Context: The Adult Treatment Panel III recommends 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, as first-line lipid-altering therapy for all adult patients with diabetes mellitus. This is based on the well-characterized efficacy and safety profiles of this class of agents as well as several clinical trials demonstrating that statin treatment reduces the risk of cardiovascular events.
Evidence Acquisition: This review provides an overview of the effectiveness and mechanisms of action of statins in patients with diabetes mellitus using small efficacy trials and large clinical outcomes trials as well as studies of the effects of statins on apolipoprotein B (apoB) metabolism.
Evidence Synthesis: The major findings presented are a review of mechanistic studies of selected subjects with diabetes mellitus and dyslipidemia and a compilation of results from large-scale clinical trials of patients with diabetes.
Conclusions: Statins are highly efficacious as low-density lipoprotein cholesterol-lowering agents and have more modest effects on very low-density lipoprotein triglyceride and high-density lipoprotein cholesterol levels. The effects of statins on plasma lipids and lipoproteins result from their ability to both increase the efficiency with which very low-density lipoprotein and low-density lipoprotein are cleared from the circulation and reduce the production of apoB-containing lipoproteins by the liver. Additional investigations are needed to clarify the mechanisms by which statins reduce apoB secretion from the liver.
DURING THE PAST decade, major advances in the treatment of lipid disorders have translated into demonstrated benefits for patients at risk for coronary heart disease (CHD) events. More recently, accumulated evidence indicates similar benefits of lipid-altering therapy in patients with type 2 diabetes mellitus (T2DM). Although several lipid-altering therapies have been shown to benefit patients at risk for CHD, lowering of low-density lipoprotein (LDL) cholesterol with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) has shown the most striking results. This review of the use of statin therapy in diabetic dyslipidemia first looks at the association between T2DM and risk for atherosclerotic cardiovascular disease (ASCVD), the pathophysiology of diabetic dyslipidemia, and the demonstrated mechanisms by which statins improve dyslipidemia. We then review the clinical trial evidence that statins reduce ASCVD events in patients with T2DM. The article concludes with a brief consideration of the safety of statin therapy and the possibility of combination lipid-altering therapy in selected patients.
Diabetic Dyslipidemia: Link to ASCVD
ASCVD risk is increased 2- to 4-fold in T2DM, and outcomes are worse for these patients after myocardial infarction (MI) or stroke (1). Atherosclerosis accounts for approximately 80% of all mortality in diabetic subjects, with 75% due to coronary atherosclerosis and 25% to cerebral or peripheral vascular disease (2–5), and more than 75% of all hospitalizations for diabetic complications. It is estimated that more than 50% of patients with newly diagnosed T2DM have CHD. Indeed, several studies suggest that high-risk patients with T2DM and no history of clinical CHD have rates of new events similar to those of nondiabetic subjects with CHD (6, 7). Furthermore, in several major trials of lipid-altering therapy, subjects with diabetes had higher event rates than those without diabetes during both placebo and treatment (8–10). Such data prompted the National Cholesterol Education Program Adult Treatment Panel III to define diabetes as a CHD risk-equivalent disorder (11).
Diabetic Dyslipidemia: Pathophysiology and Link to Insulin Resistance and T2DM
Numerous metabolic abnormalities associated with T2DM increase the risk for ASCVD. Among these are advanced glycation end products (12, 13), increased procoagulant and antifibrinolytic molecules (14, 15), and hypertension (16). A central feature of the disordered metabolism present in T2DM (17, 18) and an integral component of the insulin resistance syndrome (referred to as syndrome X or the metabolic syndrome) (19, 20) is dyslipidemia (21). Figure 1A provides a simple schema describing the metabolism of very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), or chylomicron remnants and LDL apolipoprotein B (apoB) in normal subjects, and Fig. 1B depicts the changes that occur in the insulin-resistant patient with T2DM. These figures are the basis for the following discussion.
A, Normal apoB metabolism: In the liver, TG and cholesteryl ester (CE) availability regulates the assembly and secretion of VLDL. In adipose tissue (and, during exercise or fasting, in skeletal muscle), LpL hydrolyzes the VLDL TG, and free fatty acids (FFA) are released and taken up by fat cells. The result is the formation of VLDL remnants (also called IDL). In the postprandial period, chylomicron TG are hydrolyzed by LpL and chylomicron remnants are formed. The VLDL remnants are either taken up by the liver, mainly through LDL receptors, or converted to LDL after interaction with HL (chylomicron remnants are all taken up by the liver). LDL is removed from the circulation by LDL receptors in both the liver and the periphery. B, ApoB metabolism in T2DM. Insulin resistance and/or deficiency lead to several abnormalities that result in the secretion of more VLDL and defects in the catabolism of VLDL, chylomicrons, their remnants, and LDL. In the liver, less apoB is degraded via insulin-sensitive pathways, and more TG is made from lipogenesis. Additionally, there is increased release of FFA from insulin-resistant adipose tissue, and both VLDL and chylomicron remnants can return to the liver with more TG. All of these abnormalities result in increased VLDL secretion and elevated plasma TG levels. The severity of the hypertriglyceridemia can be modified by any reduction in LpL activity. LDL levels can vary, depending on whether more or less VLDL remnants are taken up via the LDL receptor or are converted to LDL (these alternative pathways are affected by HL activity, which can vary), and whether LDL receptor clearance of LDL is normal, reduced, or even increased. Finally, LDL loses cholesteryl ester to VLDL and chylomicron remnants via CETP, and small dense LDL are formed.
Dyslipidemia in the metabolic syndrome is characterized by elevated levels of triglycerides (TG), low levels of high-density lipoprotein (HDL) cholesterol, and small, dense LDL particles with normal or slightly elevated LDL cholesterol levels (22). Data from the Framingham Offspring Study (23), using cutpoints that are more extreme than those used in Adult Treatment Panel III (24), demonstrate the increased prevalence of low HDL cholesterol (<0.91 mmol/liter; <35 mg/dl) and elevated TG (>2.82 mmol/liter; >250 mg/dl) in individuals with diabetes. Among men with diabetes compared with nondiabetic controls, low HDL cholesterol was present in 43.9% vs. 20.3%, elevated TG in 22.6% vs. 9.3%, and the combination in 11.7% vs. 4.9%, respectively. Among women with diabetes, the prevalence of low HDL cholesterol, high TG, or both was 37.7%, 29.3%, and 23.4%, respectively, compared with 9.3%, 3%, and 1%, respectively, for nondiabetics. In addition, diabetic women were more likely to have elevated LDL cholesterol and total cholesterol levels. Similar findings were reported in the United Kingdom Prospective Diabetes Study cohort (25).
