be given to the risk of toxicity in individual patients before exposing them to combination therapy.

Some lipid-lowering treatments (e.g., statins plus fibrates) are known to be associated with an increased risk for muscle toxicity when used in combination.  Several factors have been identified as increasing an individual’s risk for muscle toxicity with statins and fibrates including drug interactions, advanced age, impaired renal function, female gender, alcoholism, and hypothyroidism.  Furthermore, since the risk of adverse events increases with higher doses of statins, combination of these agents should be limited to the lowest possible dose of statins needed to achieve lipid goals.

Despite the lack of clinical outcome data, NCEP ATP-III recognizes that some individuals may require combination therapy to achieve their lipid goals.  Examples of these individuals may include those needing additional LDL-C lowering (not achieved with monotherapy), those with very high TG levels (>500 mg/dL) and those with mixed dyslipidemias (low HDL-C, high TGs and elevated LDL-C).

It should be emphasized that the available clinical trials, evaluating certain lipid-lowering combinations, do not necessarily represent the patients identified by NCEP ATP-III as being potential candidates for combination therapy.  For example, there has never been a randomized clinical trial evaluating combination lipid-lowering agents in patients with very high TG levels.  However, consideration of combination lipid-altering treatments in these individuals is based upon clinical reasoning.

recommendations

LDL-C Lowering Combination Therapy [ONLY FOR SECONDARY PREVENTION]

1. For patients not at goal, monotherapy should be titrated until goal is achieved or maximum tolerable dose has been reached.  [C]
2. Combination therapy to achieve LDL-C goal may be considered for carefully selected patients who do not achieve the LDL-C goal with maximally tolerated monotherapy.  [I]
3. Combination lipid-lowering therapy should include a statin unless the patient is unable to tolerate statins. [A]
4. Addition of a resin to the statin can be considered for secondary prevention in patients not meeting their LDL-C goals on maximally tolerated doses of statins.  [B]
5. Addition of niacin or a resin to the statin can be considered in patients not meeting their LDL-C goals to further reduce the LDL-C level.  [B]
6. Addition of ezetimibe to the statin can be considered in patients not meeting their LDL-C goals on maximally tolerated doses of statins and unable to tolerate niacin or a resin to reduce the LCL-C level.  [I]
7. In patients unable to tolerate statins and not achieving their LDL-C goals with niacin or resins, a combination of both resin and niacin may be considered.  [B]
8. In any combination therapy the lowest possible dose of statin should be used to achieve lipid goals. When combined with fibrates (greatest risk), niacin or possibly ezetimibe, the risk of adverse events with statins (e.g., muscle toxicity) appears to increase with increasing statin doses.  [C]

Elevated LDL-C and Very High Triglycerides (>500 mg/dL)

9. Combination therapy with statins and niacin, fish oils or fibrates can be considered for the secondary prevention of CVD in patients with elevated LDL-C and very high TGs.  [C]
10. Combination therapy with niacin and fibrates can be considered for the secondary prevention of CVD in patients with elevated LDL-C and very high TGs in patients unable to tolerate statins.  [C]

Very High Triglycerides and/or Low HDL-C Without Elevated LDL-C

If non-HDL goals cannot be achieved with a statin (or other LDL-lowering regimen) alone, a TG-lowering drug may be added to the statin.  Choices are niacin, a fibrate, and fish oils.

11. For secondary prevention of CVD in patients with either low HDL-C or very high triglycerides and no elevation of LDL-C levels, combination therapy with statin plus niacin, fibrate or fish oil may be considered.  [C]
12. Combination therapy with niacin and fibrates and/or fish oils can be considered in patients unable to tolerate statins.  [C]

