In 2012, the FDA issued an alert reporting a relationship between statin use and increase in blood glucose and new incidence of diabetes. Which of the following statements is TRUE?
1. A large meta-analysis has reported an approximate 18% increase in relative risk of developing diabetes on statin therapy.
2. This observation appears to be dose dependent with a meta-analysis of high- versus moderate-dose trials reporting an absolute increase in rate of 0.4%.
3. Increase in blood glucose with statins does not attenuate the CVD reduction benefit of statins.
4. Development of diabetes on statin therapy is independent of risk factors for diabetes
. 5. Reducing the dose of statin should be utilized to avoid diabetes development in those at risk, for example, metabolic syndrome, obesity, and impaired fasting glucose.
2 and 3. Sattar in a meta-analysis of 13 statin trials in 91,140 patients noted that 4,278 developed DM (4.89% on statins versus 4.5% on placebo; 0.39% absolute increased difference and 9% relative risk of incident diabetes). This represented 1 additional case of DM per 1,000 patient-years. Preiss published a meta-analysis of 5 trials in 32,772 patients comparing high- versus moderate-dose statins and reported 2,749 developed DM (8.8% versus 8.4% or an absolute increase of 0.4%). There were two additional cases of DM (18.9 versus 16.9) per 1,000 patient-years of follow-up. The development of diabetes did not appear to reduce the benefits of treatment.
Sattar found 5.4 less cardiac events for 255 patients treated over 4 years for each 1 mmol/L reduction in LDL-C compared with 1 extra case of diabetes for the same time period. Preiss noted 1 additional case of diabetes for every 498 patients over 1 year compared with 1 fewer CVD event for every 155 patients over 1 year. In a separate analysis of three high-dose atorvastatin trials, Waters et al. reported no difference in CVD events occurring in 11.3% with new DM and 10.8% without new DM. This compared with those with diabetes at baseline (10.1% versus 17.5%). The FDA reported this association in February 2012 but added that it does not appear to reduce the benefits of statin therapy in appropriately selected patients. Therefore, statin therapy should not be denied or appropriate doses reduced to avoid diabetes. However, since the individuals that developed diabetes are those at risk for diabetes it is prudent to measure for glycemic control more frequently and emphasize lifestyle interventions to reduce diabetes risk. This approach has been supported in the ACC/AHA 2013 guidelines.
Your patient is a 51-year-old man with heterozygous FH with predrug therapy LDL-C of 202 mg/dL who had been tried on atorvastatin, simvastatin, and lovastatin in the past but stopped all three due to complaints of muscle aching, had gastrointestinal complaints with resins, and refused further treatment. He recently had an ST-segment elevation MI treated with direct stenting. He was given a prescription to start atorvastatin again but was hesitant to have it filled and comes to you for advice. He has increased his frequency of aerobic exercise and has been following a low-saturated fat diet. LDL-C measured 2 months after the MI was 188 mg/dL. Appropriate options to consider in managing this patient include:
1. trial of rosuvastatin beginning at 5 mg two to three times a week followed by slow titration.
2. pretreatment with coenzyme Q10 followed by rechallenge with a different statin or lower dose of previously used statin.
3. niacin titrated to highest tolerated dose in combination with ezetimibe.
4. LDL-C apheresis.
5. emphasis on aggressive lifestyle intervention including very low saturated fat to vegetarian diet, plant sterols/stanols, and high dietary and supplementary fiber.
1, 2, 3, and 5. This patient is at very high risk for recurrent events. Since the greatest reduction in CVD events has been demonstrated with statins, further attempts to rechallenge with statins are appropriate. Small clinical trials and observational studies have shown that tolerance may be improved by trying multiple alternate statins, often using a potent statin beginning at low and intermittent rather than daily dosing with slow titration. Small investigations of coenzyme Q10 appear to lower the incidence of muscle complaints when added to statins. An analysis of patients referred to the Cleveland Clinic for intolerance to statins (the majority due to muscle complaints) revealed that over two-thirds of patients were able to tolerate some statin regimen with average LDL-C reduction of ~28% in those able to tolerate daily dosing. Niacin in high doses has been shown in the Coronary Drug Project to reduce recurrent MI and mortality after MI and is a reasonable component of a combination therapy program in patients resistant to all statins. Both LDL-C apheresis and mipomersen can lower LDL-C but with LDL-C levels in this range he would not meet the FDA recommendation for apheresis and although trials with mipomersen have been shown to be effective in both homozygous and heterozygous FH patients it is only currently approved for homozygotes.
Statements regarding fibrates include all of the following except that:
Although difficult to demonstrate in individual studies, meta-analysis of fibrate trials has demonstrated reduction in cardiovascular mortality on therapy. An increase in myopathy has been reported with both gemfibrozil and fenofibrate as monotherapy but to a greater extent when added to statins (5.5-fold increased risk of myopathy when combined with statins) and more so with gemfibrozil compared with fenofibrate. A meta-analysis of monotherapy fibrate trials published in 2007 in the American Heart Journal reported a reduction in nonfatal MI but no reduction in fatal MI or total/cardiovascular mortality. Subanalyses of individuals with a metabolic dyslipidemia in fibrate trials such as BIP (bezafibrate infarction prevention), FIELD (fenofibrate intervention and event lowering in diabetes), and ACCORD trials demonstrated significant reduction in the primary endpoint of combined cardiovascular events, although not in the overall populations studied. Renal status should be evaluated within 3 months of initiation of therapy and every 6 months thereafter. Plasma half-life of fenofibric acid is prolonged in renal insufficiency and requires lower dose with glomerular filtration rate (GFR) 30 to 59 and avoidance if GFR <30. An increase in creatinine of 12% was reported in the FIELD study using fenofibrate, usually reversible with discontinuation of therapy.
The following statements regarding use of niacin are true except that:
Niacin can raise HDL-C from 20% to 25% and lower TGs from 30% to 50% depending on the dose and pretreatment TG levels but has little effect on LDL-C. Flushing and skin reactions are the most common reasons limiting niacin use. Gout episodes are more common in individuals with a prior history of gout. A small increase in blood glucose levels and HbA1c has been reported but is generally not of clinical significance and manageable with adjustments in glucose-lowering therapies. Baseline LFTs, fasting glucose, or HBA1c and uric acid should be obtained prior to therapy. While studies have suggested a benefit on surrogate markers for CVD events such as CIMT in the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) trials, there are currently no large longitudinal controlled trials demonstrating incremental benefit on clinical events when niacin is added to adequate statin therapy. Results of the AIM-HIGH and HPS-THRIVE were reviewed in Question 25. Niacin has a beneficial effect on multiple components of the lipid panel including a 20% to 35% increase in HDL-C, up to 20% lowering of LDL-C, and up to 30% to 50% reduction in TG. The Coronary Drug Project, initiated in the late 1960s, was a large secondary prevention study among men with several treatment arms, one of which utilized up to 3 g/day of niacin (table below).
Pharmacologic Therapies for Lipid Management:
Compared with placebo, niacin lowered TC by 10% and TG by 26% (although HDL-C data not available) and after 6 years, significantly reduced nonfatal MI by 27%. A 15-year follow-up analysis (9 years after the interventions had ended) revealed a significant 11% decrease (p <0.004) in total mortality. Further analysis has demonstrated equivalent reductions in CVD risk regardless of entry fasting glucose level, presence or absence of diabetes at entry, or change in fasting glucose while on therapy.
© 2010-2030 Your Doctor - Dr.Khalil Al-Yousifi - Kuwait - Contact Us