Effects of Insulin Resistance and T2DM on VLDL Metabolism
In general, individuals with T2DM and reasonably well-controlled glycemia have a dyslipidemia profile similar to that found in nondiabetic subjects with insulin resistance; lipid abnormalities in poorly controlled T2DM, however, respond only modestly to improvements in glycosylated hemoglobin (26, 27). Indeed, insulin resistance is a major underlying abnormality that drives dyslipidemia, although uncontrolled hyperglycemia may exacerbate each lipid abnormality, particularly hypertriglyceridemia. Furthermore, although insulin resistance affects each component of dyslipidemia, convincing data indicate that the central abnormality is increased assembly and secretion of VLDL, apoB, and TG (28, 29). Increased assembly and secretion of VLDL, and the resulting hypertriglyceridemia, lead to lower HDL cholesterol levels and smaller cholesteryl ester-depleted LDL (30). A complex, posttranslational regulation of apoB processing and transport in hepatocytes is the basis for the interaction between insulin resistance and VLDL secretion (31–33). Studies of cultured liver cells demonstrate that whether apoB is targeted for secretion as VLDL or for intracellular degradation is determined significantly by the availability of its lipid ligands, particularly TG. If hepatic lipids are unavailable for assembly into VLDL, apoB can be degraded by the proteasome after cotranslational ubiquitination (33). Limited lipid availability can also target apoB for posttranslational degradation, some of which occurs in the endoplasmic reticulum (ER) and some distal to the ER (34). There are three main sources of TG for VLDL assembly: fatty acid flux from adipose tissue to the liver (35–37); hepatic uptake of TG-enriched VLDL, IDL, and chylomicron remnants (38, 39); and de novo lipogenesis (40–42). Insulin resistance affects each of these pathways, resulting in increased lipid availability in the liver for assembly with apoB into VLDL.
ApoB can also be acutely targeted for degradation by insulin, acting via a phosphotidylinositol 3-kinase pathway (43). This degradation is posttranslational and probably post-ER. Decreased VLDL secretion, both TG and apoB, has been observed in normal subjects treated with large quantities of insulin and glucose (via euglycemic clamps) (44, 45). However, chronic hyperinsulinemia secondary to insulin resistance does not have the same effect. Thus, the presence of insulin resistance appears to significantly reduce the effects of insulin on apoB degradation in cultured cells (46), animals (47), and humans (44, 48). Absolute deficiency of insulin, occurring in the later phase of T2DM, exacerbates the qualitative defect in insulin action.
The reduced ability of insulin to degrade apoB together with increased lipid availability lead to increased hepatic assembly and secretion of apoB and TG as VLDL. Removal of excess TG delivered into the circulation may be reduced because lipoprotein lipase (LpL), an insulin-regulated enzyme that plays a key role in the lipolysis of VLDL and chylomicron TG, may be reduced modestly (49). This may be particularly important in severely hyperglycemic patients, who are generally the most insulin deficient and insulin resistant. Because postprandial hyperlipidemia is common in patients with T2DM (50), the efficiency with which both chylomicrons and VLDL are cleared from the circulation is obviously impaired in these patients. The mechanisms underlying postprandial hyperlipidemia include the modest reductions in LpL mentioned above, possibly increased production and higher plasma levels of apoC-III (an inhibitor of LpL), and the defective suppression of hepatic VLDL secretion during the hyperinsulinemic postprandial period (44, 45). Because VLDL and chylomicrons compete for the same LpL- and receptor-mediated pathways for TG removal from the circulation, nonsuppressed VLDL secretion leads to less efficient clearance of chylomicrons and their remnants. Optimal control of glycemia may have modest effects to increase LpL activity and thereby reduce fasting and postprandial TG levels.
Effects of Insulin Resistance and T2DM on LDL Metabolism
LDL cholesterol levels in patients with T2DM are usually the same (male) or modestly increased (females) compared with those in nondiabetic subjects; similar findings have been reported in individuals with insulin resistance without T2DM. Production of LDL can be increased because of increased VLDL production (28) or direct production of LDL particles from the liver (direct LDL production) (51). Determinants of whether the liver secretes apoB as VLDL or LDL most likely include the typical stimuli for hepatic TG secretion, such as obesity, simple carbohydrates, alcohol, and the level of physical activity. In some studies, increased production of LDL was offset by increased fractional clearance of these lipoproteins. Most persons with T2DM have normal or increased fractional removal of VLDL and LDL (28, 51, 52). However, with greater insulin deficiency, LDL receptors, which are regulated in part via insulin (53), are reduced, and the fractional clearance of LDL is low; this results in elevated LDL levels that can be reduced with better glycemic control. Unfortunately, even when LDL cholesterol levels are normal, increased numbers of LDL particles (indicated by elevated apoB levels) are common in patients with T2DM (54). Furthermore, patients with insulin resistance or T2DM also have LDL that has an abnormal composition, characterized by cholesteryl ester depletion and small size. This has been called the pattern B profile of LDL (55). Small, dense LDL in patients with insulin resistance is derived in large part from the action of cholesteryl ester transfer protein (CETP) (56). This protein mediates the exchange of VLDL (or chylomicron) TG for LDL cholesteryl ester, thereby creating a TG-enriched, cholesteryl ester-depleted LDL particle. TG-enriched LDL then interacts with LpL or hepatic lipase (HL), which lipolyzes the TG to produce small, dense LDL. The finding of small, dense LDL in insulin-resistant and T2DM patients with relatively normal TG levels suggests, however, that other factors are also at play. HL, which is increased in insulin resistance, may more effectively hydrolyze TG in LDL in patients with T2DM.
Effects of Insulin Resistance and T2DM on HDL Metabolism
Individuals with insulin resistance, with or without T2DM, have low levels of HDL cholesterol and apoA-I. As in the case of small, dense LDL, this derives largely from the action of CETP-mediated transfer of cholesteryl esters from HDL to TG-rich lipoproteins (chylomicrons and VLDL). HDL TG is hydrolyzed, mainly by HL, leading to small, dense HDL (57). Increased HL activity, which is common in insulin-resistant individuals, accelerates this process and may explain the reduced HDL observed with only modest hypertriglyceridemia. These compositional and physical changes are associated with increased fractional clearance of apoA-I from the circulation in T2DM with low HDL, leading to fewer HDL particles in the circulation (58). Thus, there are two defects in HDL metabolism in patients with T2DM: HDL cholesteryl ester is removed and transferred to atherogenic apoB-containing lipoproteins, and apoA-I levels are cleared from the circulation faster, leading to fewer HDL particles.
