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care.diabetesjournals.

org Cardiovascular Disease and Risk Management S81

Combination Therapy for LDL Low levels of HDL cholesterol, often niacin is not recommended given the
Cholesterol Lowering associated with elevated triglyceride lack of efcacy on major ASCVD out-
Statins and Ezetimibe levels, are the most prevalent pattern comes, possible increase in risk of ische-
The IMProved Reduction of Outcomes: of dyslipidemia in individuals with mic stroke, and side effects.
Vytorin Efcacy International Trial type 2 diabetes. However, the evidence
(IMPROVE-IT) was a randomized con- for the use of drugs that target these Diabetes With Statin Use
trolled trial comparing the addition of eze- lipid fractions is substantially less robust Several studies have reported an in-
timibe to simvastatin therapy versus than that for statin therapy (67). In a creased risk of incident diabetes with
simvastatin alone. Individuals were $50 large trial in patients with diabetes, fe- statin use (72,73), which may be limited
years of age, had experienced an ACS nobrate failed to reduce overall cardio- to those with diabetes risk factors.
within the preceding 10 days, and had vascular outcomes (68). An analysis of one of the initial studies
an LDL cholesterol level $50 mg/dL suggested that although statins were
(1.3 mmol/L). In those with diabetes Combination Therapy linked to diabetes risk, the cardiovascu-
(27%), the combination of moderate- Statin and Fibrate lar event rate reduction with statins far
intensity simvastatin (40 mg) and ezetimibe Combination therapy (statin and - outweighed the risk of incident diabetes
(10 mg) showed a signicant reduction of brate) is associated with an increased even for patients at highest risk for di-
major adverse cardiovascular events with risk for abnormal transaminase levels, abetes (74). The absolute risk increase
an absolute risk reduction of 5% (40% vs. myositis, and rhabdomyolysis. The risk was small (over 5 years of follow-up,
45%) and RR reduction of 14% (RR 0.86 of rhabdomyolysis is more common 1.2% of participants on placebo devel-
[95% CI 0.780.94]) over moderate-intensity with higher doses of statins and renal oped diabetes and 1.5% on rosuvastatin
simvastatin (40 mg) alone (63). Therefore, insufciency and appears to be higher developed diabetes) (74). A meta-analysis
for people meeting IMPROVE-IT eligibil- when statins are combined with gem- of 13 randomized statin trials with
ity criteria, ezetimibe should be added brozil (compared with fenobrate) (69). 91,140 participants showed an odds ratio
to moderate-intensity statin therapy. In the ACCORD study, in patients with of 1.09 for a new diagnosis of diabetes, so
Though not explicitly studied, these re- type 2 diabetes who were at high risk for that (on average) treatment of 255 patients
sults may also suggest that the addition ASCVD, the combination of fenobrate with statins for 4 years resulted in one
of ezetimibe should be considered for and simvastatin did not reduce the rate additional case of diabetes while simulta-
any patient with diabetes and history of of fatal cardiovascular events, nonfatal neously preventing 5.4 vascular events
ASCVD who cannot tolerate high-intensity MI, or nonfatal stroke as compared with among those 255 patients (73).
statin therapy. simvastatin alone. Prespecied sub-
Statins and Cognitive Function
group analyses suggested heterogeneity
Statins and PCSK9 Inhibitors A recent systematic review of the U.S.
in treatment effects with possible ben-
Placebo-controlled trials evaluating Food and Drug Administrations post-
et for men with both a triglyceride
the addition of the PCSK9 inhibitors marketing surveillance databases, ran-
level $204 mg/dL (2.3 mmol/L) and
evolocumab and alirocumab to maxi- domized controlled trials, and cohort,
an HDL cholesterol level #34 mg/dL
mally tolerated doses of statin therapy case-control, and cross-sectional stud-
(0.9 mmol/L) (70).
in participants who were at high risk for ies evaluating cognition in patients re-
ASCVD demonstrated an average reduc- Statin and Niacin ceiving statins found that published
tion in LDL cholesterol ranging from 36% The Atherothrombosis Intervention in data do not reveal an adverse effect of
to 59%. These agents may therefore be Metabolic Syndrome With Low HDL/High statins on cognition. Therefore, a concern
considered as adjunctive therapy for Triglycerides: Impact on Global Health that statins might cause cognitive dys-
patients with diabetes at high risk for Outcomes (AIM-HIGH) trial randomized function or dementia should not deter
ASCVD events who require additional over 3,000 patients (about one-third their use in individuals with diabetes at
lowering of LDL cholesterol or who re- with diabetes) with established ASCVD, high risk for ASCVD (75).
quire but are intolerant to high-intensity low LDL cholesterol levels (,180 mg/dL
statin therapy (64,65). It is important to [4.7 mmol/L]), low HDL cholesterol lev- ANTIPLATELET AGENTS
note that the effects of this novel class els (men ,40 mg/dL [1.0 mmol/L] and
Recommendations
of agents on ASCVD outcomes are un- women ,50 mg/dL [1.3 mmol/L]), and
c Use aspirin therapy (75162 mg/day)
known as phase 4 studies are currently triglyceride levels of 150400 mg/dL
as a secondary prevention strat-
under way. (1.74.5 mmol/L) to statin therapy
egy in those with diabetes and a
plus extended-release niacin or pla-
history of atherosclerotic cardio-
Treatment of Other Lipoprotein cebo. The trial was halted early due to
vascular disease. A
Fractions or Targets lack of efcacy on the primary ASCVD
c For patients with atherosclerotic
Hypertriglyceridemia should be ad- outcome (rst event of the composite
cardiovascular disease and docu-
dressed with dietary and lifestyle of death from CHD, nonfatal MI, ische-
mented aspirin allergy, clopidogrel
changes including abstinence from alco- mic stroke, hospitalization for an ACS,
(75 mg/day) should be used. B
hol (66). Severe hypertriglyceridemia or symptom-driven coronary or cere-
c Dual antiplatelet therapy is reason-
(.1,000 mg/dL) may warrant pharma- bral revascularization) and a possible
able for up to a year after an acute
cologic therapy (bric acid derivatives increase in ischemic stroke in those on
coronary syndrome and may have
and/or sh oil) to reduce the risk of combination therapy (71). Therefore,
benets beyond this period. B
acute pancreatitis. combination therapy with a statin and