Table 8.  Potential Combination Pharmacological Treatments for Dyslipidemia

Drug Combination	Expected Change in Lipoproteins (%)						Outcome DATA
	LDL	HDL			TG
↑ LDL-C When Monotherapy is Inadequate
Statin + Resin	-30 to -60		-		+10		No Data
Statin + Niacin	-25 to -57		13 to 36		-19 to -38		No Data
Statin + Ezetimibe	-34 to -60		3 to 9		-11 to -24		No Data
Niacin + Resin	-32 to -43		37 to 43		-27 to -29		No Data
Statin + Resin or Ezetimibe + Niacin	No Data						No Data
↑ LDL-C and ↑ TG  (>500 mg/dL)
Statin + Niacin  ***	-25 to -57		13 to 36		-19 to -38		No Data
Statin + Fibrate	-		19 to 22		-41 to -53		No Data
Statin + Fish Oil	-		-		-20 to -30		No Data
Niacin + Fibrate	No Data TC -13		45		-20		No Data
Ezetimibe + Niacin Ezetimibe + Fish Oil	No Data						No Data
Very High TG and/or Low HDL-C Without Elevated LDL-C*
Statin + Niacin   *** Statin + Fibrate Statin + Fish Oil Fibrate + Niacin	See above for effect on lipids. No data in patients with TG >400 mg/dL.					No Data
Fibrate or Niacin + Fish Oil	No Data					No Data
Fibrate + Niacin + Fish Oil	No Data					No Data
Low HDL-C, high LDL-C and high TG)*
Statin + Niacin	See Above					No Data
Statin + Fibrate	See Above					No Data
Fibrate + Niacin + Resin	26		36	50		No Data

(Guyton 1999, Worz & Bottorff, 2003, NCEP ATP-III, 2002), *Combination studies did not include patients with very high TG (>500 mg/dL).
- =No additional benefit with combination, N=niacin, NR=not reported, R=resin, S=statin, TC=total cholesterol. The manufacturers of ezetimibe recommend avoiding the combination of ezetimibe plus fibrates (Fibrates can increase cholesterol excretion into the bile. In a dog study, ezetimibe also increased cholesterol excretion into the bile). There is no data on the combination of ezetimibe plus fish oils.
*** No clinical trial data in patients with TG >400 mg/dL

 

discussion

Combination Pharmacotherapy

There is increasing interest in combination pharmacologic therapy for managing dyslipidemia. Several explanations for the interest include the “optional” more aggressive LDL-C lowering goal in the very high-risk patient who is unable to reach their LDL-C goal with statin monotherapy, increasing recognition of the importance of addressing atherogenic dyslipidemia frequently associated with metabolic syndrome and management of mixed dyslipidemias not optimized with statins alone.  Although it seems reasonable to address and improve the total lipid profile, there are no large randomized clinical endpoint trials examining the benefit of combination therapy.  There are, however, several angiographic and many LDL-C lowering trials demonstrating benefit in those surrogate endpoints.

Bile acid sequestrants, niacin, and ezetimibe combined with a low dose statin can produce similar LDL-C lowering as quadruple the statin dose (e.g., simvastin 10 mg + ezetimibe 10 mg = simvastin 80 mg daily). However, since most of the large health outcome statin trials utilized higher statin doses (20-40 mg/d), it is not known whether the same clinical benefit will be seen if a low dose statin is combined with another lipid-lowering agent.

The risk of toxicity from combining certain lipid-lowering treatments (e.g., statin + fibrates) must be carefully considered prior to initiating therapy.  Furthermore, since the risk of adverse events increases with higher doses of statins, combination of these agents should be limited to moderate dose statins.

Box 6.  Key Elements in Management of Combination Therapy

Treatment of LDL and non-HDL should focus on statin therapy alone. Reserve combination therapy for high-risk patients (secondary prevention or familial hypercholesterolemia) Discuss the risks and unproven clinical benefits of statin-fibrate therapy with the patient and document it in the patient’s medical record. Prescribe the lowest effective dosages of the statin and fibrate to achieve treatment goals. Use caution in patients with the following characteristics: advanced age, female gender, compromised renal function, heavy alcohol use, frailty and hyperthyroidism. Be cautious about use of drugs that could interfere with the metabolism of the statin, or are known potent CYP 3A4 inhibiting medications (e.g., macrolides, azole antifungals, protease inhibitors, cyclosporine, etc.) Obtain a baseline CK level and repeat the measurement during therapy, if the patient reports symptoms consistent with myopathy. Teach patients to recognize and report generalized muscle weakness, tenderness, or pain; be prepared to evaluate those who experience these symptoms. (Evaluate CK and UA.) Discontinue therapy for myopathic symptoms and elevated CK If TG-lowering drug is added to a statin, caution is required due to particularly higher risk of myopathy.  Fibrate and niacin combinations with statin may be more toxic than combination with fish oil.