Importantly, correction of fasting hypertriglyceridemia does not generally normalize either HDL cholesterol or apoA-I levels. This may relate to persistently increased HL or to sustained postprandial hypertriglyceridemia despite reductions in fasting TG levels. Additionally, as with small, dense LDL, CETP-mediated core lipid exchange does not fully account for the low HDL levels. Whether low HDL in insulin resistance involves defective ATP-binding cassette transporter A1- or ATP-binding cassette transporter G1-mediated efflux of cellular free cholesterol, defective lecithin:cholesterol acyltransferase activity, or increased selective delivery of HDL cholesteryl ester to hepatocytes is under investigation. However, the fact that low HDL cholesterol and apoA-I levels are frequently present, even when TG levels are relatively normal, suggests that non-CETP mechanisms are important.
Briefly, significant evidence links each of the lipid and lipoprotein abnormalities described above to increases in ASCVD in patients with T2DM. Chylomicron and VLDL remnants have been shown to enter the arterial wall (59, 60) and, therefore, may be directly atherogenic. Small, dense LDL has been associated with ASCVD, although there is controversy regarding whether this subclass of LDL is an independent risk factor (61, 62). Finally, the association between low HDL cholesterol and ASCVD is clear; whether that link is via reduced reverse cholesterol transport or loss of direct effects of HDL on the vessel wall remains uncertain (63).
Diabetic Dyslipidemia: Mechanisms of Action of Statins
Although statins are known to lower blood LDL cholesterol levels via inhibition of hepatic cholesterol synthesis and subsequent up-regulation of hepatic LDL receptors, in vivo mechanistic studies of statin effects on plasma lipid and lipoprotein metabolism reveal a more complex story. Early studies in humans with familial hypercholesterolemia (FH) (64, 65) or normal subjects (66) demonstrated that statin therapy increases receptor-mediated clearance of LDL, consistent with the expected response of LDL receptors to inhibition of hepatic cholesterol synthesis (67). However, a more recent study in heterozygous FH patients showed decreased VLDL production during simvastatin therapy (68), suggesting that statins do more than raise LDL receptor activity, even in patients with only elevated LDL cholesterol levels.
Data are even more variable in dyslipidemic patients and patients with combined hyperlipidemia; both groups are typically insulin resistant, with or without concomitant T2DM. In a study of patients with dyslipidemia, we found that secretion of apoB lipoproteins into plasma was significantly reduced by lovastatin therapy. VLDL apoB secretion was not affected by lovastatin; however, there was a significant reduction (44%) in direct LDL production (69). Also, LDL fractional clearance was unaffected by lovastatin treatment in non-FH patients with dyslipidemia, but increased during treatment in FH patients studied simultaneously. In contrast, Vega and Grundy (70) reported about the same time that LDL cholesterol reductions with lovastatin in patients with mixed hyperlipidemia were associated with increased LDL fractional clearance and no change in LDL production; VLDL metabolism was not studied.
Since those early studies, which used exogenously radiolabeled lipoproteins as tracers, a number of reports have appeared in which stable isotopes of amino acids have been used to trace apoB metabolism in subjects with combined hyperlipidemia treated with statins (71). In brief, when baseline LDL fractional clearance was similar to that in control subjects, statins have usually been shown to reduce the production of apoB lipoproteins (72–74), although in one such study, only increased fractional clearance of apoB lipoproteins was observed (75). In contrast, if baseline LDL fractional clearance was low, statins improved lipid levels by increasing VLDL and LDL fractional clearance (76–80). In the first study of statin therapy in patients with T2DM, Ouguerram et al. (81) found that atorvastatin therapy was associated with decreased VLDL apoB secretion into plasma and normalization of low baseline LDL fractional clearance. Recent data from our group (51) indicate that simvastatin therapy in hypertriglyceridemic patients with T2DM reduced the secretion of apoB lipoproteins and VLDL TG into plasma; VLDL apoB production was not affected, but there was a significant reduction in direct LDL production.
Several studies have addressed the question of whether statins affect LDL size and composition; the results are variable, but overall the data indicate that the major effect of statin therapy is to reduce the number of LDL particles, although in individual patients, large concomitant reductions in plasma TG levels will usually be associated with increases in LDL size. In a recent report of the Collaborative Atorvastatin Diabetes Study (CARDS) study, atorvastatin treatment reduced the total number of LDL particles by lowering large and medium size LDL; small, dense LDL were not reduced, and there was no change in the mean size of LDL in the atorvastatin group compared with the placebo group (82).
In summary, statins increase LDL receptor-mediated clearance of apoB lipoproteins, particularly LDL, when baseline LDL receptor activity is reduced. However, in patients with dyslipidemia associated with insulin resistance/T2DM, where secretion of VLDL and LDL into the circulation is prominent, statins can improve lipid levels by reducing the assembly and secretion of apoB lipoproteins with or without concomitant changes in fractional clearance. Although beyond the scope of this review, statins may reduce the assembly and secretion of apoB lipoproteins by inhibiting cholesterol synthesis (83–85). However, there is evidence that statins reduce VLDL TG secretion; our evidence in humans with dyslipidemia (86) or T2DM (51) is supported by similar findings in several animal models (87–90). The molecular basis for statin-mediated reductions in VLDL TG secretion are unknown, although some investigators have suggested that statins may stimulate hepatic expression of the gene for peroxisome proliferator-activated receptor α and its target genes (91, 92). Regardless of the mechanisms, the ability of statins to lower both VLDL and LDL levels in patients with T2DM makes them useful agents for treating the dyslipidemic state, which is characterized by overproduction of all apoB lipoproteins.
Effects of Statins: Clinical End-Point Trials
Data from several small early efficacy studies confirm the favorable lipid-altering effects of atorvastatin, fluvastatin, lovastatin, simvastatin, and rosuvastatin in T2DM (93–97). Additional evidence for the efficacy of statins in diabetic dyslipidemia comes from more recent, larger clinical trials comparing lower vs. higher doses of individual statins. The Diabetes Atorvastatin Lipid Intervention study (DALI) compared the effects of aggressive and standard lipid-lowering therapy on fasting TG levels in 217 patients with T2DM (98) who were randomly assigned to aggressive (80 mg/d) or standard (10 mg/d) therapy with atorvastatin vs. placebo. During the 30-wk study, fasting TG levels were reduced by 35% with aggressive therapy and by 25% with moderate therapy compared with an increase of 10% with placebo. Preliminary results of A Randomized, Double-Blind Study to Compare Rosuvastatin and Atorvastatin in Patients with Type II Diabetes study (ANDROMEDA), in which rosuvastatin (10 or 20 mg/d) was administered to 450 patients with T2DM and dyslipidemia, found that LDL cholesterol was reduced by 51% and 57%, respectively, and 94% and 96% of patients achieved their LDL cholesterol goal (99).
