Ezetimibe in diabetes: more than cholesterol lowering?

Abstract

Ezetimibe, an inhibitor of cholesterol intestinal absorption, is a lipid lowering agent with potential pleiotropic actions. Ezetimibe in combination with a statin is effective in decreasing low density lipoprotein cholesterol (LDL-C), lowering triglyceride and raising high density lipoprotein cholesterol levels. Ezetimibe plus statin achieve LDL-C targets in a greater proportion of patients than statin monotherapy. Ezetimibe also seems to improve renal function, insulin resistance and inflammatory markers. These actions are useful in patients with diabetes. Ezetimibe is a well-tolerated and effective (in terms of achieving LDL-C targets) option in patients with hyperlipidemia with or without diabetes. This editorial will discuss several properties of ezetimibe, with special reference to diabetes.

Key words:

• Creatinine
• Diabetes
• Ezetimibe
• High density lipoprotein cholesterol
• Low density lipoprotein cholesterol
• Proteinuria
• Triglycerides

Ezetimibe, an inhibitor of cholesterol intestinal absorption, is a lipid lowering agent with potential pleiotropic actions (e.g. on renal function, insulin resistance and inflammatory markers). These actions are useful in patients with diabetes mellitus (DM) where there is an increased risk of impaired renal function. Furthermore, ezetimibe helps achieve lipid treatment goals which need to be strictly enforced in patients with DM. This editorial focuses on recent publications in this field.

Recently, Ruggenenti et al. reported the effect of adding ezetimibe 10 mg/day to simvastatin 40 mg/day in patients with type 2 DM (T2DM)1. Ezetimibe decreased low density lipoprotein cholesterol (LDL-C) levels by 30.9% compared with baseline (p < 0.0001). There was no change in the placebo group. More patients (71.7 vs 16.7%, p < 0.0001) in the ezetimibe group (n = 53) reached the LDL-C target (<70 mg/dl; 1.8 mmol/l) than in the placebo group (n = 54). Renal function did not change in any group in this population with normal serum creatinine and a urinary albumin excretion (UAE) <200 μg/min. High density lipoprotein cholesterol (HDL-C) decreased (6.25% by our calculations) with ezetimibe treatment but the LDL-C/HDL-C ratio improved (28.6% by our calculations)2.

A recent study in Japanese hypercholesterolemic patients who did not reach management goals (n = 76) assessed the effect of ezetimibe 5 mg/day plus previous treatment compared with a control group for 4 to 8 weeks3. About 30% of the study population had DM or impaired glucose tolerance (IGT). Ezetimibe decreased LDL-C by 24%. Ezetimibe also improved insulin resistance as defined by homeostatic model of assessment insulin resistance (HOMA-IR) (p < 0.01) but there was no change in fasting plasma glucose and glycated hemoglobin (HbA_1c). Ezetimibe attenuated urinary albumin excretion (38.6 ± 53.6 to 26.1 ± 46.4 mg albumin/g creatinine, p < 0.01) without changing the estimated glomerular filtration rate (eGFR)3. It is worth noting the large standard deviation and the possibility that the results should have been expressed as median and range. Furthermore, ezetimibe decreased body weight, body mass index, waist circumference, systolic and diastolic blood pressure (all p < 0.05). In this study3, ezetimibe decreased serum high-sensitivity C-reactive protein (hsCRP), tumour necrosis factor-α (TNF-α) (p < 0.01) and urinary excretion of a marker of oxidative stress, 8-hydroxy-2′-deoxyguanosine (8-OHdG) (p < 0.05). It is important to consider that some of the beneficial effects described in this study may be related to weight loss. Furthermore, ezetimibe increased urinary excretion of nitrate and nitrite (p < 0.05) reflecting increased bioavailability of nitric oxide (NO). This finding is supported by another study where ezetimibe decreased the serum levels of asymmetric dimethylarginine (ADMA), an inhibitor of NO synthase4.

The fall in LDL-C (30.9%) reported by Ruggenenti et al.1 is greater than that in a meta-analysis of 5039 patients (including patients with DM) where adding ezetimibe 10 mg/day to a statin decreased LDL-C levels by 23.6%5. However, a decrease in LDL-C (31.4% and 33%) similar to that in the Ruggenenti et al. study (30.9%)1 was reported in two community-based studies, the Slovenia (SI) Statin Plus Ezetimibe in Cholesterol Treatment (SI-SPECT) study (n = 1053)6 and a study carried out in Greece (n = 1514)7. Both studies included diabetic patients (about 30% of participants). In contrast, there was a 21% fall in LDL-C in the recent study by Miyashita et al.8 in Japanese patients with T2DM (n = 40). In another study, the addition of ezetimibe to open-label statin resulted in a fall in LDL-C by 27.3% in the patients with DM (n = 92)9. Therefore, it is important to establish if the LDL-C response when adding ezetimibe to a statin in patients with T2DM differs from that in non-diabetic patients.