Numerous primary and secondary prevention trials provide strong evidence that statins decrease the risk of cardiovascular events in patients with diabetes (Table 1) (8, 9, 100–106). These cardiovascular benefits are closely linked to the lipid-altering effects of the statin and support recommendations by the National Cholesterol Education Program (11) (Table 2) and the American Diabetes Association (107) (Table 3) for aggressive use of statins as first-line therapy in the treatment of diabetic dyslipidemia.
Major placebo-controlled clinical trials of statin therapy in patients with type 2 diabetes mellitus
| Trial | N DM (overall) | Treatment (mg/d) | Mean follow-up (yr) | % Change from baseline | Major CHD1 event rates (%) | RRR, % (P value) | ARR (%) | NNT | |||
|---|---|---|---|---|---|---|---|---|---|---|---|
| LDL | TG | HDL | Treatment | Placebo | |||||||
| Secondary prevention | |||||||||||
| 4S (8) | 202 (4,444) | Simvastatin, 20–40 | 5.4 (median) | −36 | −11 | +7 | 22.9 | 45.4 | 55 (0.002) | 22.5 | 4 |
| 4S reanalysis (100) | 483 (4,398) | Simvastatin, 20–40 | 5.4 (median) | ∼−36 | ∼−11 | ∼6 | 23.5 | 37.5 | 42 (0.001) | 14.0 | 7 |
| CARE (9) | 586 (4,159) | Pravastatin, 40 | 5.0 | −27 | −13 | +4 | 17.7 | 20.4 | 13 (NS) | 2.7 | 37 |
| 28.72 | 36.82 | 25 (0.05) | 8.1 | 12 | |||||||
| LIPID (101) | DM: 1,077 | Pravastatin, 40 | 6.0 | ∼−28 | ∼−19 | ∼4 | 19.6 | 23.4 | DM: 19 (0.11) | 3.8 | 26 |
| IFG: 940 (9,014) | 11.8 | 17.8 | IFG: 36 (0.009) | 6.0 | 17 | ||||||
| HPS (102) | 5,963 (20,536) | Simvastatin, 40 | 4.8 | −28 | −13 | +1 | 9.4 20.23 | 12.6 | 27 (<0.0001) | 4.9 | 20 |
| 25.13 | 22 (<0.0001) | ||||||||||
| Primary prevention | |||||||||||
| ALLHAT-LLT (103) | 3,638 (10,355) | Pravastatin, 20–40 | 4.8 | −284 | −34 | +34 | Not reported for diabetic population | 11 (NS) | |||
| ASCOT-LLA (104) | 2,532 (10,305) | Atorvastatin, 10 | 3.3 (median) | −334 | −224 | 04 | 3.0 | 3.6 | 16 (0.43) | 0.6 | 167 |
| CARDS (105) | 2,838 (2,838) | Atorvastatin, 10 | 3.9 (median) | −31 | −17 | −9 | 5.85 | 9.05 | 37 (0.001) | 3.2 | 31 |
| 4D (106) | 1,255 (1,255) | Atorvastatin, 20 | 3.96 | −42 | NA | NA | 386 | 376 | 8 (0.37) | ||
| Trial | N DM (overall) | Treatment (mg/d) | Mean follow-up (yr) | % Change from baseline | Major CHD1 event rates (%) | RRR, % (P value) | ARR (%) | NNT | |||
|---|---|---|---|---|---|---|---|---|---|---|---|
| LDL | TG | HDL | Treatment | Placebo | |||||||
| Secondary prevention | |||||||||||
| 4S (8) | 202 (4,444) | Simvastatin, 20–40 | 5.4 (median) | −36 | −11 | +7 | 22.9 | 45.4 | 55 (0.002) | 22.5 | 4 |
| 4S reanalysis (100) | 483 (4,398) | Simvastatin, 20–40 | 5.4 (median) | ∼−36 | ∼−11 | ∼6 | 23.5 | 37.5 | 42 (0.001) | 14.0 | 7 |
| CARE (9) | 586 (4,159) | Pravastatin, 40 | 5.0 | −27 | −13 | +4 | 17.7 | 20.4 | 13 (NS) | 2.7 | 37 |
| 28.72 | 36.82 | 25 (0.05) | 8.1 | 12 | |||||||
| LIPID (101) | DM: 1,077 | Pravastatin, 40 | 6.0 | ∼−28 | ∼−19 | ∼4 | 19.6 | 23.4 | DM: 19 (0.11) | 3.8 | 26 |
| IFG: 940 (9,014) | 11.8 | 17.8 | IFG: 36 (0.009) | 6.0 | 17 | ||||||
| HPS (102) | 5,963 (20,536) | Simvastatin, 40 | 4.8 | −28 | −13 | +1 | 9.4 20.23 | 12.6 | 27 (<0.0001) | 4.9 | 20 |
| 25.13 | 22 (<0.0001) | ||||||||||
| Primary prevention | |||||||||||
| ALLHAT-LLT (103) | 3,638 (10,355) | Pravastatin, 20–40 | 4.8 | −284 | −34 | +34 | Not reported for diabetic population | 11 (NS) | |||
| ASCOT-LLA (104) | 2,532 (10,305) | Atorvastatin, 10 | 3.3 (median) | −334 | −224 | 04 | 3.0 | 3.6 | 16 (0.43) | 0.6 | 167 |
| CARDS (105) | 2,838 (2,838) | Atorvastatin, 10 | 3.9 (median) | −31 | −17 | −9 | 5.85 | 9.05 | 37 (0.001) | 3.2 | 31 |
| 4D (106) | 1,255 (1,255) | Atorvastatin, 20 | 3.96 | −42 | NA | NA | 386 | 376 | 8 (0.37) | ||
ARR, Absolute risk reduction; DM, diabetes mellitus; IFG, impaired fasting glucose; NA, not available; NNT, number needed to treat to prevent one event; NS, not significant; RAR, relative risk reduction. NNT was rounded to the nearest whole number.
Combined coronary death and nonfatal MI.
Combined major CHD events, coronary artery bypass graft and percutaneous transluminal coronary angioplasty.
Combined major CHD events, stroke and revascularization.
For overall population.
Combined major CHD events, unstable angina and nonfatal cardiac arrest.
Combined major CHD events, stroke.
Major placebo-controlled clinical trials of statin therapy in patients with type 2 diabetes mellitus
| Trial | N DM (overall) | Treatment (mg/d) | Mean follow-up (yr) | % Change from baseline | Major CHD1 event rates (%) | RRR, % (P value) | ARR (%) | NNT | |||
|---|---|---|---|---|---|---|---|---|---|---|---|
| LDL | TG | HDL | Treatment | Placebo | |||||||
| Secondary prevention | |||||||||||
| 4S (8) | 202 (4,444) | Simvastatin, 20–40 | 5.4 (median) | −36 | −11 | +7 | 22.9 | 45.4 | 55 (0.002) | 22.5 | 4 |
| 4S reanalysis (100) | 483 (4,398) | Simvastatin, 20–40 | 5.4 (median) | ∼−36 | ∼−11 | ∼6 | 23.5 | 37.5 | 42 (0.001) | 14.0 | 7 |
| CARE (9) | 586 (4,159) | Pravastatin, 40 | 5.0 | −27 | −13 | +4 | 17.7 | 20.4 | 13 (NS) | 2.7 | 37 |
| 28.72 | 36.82 | 25 (0.05) | 8.1 | 12 | |||||||
| LIPID (101) | DM: 1,077 | Pravastatin, 40 | 6.0 | ∼−28 | ∼−19 | ∼4 | 19.6 | 23.4 | DM: 19 (0.11) | 3.8 | 26 |
| IFG: 940 (9,014) | 11.8 | 17.8 | IFG: 36 (0.009) | 6.0 | 17 | ||||||
| HPS (102) | 5,963 (20,536) | Simvastatin, 40 | 4.8 | −28 | −13 | +1 | 9.4 20.23 | 12.6 | 27 (<0.0001) | 4.9 | 20 |
| 25.13 | 22 (<0.0001) | ||||||||||
| Primary prevention | |||||||||||
| ALLHAT-LLT (103) | 3,638 (10,355) | Pravastatin, 20–40 | 4.8 | −284 | −34 | +34 | Not reported for diabetic population | 11 (NS) | |||
| ASCOT-LLA (104) | 2,532 (10,305) | Atorvastatin, 10 | 3.3 (median) | −334 | −224 | 04 | 3.0 | 3.6 | 16 (0.43) | 0.6 | 167 |
| CARDS (105) | 2,838 (2,838) | Atorvastatin, 10 | 3.9 (median) | −31 | −17 | −9 | 5.85 | 9.05 | 37 (0.001) | 3.2 | 31 |
| 4D (106) | 1,255 (1,255) | Atorvastatin, 20 | 3.96 | −42 | NA | NA | 386 | 376 | 8 (0.37) | ||
| Trial | N DM (overall) | Treatment (mg/d) | Mean follow-up (yr) | % Change from baseline | Major CHD1 event rates (%) | RRR, % (P value) | ARR (%) | NNT | |||
|---|---|---|---|---|---|---|---|---|---|---|---|
| LDL | TG | HDL | Treatment | Placebo | |||||||
| Secondary prevention | |||||||||||
| 4S (8) | 202 (4,444) | Simvastatin, 20–40 | 5.4 (median) | −36 | −11 | +7 | 22.9 | 45.4 | 55 (0.002) | 22.5 | 4 |
| 4S reanalysis (100) | 483 (4,398) | Simvastatin, 20–40 | 5.4 (median) | ∼−36 | ∼−11 | ∼6 | 23.5 | 37.5 | 42 (0.001) | 14.0 | 7 |
| CARE (9) | 586 (4,159) | Pravastatin, 40 | 5.0 | −27 | −13 | +4 | 17.7 | 20.4 | 13 (NS) | 2.7 | 37 |
| 28.72 | 36.82 | 25 (0.05) | 8.1 | 12 | |||||||
| LIPID (101) | DM: 1,077 | Pravastatin, 40 | 6.0 | ∼−28 | ∼−19 | ∼4 | 19.6 | 23.4 | DM: 19 (0.11) | 3.8 | 26 |
| IFG: 940 (9,014) | 11.8 | 17.8 | IFG: 36 (0.009) | 6.0 | 17 | ||||||
| HPS (102) | 5,963 (20,536) | Simvastatin, 40 | 4.8 | −28 | −13 | +1 | 9.4 20.23 | 12.6 | 27 (<0.0001) | 4.9 | 20 |
| 25.13 | 22 (<0.0001) | ||||||||||
| Primary prevention | |||||||||||
| ALLHAT-LLT (103) | 3,638 (10,355) | Pravastatin, 20–40 | 4.8 | −284 | −34 | +34 | Not reported for diabetic population | 11 (NS) | |||
| ASCOT-LLA (104) | 2,532 (10,305) | Atorvastatin, 10 | 3.3 (median) | −334 | −224 | 04 | 3.0 | 3.6 | 16 (0.43) | 0.6 | 167 |
| CARDS (105) | 2,838 (2,838) | Atorvastatin, 10 | 3.9 (median) | −31 | −17 | −9 | 5.85 | 9.05 | 37 (0.001) | 3.2 | 31 |
| 4D (106) | 1,255 (1,255) | Atorvastatin, 20 | 3.96 | −42 | NA | NA | 386 | 376 | 8 (0.37) | ||
ARR, Absolute risk reduction; DM, diabetes mellitus; IFG, impaired fasting glucose; NA, not available; NNT, number needed to treat to prevent one event; NS, not significant; RAR, relative risk reduction. NNT was rounded to the nearest whole number.
Combined coronary death and nonfatal MI.
Combined major CHD events, coronary artery bypass graft and percutaneous transluminal coronary angioplasty.
Combined major CHD events, stroke and revascularization.
For overall population.
Combined major CHD events, unstable angina and nonfatal cardiac arrest.
Combined major CHD events, stroke.