In addition to lowering the ‘quantity’ of LDL-C, improving the ‘quality’ of the LDL fraction may be relevant10; small dense LDL appears to be more atherogenic. Ezetimibe decreased large buoyant LDL-I subfraction by 13.9% (p = 0.0001) in 72 healthy men with a mean LDL-C of 2.9 ± 0.8 mmol/l (111 ± 30 mg/dl)11. In contrast, in one of our studies ezetimibe monotherapy (10 mg/day) for 16 weeks resulted in a decrease in small and dense LDL-C levels only in patients (none had DM) with high levels of baseline triglycerides (>1.7 mmol/l)12. Similar findings were reported in a post hoc analysis of 1013 patients with hypercholesterolemia and T2DM13. Treatment with ezetimibe/simvastatin (10/20 or 10/40 mg/day) decreased LDL₁-C, LDL₂-C and LDL₃-C more compared with atorvastatin (10, 20 or 40 mg/day) alone regardless of baseline TG levels13. LDL₁-C and LDL₂-C are buoyant fractions whereas LDL₃-C and LDL₄-C are small dense fractions. Both treatments (ezetimibe/simvastatin or atorvastatin) resulted in a similar decrease of LDL₁-C and LDL₃-C in the group with ‘high’ baseline TG levels >2.3 mmol/l (>200 mg/dl) and the group with ‘low’ baseline TG levels <2.3 mmol/l (<200 mg/dl). The fall in LDL₄-C (i.e. small dense LDL) was greater in the group with the higher TG levels13. Therefore, it is important to specifically look at populations where TG levels are elevated14.

Small dense LDL-C is prone to forming oxidized LDL (oxLDL) which is associated with increased cardiovascular risk10. In this context, in patients with coronary artery disease or equivalent (n = 100), treatment with atorvastatin 40 mg plus ezetimibe 10 mg for 8 weeks significantly decreased oxLDL (p = 0.01) compared with atorvastatin 40 mg alone; the small dense LDL subfraction also decreased significantly15. The fall in oxLDL correlated with that in total LDL and large buoyant LDL (r = 0.6 and 0.5, respectively p < 0.01)15, but not with the fall in small dense LDL. Therefore, according to these results, a significant decrease in buoyant LDL subfraction may be associated with a significant decrease in small dense and atherogenic oxLDL in patients on ezetimibe plus a statin.

Ruggenenti et al.1 reported a decrease in HDL-C after adding ezetimibe treatment in T2DM patients already on simvastatin. However, no significant fall in HDL-C levels was reported in the post hoc analysis of the diabetic group (n = 191) of a larger study (n = 769) that assessed the effect of ezetimibe (10 mg/day) added to open-label statin treatment9. Baseline HDL-C levels in the latter two studies1,9 were very similar (48 ± 11 and 49 ± 11 mg/dl, respectively; approximately 1.2 ± 0.3 mmol/l). The meta-analysis of 5039 patients showed that combination of ezetimibe 10 mg/day plus statin significantly increased HDL-C (1.7%, p < 0.0001) compared with statin alone5. The two large community-based studies mentioned above reported that the combination of ezetimibe with a statin increased HDL-C by 10% (p < 0.0001)7 and 1% (p = 0.003 for the whole population, which included a few patients on ezetimibe monotherapy and addition of ezetimibe to fibrates)6. A non-significant increase in HDL-C of 3.5% was reported in a smaller study (n = 42) of Japanese T2DM patients8. More studies are needed to elucidate the effect of ezetimibe on HDL-C in diabetic patients.