NCEP lipid goals and therapeutic considerations for patients with diabetic dyslipidemia
| LDL goal | Non-HDL goal (if TG ≥200 mg/dl) | Therapeutic considerations for all patients |
|---|---|---|
| <100 mg/dl | <130 mg/dl | Initiate TLC |
| Intensively treat nonlipid risk factors (hypertension, cigarette smoking, hyperglycemia) | ||
| Optional goal: <70 mg/dl for very high risk patients | If TG ≥200 mg/dl, consider treatment with fibrate or nicotinic acid (either as alternative to or in combination with LDL-lowering drug) to achieve goal for non-HDL cholesterol1 | If nicotinic acid is employed, use relatively low doses (<3 g/d) |
| Additional therapeutic considerations depending on baseline LDL cholesterol level | ||
| LDL ≥130 mg/dl | Many persons with type 1 or 2 diabetes will require LDL-lowering drugs (statins usually first choice) along with TLC | |
| Type 1 diabetes: clinical judgment required for intensity of LDL-lowering therapy to reach goal | ||
| Type 2 diabetes: generally delay management of atherogenic dyslipidemia (high TG, low HDL, small LDL) until LDL goal has been achieved | ||
| LDL 100–129 mg/dl | Consider: intensifying TLC; use of LDL-lowering drug; drug to lower TG or raise HDL; control of nonlipid risk factors | |
| Additional therapeutic considerations depending on on-treatment LDL cholesterol level | ||
| LDL 100–129 mg/dl | Intensify TLC in all persons | |
| If TG <200 mg/dl, consider intensifying LDL-lowering therapy (e.g. higher dose of statin or combining a statin with a bile acid sequestrant) | ||
| LDL goal | Non-HDL goal (if TG ≥200 mg/dl) | Therapeutic considerations for all patients |
|---|---|---|
| <100 mg/dl | <130 mg/dl | Initiate TLC |
| Intensively treat nonlipid risk factors (hypertension, cigarette smoking, hyperglycemia) | ||
| Optional goal: <70 mg/dl for very high risk patients | If TG ≥200 mg/dl, consider treatment with fibrate or nicotinic acid (either as alternative to or in combination with LDL-lowering drug) to achieve goal for non-HDL cholesterol1 | If nicotinic acid is employed, use relatively low doses (<3 g/d) |
| Additional therapeutic considerations depending on baseline LDL cholesterol level | ||
| LDL ≥130 mg/dl | Many persons with type 1 or 2 diabetes will require LDL-lowering drugs (statins usually first choice) along with TLC | |
| Type 1 diabetes: clinical judgment required for intensity of LDL-lowering therapy to reach goal | ||
| Type 2 diabetes: generally delay management of atherogenic dyslipidemia (high TG, low HDL, small LDL) until LDL goal has been achieved | ||
| LDL 100–129 mg/dl | Consider: intensifying TLC; use of LDL-lowering drug; drug to lower TG or raise HDL; control of nonlipid risk factors | |
| Additional therapeutic considerations depending on on-treatment LDL cholesterol level | ||
| LDL 100–129 mg/dl | Intensify TLC in all persons | |
| If TG <200 mg/dl, consider intensifying LDL-lowering therapy (e.g. higher dose of statin or combining a statin with a bile acid sequestrant) | ||
The combination of statins plus fibrate is accompanied by increased risk for myopathy. Subjects should be instructed to be aware of the signs and symptoms of myopathy and report these immediately to their physician.
NCEP lipid goals and therapeutic considerations for patients with diabetic dyslipidemia
| LDL goal | Non-HDL goal (if TG ≥200 mg/dl) | Therapeutic considerations for all patients |
|---|---|---|
| <100 mg/dl | <130 mg/dl | Initiate TLC |
| Intensively treat nonlipid risk factors (hypertension, cigarette smoking, hyperglycemia) | ||
| Optional goal: <70 mg/dl for very high risk patients | If TG ≥200 mg/dl, consider treatment with fibrate or nicotinic acid (either as alternative to or in combination with LDL-lowering drug) to achieve goal for non-HDL cholesterol1 | If nicotinic acid is employed, use relatively low doses (<3 g/d) |
| Additional therapeutic considerations depending on baseline LDL cholesterol level | ||
| LDL ≥130 mg/dl | Many persons with type 1 or 2 diabetes will require LDL-lowering drugs (statins usually first choice) along with TLC | |
| Type 1 diabetes: clinical judgment required for intensity of LDL-lowering therapy to reach goal | ||
| Type 2 diabetes: generally delay management of atherogenic dyslipidemia (high TG, low HDL, small LDL) until LDL goal has been achieved | ||
| LDL 100–129 mg/dl | Consider: intensifying TLC; use of LDL-lowering drug; drug to lower TG or raise HDL; control of nonlipid risk factors | |
| Additional therapeutic considerations depending on on-treatment LDL cholesterol level | ||
| LDL 100–129 mg/dl | Intensify TLC in all persons | |
| If TG <200 mg/dl, consider intensifying LDL-lowering therapy (e.g. higher dose of statin or combining a statin with a bile acid sequestrant) | ||
| LDL goal | Non-HDL goal (if TG ≥200 mg/dl) | Therapeutic considerations for all patients |
|---|---|---|
| <100 mg/dl | <130 mg/dl | Initiate TLC |
| Intensively treat nonlipid risk factors (hypertension, cigarette smoking, hyperglycemia) | ||
| Optional goal: <70 mg/dl for very high risk patients | If TG ≥200 mg/dl, consider treatment with fibrate or nicotinic acid (either as alternative to or in combination with LDL-lowering drug) to achieve goal for non-HDL cholesterol1 | If nicotinic acid is employed, use relatively low doses (<3 g/d) |
| Additional therapeutic considerations depending on baseline LDL cholesterol level | ||
| LDL ≥130 mg/dl | Many persons with type 1 or 2 diabetes will require LDL-lowering drugs (statins usually first choice) along with TLC | |
| Type 1 diabetes: clinical judgment required for intensity of LDL-lowering therapy to reach goal | ||
| Type 2 diabetes: generally delay management of atherogenic dyslipidemia (high TG, low HDL, small LDL) until LDL goal has been achieved | ||
| LDL 100–129 mg/dl | Consider: intensifying TLC; use of LDL-lowering drug; drug to lower TG or raise HDL; control of nonlipid risk factors | |
| Additional therapeutic considerations depending on on-treatment LDL cholesterol level | ||
| LDL 100–129 mg/dl | Intensify TLC in all persons | |
| If TG <200 mg/dl, consider intensifying LDL-lowering therapy (e.g. higher dose of statin or combining a statin with a bile acid sequestrant) | ||
The combination of statins plus fibrate is accompanied by increased risk for myopathy. Subjects should be instructed to be aware of the signs and symptoms of myopathy and report these immediately to their physician.