The fall in triglycerides in the Ruggenenti et al. study1 was 12%, which is similar to that reported in the meta-analysis (10.7%)5. In another study in patients who could not reach LDL-C target on statin monotherapy (13% of patients had T2DM), the addition of ezetimibe decreased TG levels by 20% in those with TG levels ≥1.5 mmol/l, while in patients with TG levels ≤1.5 mmol/l the decrease was only 7%16. In the SI-SPECT study6 baseline TG levels were considerably higher (263 mg/dl; 2.97 mmol/l) than in the study of Ruggenenti et al.1 (123 mg/dl; 1.4 mmol/l). It is of interest that the fall in TG levels was 28.7%6 and 12%1, respectively. In another study the fall achieved by ezetimibe/simvastatin (10/20 and 10/40 mg/day) in very low density lipoprotein (VLDL), the main TG-carrying lipoprotein fraction, was greater in T2DM patients with baseline TG levels >200 mg/dl (2.3 mmol/l) compared with <200 mg/dl13. Therefore, the fall in TG levels after adding ezetimibe to a statin may depend on the baseline TG value. However, the responses may differ in diabetic and non-diabetic patients.

Yagi et al.3 reported an improvement in HOMA-IR after treatment with ezetimibe 10 mg/day in hypercholesterolemic patients (30% had T2DM/IGT). In contrast, there is some evidence that statin therapy is associated with a slight increased risk of new onset DM17–18. It would be helpful if an agent (e.g. ezetimibe) that can be combined with a statin improved insulin sensitivity and thus negated any diabetogenic effect.

T2DM is associated with an increased risk of impaired renal function. In this context it is of interest that statins exert a renoprotective effect. In one study, proteinuria improved with pitavastatin 2 mg/day in patients with stage I or II chronic kidney disease (CKD) without DM and this decrease was significantly greater (p < 0.05) when ezetimibe 10 mg/day was added19. Proteinuria was reduced with ezetimibe 10 mg/day monotherapy for 6 months in 10 non-diabetic patients with CKD stage I or II4. A marker of tubular injury, L-fatty acid binding protein, was decreased with combination treatment of ezetimibe 10 mg/day plus pitavastatin 2 mg/day compared with baseline and with pitavastatin treatment alone19. A decrease in serum creatinine levels after adding ezetimibe 10 mg/day to a statin was found only in patients (13 to 29.9% had T2DM) with ‘higher’ baseline creatinine levels within the reference range7,16. Therefore, ezetimibe could exert a protective effect on the kidneys. A similar effect could occur in diabetic patients. However, this has to be proven because another study showed no significant change in proteinuria in 77 renal transplant patients (9.1% had DM) treated with ezetimibe 10 mg/day plus simvastatin 10 mg/day for 6 months20.

Inflammatory markers could be predictors of atherosclerosis severity21. As mentioned earlier, ezetimibe treatment was reported to improve both circulating4 and urinary3 markers of oxidative stress. Another study in pre-diabetic patients (n = 50) showed that ezetimibe 10 mg or simvastatin 20 mg decreased hsCRP levels after 12 week treatment but this decrease was only significant when combination therapy was used22. However, during this study other circulating markers of inflammation (TNF-α and interleukin-6) did not change22.

Recently, the role of ezetimibe on non-alcoholic fatty liver disease (NAFLD) has been reviewed23. It is of interest that the human liver has Niemann-Pick C1-like 1 protein (a cholesterol transporter) where ezetimibe exerts its actions23. More clinical trials are needed in this field since NAFLD is a common finding in diabetic and nondiabetic patients23,24. In this context, in obese or overweight patients (n = 86) treatment with ezetimibe 10 mg alone or in combination with orlistat for 6 months significantly improved alanine transaminase and γ-glutamyl transferase (γ-GT) activity24.

Ezetimibe is an alternative therapeutic option in statin-intolerant patients25. Patients with polygenic hypercholesterolemia or combined hyperlipidemia with or without DM (n = 1170), who had adverse effects from statin treatment were shifted to combination therapy with ezetimibe 10 mg plus simvastatin 10 mg and followed-up for 6 months. There was an improvement in TG, LDL-C and HDL-C levels without any adverse event being reported26. In CKD, the addition of ezetimibe (10 mg/day) to simvastatin (20 mg/day) did not have any serious adverse effects in the 6-month follow-up period of the Second United Kingdom Heart And Renal Protection (UK-HARP-II) study (n = 203)27. In this study there was no increase in creatine kinase activity.

In conclusion, ezetimibe is an effective lipid lowering agent which could exert pleiotropic actions (e.g. on renal function, insulin resistance and inflammatory markers) that are important in diabetic patients. The efficacy of ezetimibe monotherapy in T2DM is further supported by the finding that it improves measures of arterial stiffness such as cardio-ankle vascular index8. Ezetimibe is a safe lipid-lowering agent but clinical trials evaluating cardiovascular events are required28. Nevertheless, there is a need for endpoint-based studies, especially in patients with T2DM, to confirm or refute that the potential advantages discussed above are relevant29.