American Diabetes Association dyslipidemia treatment goals and recommendations for adults with diabetes
| Dyslipidemia treatment goals |
| Lower LDL-C to <100 mg/dl (2.6 mmol/liter) or in patients >40 yr of age ∼30% if total cholesterol ≥135 mg/dl (3.5 mmol/liter) regardless of baseline LDL |
| Lower TG to <150 mg/dl (1.7 mmol/liter) |
| Raise HDL-C to >40 mg/dl (1.15 mmol/liter) for men; >50 mg/dl (1.3 mol/liter) for women |
| Recommendations |
| Lifestyle modification to improve lipid profile if LDL-C is ≥100 mg/dl (2.6 mmol/liter) |
| Reduction of saturated fat and cholesterol intake, weight loss, exercise, smoking cessation |
| Pharmacological therapy (for those not achieving lipid goals with lifestyle modifications) |
| Aggressive statin therapy to lower LDL-C and reduce cardiovascular events |
| Fibrate therapy to lower TG, increase HDL, and reduce cardiovascular events in patients with CVD, low HDL, and near-normal LDL cholesterol |
| Combination therapy with statins and fibrates or niacin to achieve lipid targets, although outcome studies for event reduction or safety are not available |
| Dyslipidemia treatment goals |
| Lower LDL-C to <100 mg/dl (2.6 mmol/liter) or in patients >40 yr of age ∼30% if total cholesterol ≥135 mg/dl (3.5 mmol/liter) regardless of baseline LDL |
| Lower TG to <150 mg/dl (1.7 mmol/liter) |
| Raise HDL-C to >40 mg/dl (1.15 mmol/liter) for men; >50 mg/dl (1.3 mol/liter) for women |
| Recommendations |
| Lifestyle modification to improve lipid profile if LDL-C is ≥100 mg/dl (2.6 mmol/liter) |
| Reduction of saturated fat and cholesterol intake, weight loss, exercise, smoking cessation |
| Pharmacological therapy (for those not achieving lipid goals with lifestyle modifications) |
| Aggressive statin therapy to lower LDL-C and reduce cardiovascular events |
| Fibrate therapy to lower TG, increase HDL, and reduce cardiovascular events in patients with CVD, low HDL, and near-normal LDL cholesterol |
| Combination therapy with statins and fibrates or niacin to achieve lipid targets, although outcome studies for event reduction or safety are not available |
Source: Ref.107 .
American Diabetes Association dyslipidemia treatment goals and recommendations for adults with diabetes
| Dyslipidemia treatment goals |
| Lower LDL-C to <100 mg/dl (2.6 mmol/liter) or in patients >40 yr of age ∼30% if total cholesterol ≥135 mg/dl (3.5 mmol/liter) regardless of baseline LDL |
| Lower TG to <150 mg/dl (1.7 mmol/liter) |
| Raise HDL-C to >40 mg/dl (1.15 mmol/liter) for men; >50 mg/dl (1.3 mol/liter) for women |
| Recommendations |
| Lifestyle modification to improve lipid profile if LDL-C is ≥100 mg/dl (2.6 mmol/liter) |
| Reduction of saturated fat and cholesterol intake, weight loss, exercise, smoking cessation |
| Pharmacological therapy (for those not achieving lipid goals with lifestyle modifications) |
| Aggressive statin therapy to lower LDL-C and reduce cardiovascular events |
| Fibrate therapy to lower TG, increase HDL, and reduce cardiovascular events in patients with CVD, low HDL, and near-normal LDL cholesterol |
| Combination therapy with statins and fibrates or niacin to achieve lipid targets, although outcome studies for event reduction or safety are not available |
| Dyslipidemia treatment goals |
| Lower LDL-C to <100 mg/dl (2.6 mmol/liter) or in patients >40 yr of age ∼30% if total cholesterol ≥135 mg/dl (3.5 mmol/liter) regardless of baseline LDL |
| Lower TG to <150 mg/dl (1.7 mmol/liter) |
| Raise HDL-C to >40 mg/dl (1.15 mmol/liter) for men; >50 mg/dl (1.3 mol/liter) for women |
| Recommendations |
| Lifestyle modification to improve lipid profile if LDL-C is ≥100 mg/dl (2.6 mmol/liter) |
| Reduction of saturated fat and cholesterol intake, weight loss, exercise, smoking cessation |
| Pharmacological therapy (for those not achieving lipid goals with lifestyle modifications) |
| Aggressive statin therapy to lower LDL-C and reduce cardiovascular events |
| Fibrate therapy to lower TG, increase HDL, and reduce cardiovascular events in patients with CVD, low HDL, and near-normal LDL cholesterol |
| Combination therapy with statins and fibrates or niacin to achieve lipid targets, although outcome studies for event reduction or safety are not available |
Source: Ref.107 .
Subanalyses of four secondary prevention trials [Scandinavian Simvastatin Survival Study (4S; two analyses), Cholesterol and Recurrent Events (CARE), Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID), and the Heart Protection Study (HPS)] incorporating more than 9000 patients with mostly type 2 diabetes or impaired fasting glucose indicate that statin treatment significantly reduces the coronary event rate vs. placebo in this population, and that the risk reductions are similar to those in statin-treated nondiabetic patients (8, 9, 100–102). The relative risk reduction in these studies ranged from 13–55% compared with placebo. Of note, HPS also included primary prevention patients, but did not separate out findings by prevention status. In all of these studies, statin therapy was well tolerated. The data for the subset of patients with diabetes included in the Treating to New Targets (TNT) trial have not yet been published, although a presentation at the Annual Meeting of the American Diabetes Association in June 2005 indicated similar benefits of more aggressive LDL lowering in the patients with diabetes as was observed in the overall cohort.
Among four primary prevention studies [Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT), Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT–LLA), CARDS, and Die Deutsche Diabetes Dialyze (4D)] including more than 9000 patients, only CARDS reported an unequivocal significant reduction in cardiovascular event rates (103–106). The lack of treatment effect in ASCOT-LLA is probably attributable to an inadequate number of absolute events in the smaller subgroup with diabetes (104), because the 16% reduction in MI was not significantly different from that observed in the overall ASCOT-LLA population. The negative outcome in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial study is probably a result of a high rate of LDL cholesterol-lowering treatments in the usual care group, resulting in a small (11%) difference in LDL cholesterol concentrations between the treated and usual care groups (103). Finally, the Die Deutsche Diabetes Dialyze trial enrolled patients with end-stage renal disease, and thus the lack of significant improvement in CHD risk rates suggests either that statin treatment may need to be provided to patients with T2DM at an earlier stage of disease or that cardiovascular events in patients with end-stage renal disease is not amenable to statin therapy (106). The results of CARDS, in which a 40% reduction in LDL cholesterol was associated with a 37% reduction in the primary end point of time to first acute CHD event, revascularization, or stroke (105), does provide strong support for the view that primary prevention is beneficial in patients with T2DM.
Ongoing Studies
The results of ongoing clinical trials will provide greater clarity about the role of statins in preventing cardiovascular events in patients with T2DM. The Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints (ASPEN) in noinsulin-dependent diabetic patients randomized more than 2400 diabetic subjects, with and without previous MI, to treatment with atorvastatin 10 mg/d or placebo for at least 4 yr (108). The Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) is comparing 20 vs. 80 mg simvastatin for reduction of CHD events in 12,000 post-MI patients, including a substantial number with T2DM (number not yet reported) (109). SEARCH also will test the hypothesis that lowering plasma homocysteine with folic acid and vitamin B12 will reduce CHD events.
The Incremental Decrease in Endpoints through Aggressive Lipid Lowering trial (IDEAL) randomized more than 1000 subjects with CHD and T2DM to 80 mg/d atorvastatin or 20–40 mg/d simvastatin treatment (110). Study completion is expected shortly. The lipid arm of the Action to Control Cardiovascular Risk in Diabetes study (ACCORD) will randomize 10,000 patients with T2DM (www.accordtrial.org) to receive 20–40 mg/d simvastatin and either placebo or fenofibrate (160 mg/d) to determine whether raising HDL cholesterol levels and lowering TG levels in the context of desirable LDL cholesterol levels will further reduce the rate of ASCVD events. A Study Evaluating the Use of Rosuvastatin in Patients Requiring Ongoing Renal Dialysis: an Assessment of Survival and Cardiovascular Events (AURORA) will follow 2700 patients with end-stage renal disease receiving hemodialysis (25% of whom have diabetes) to evaluate the effect of 10 mg rosuvastatin on survival and the incidence of major cardiovascular events (111). Results are expected in 2007.
Safety Considerations
Statins have probably been the most studied class of drugs in the past 2 decades; as reviewed above and in Table 1, more than 15,000 patients with diabetes mellitus have been enrolled in completed, placebo-controlled clinical trials. Overall, the safety of statins in patients with T2DM appears to be equivalent to that in nondiabetics. There do not appear to be any increases in liver enzymes above the levels in the placebo group, at least when doses below the highest dose of any statin are used. For example, among 2838 subjects with T2DM in the recently reported CARDS study, there were no occurrences of rhabdomyolysis, and one case of myopathy was seen in each of the placebo and atorvastatin groups (105). Myalgia was noted in 72 patients allocated placebo and in 61 allocated atorvastatin. Ten individuals in the placebo group (0.7% of those randomized) and two (0.1%) in the atorvastatin group had at least one increase in creatine kinase of 10 times or more the upper limit of normal on routine safety screening. Of subjects taking placebo or atorvastatin, 1% in each group had at least one increase in alanine transaminase of three times or more the upper limit of normal. At least one rise in aspartate transaminase of three times or more the upper limit of normal was reported in four (0.3%) patients in the placebo group and six (0.4%) in the atorvastatin group. When one considers the benefit to risk ratio in patients with T2DM, there is no doubt that statins are effective and safe agents.
Combined Therapy with Statins and Other Lipid-Altering Agents
As recommended goals for LDL are lowered (112), and TG and HDL become targets (113), the use of statins in combination with other agents must be considered. Additional LDL lowering can be achieved when statins are combined with bile acid-binding resins (15–20% additional lowering), stanol and sterol esters from plants (10–15% additional lowering), and inhibitors of cholesterol absorption (15–20% additional lowering). The latter approach might have been particularly relevant to patients with T2DM, because of older reports of increased absorption of cholesterol in this group. However, a recent study indicated that cholesterol absorption is not increased in T2DM (52). Combining statins with fibrates or niacin offers significant reductions in TG and increases in HDL. The use of combined fibrates and statins has been limited by the concern that the incidence of myositis and rhabdomyolysis would increase (114). However, recent pharmacokinetic studies indicate that fenofibrate, unlike gemfibrozil, does not increase blood levels of statins and, therefore, may be safe to use in combination therapy (115). More data will be needed, but experts are optimistic that fenofibrate-statin combinations will be as safe as statin monotherapy. The combination of niacin and a statin probably does not carry any increased risk for myositis or rhabdomyolysis. Niacin use does carry with it a risk for worsening of diabetic control (116), although recent studies indicate that this is mild and can be readily corrected with titration of antiglycemic medications (117, 118). Combination therapy with statins and fish oils also offers additional TG lowering compared with statin therapy alone, although increases in HDL cholesterol levels usually will not match those seen with fibrates or niacin.
Conclusions
3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors are clearly very efficacious at reducing blood levels of LDL cholesterol. The effects of statins on VLDL TG are more variable, possibly because of their varied effects on VLDL apoB and TG metabolism. Although large clinical trials have shown clinically relevant reductions in ASCVD events in patients with T2DM, the results of several ongoing trials will further elucidate the role of statin therapy in the prevention of cardiovascular events in this patient population. However, the large and convincing body of evidence, ranging from small mechanistic studies to large clinical end-point trials, provides an extremely strong case for aggressive, early statin treatment of diabetic dyslipidemia.
Note Added in Proof
The Incremental Decrease in Endpoints through Aggressive Lipid Lowering (IDEAL) study (119) was published while this review was going to press. The overall study showed a trend toward reductions (−9.3%; P = 0.07) in the primary endpoint of major coronary events (coronary death, nonfatal MI, resuscitated cardiac arrest). No subgroup data were provided.
Abbreviations:
- apoB,
Apolipoprotein B;
- ASCVD,
atherosclerotic cardiovascular disease;
- CARDS,
Collaborative Atorvastatin Diabetes Study;
- CETP,
cholesteryl ester transfer protein;
- CHD,
coronary heart disease;
- ER,
endoplasmic reticulum;
- FH,
familial hypercholesterolemia;
- HDL,
high-density lipoprotein;
- HL,
hepatic lipase;
- IDL,
intermediate-density lipoprotein;
- LDL,
low-density lipoprotein;
- LpL,
lipoprotein lipase;
- MI,
myocardial infarction;
- T2DM,
type 2 diabetes mellitus;
- TG,
triglycerides;
- VLDL,
very low-density lipoprotein.
