Should statin therapy be offered to all patients with type 2 diabetes?
For patients older than 40 years with type 2 diabetes who are not known to have cardiovascular disease, statins are recommended if other cardiovascular risk factors are present, regardless of the initial low-density lipoprotein (LDL) level, if the patient has failed to reach the target LDL goal of less than 100 mg per dL (2.6 mmol per L) by lifestyle modification for primary prevention.1–3 [Strength of recommendation: A]
There is no clear evidence to support routine use of statins in patients with type 2 diabetes who are younger than 40 years, who have no cardiovascular risk factors, and who have an LDL level lower than 130 mg per dL (3.4 mmol per L), although that has been suggested by some expert groups. [Strength of recommendation: C]
A recent systematic review and meta-analysis1 identified 14 randomized controlled trials of primary and secondary prevention of type 2 diabetes. Six studied primary prevention and eight studied secondary prevention (i.e., prevention in patients with known heart disease). All but one study in each group used statins. Lipid-lowering agents were more effective than placebo for secondary prevention of any cardiovascular event (absolute risk reduction [ARR]: 7%; 95% confidence interval [CI]: 3 to 12%; number needed to treat [NNT]: 14 for 4.9 years of treatment) (Table 11 ). This review1 included trials whose participants had diverse pretreatment LDL cholesterol levels. Lipid-lowering medications reduced the risk of any cardiovascular event in patients with diabetes who did not have known heart disease (ARR: 3%; 95% CI: 1 to 4%; NNT: 35 for 4.3 years of treatment).
For primary and secondary prevention, most of the patients came from the Heart Protection Study (HPS).2 HPS was the only individual trial that showed a statistically significant benefit for primary prevention. HPS was a large randomized, placebo-controlled trial of 5,963 patients with type 2 diabetes. Patients ranged in age from 40 to 80 years, had a total cholesterol of at least 135 mg per dL (3.5 mmol per L), and were treated with simvastatin (Zocor) or placebo for an average of 4.8 years (primary prevention was ARR: 5%; 95% CI: 3 to 7%; secondary prevention was ARR: 4%; 95% CI: zero to 9%). HPS found similar relative benefit among those whose pre-treatment LDL cholesterol level was below 116 mg per dL (3.0 mmol per L) to those with a higher LDL level.2 The Prospective Study of Pravastatin in the Elderly at Risk trial found a trend toward harm regarding primary and secondary prevention, but it was not statistically significant in either case.3 The meta-analysis did not report the impact of statin therapy on all-cause mortality and cardiovascular mortality because the information was not included in the original study.
The Collaborative Atorvastatin Diabetes Study (CARDS)4 is a recent multicenter, randomized, placebo-controlled trial on the primary prevention of cardiovascular disease in patients with type 2 diabetes that was not included in the above meta-analysis. This study randomized patients with type 2 diabetes who were 40 to 75 years of age with at least one other additional cardiac risk factor (e.g., hypertension, retinopathy, albuminuria, current smoking) and an entry LDL cholesterol level lower than 160 mg per dL (4.1 mmol per L) to either atorvastatin (Lipitor) 10 mg once daily or placebo. The mean LDL cholesterol level was 117 mg per dL (3.0 mmol per L) in the placebo and treatment groups. After a median duration of 3.9 years, ARR = 3.7% of the first occurrence of a major cardiovascular event in the treatment group (NNT: 31 for four years,P = .001).
|Trials||CHD event rate, control group, (n/n)||CHD event rate, intervention group, (n/n)||ARR for CHD event (%[95% CI])||NNT|
|AFCAPS/TexCAPS||6/71||4/84||4 (−4 to 12)||27.1|
|HHS||8/76||2/59||7 (−1 to 15)||14.0|
|HPS||367/1,976||276/2,006||5 (3 to 7)||20.8|
|PROSPER||28/205||32/191||−3 (−10 to 4)||−32.3|
|ASCOT-LLA||46/1,274||38/1,258||1 (−1 to 2)||169.5|
|Pooled*||3 (1 to 4)||34.5†|
|4S||44/97||24/105||23 (10 to 35)||4.4|
|CARE||112/304||81/282||8 (1 to 16)||12.3|
|HPS||381/1,009||325/972||4 (0 to 9)||23.1|
|LIPID||88/386||76/396||4 (−2 to 9)||27.7|
|LIPS||31/82||26/120||16 (3 to 29)||6.2|
|Post-CABG||14/53||9/63||12 (−3 to 27)||8.2|
|PROSPER||31/115||38/112||−7 (−19 to 5)||−14.3|
|VA-HIT||116/318||88/309||8 (1 to 15)||12.5|
|Pooled*||7 (3 to 12)||13.8†|
Recommendations from Others
The American Diabetes Association (ADA) recommends that lipid-lowering therapy be initiated with lifestyle intervention in patients with type 2 diabetes and clinical coronary artery disease. The primary goal for all patients with diabetes is an LDL cholesterol level lower than 100 mg per dL. Furthermore, the ADA recommends that for patients older than 40 years with diabetes, a total cholesterol greater than 135 mg per dL, and without overt cardiovascular disease, statin therapy should be offered to achieve an LDL level reduction of 30 to 40 percent regardless of baseline LDL levels. For patients younger than 40 years without overt cardiovascular disease but with additional cardiac risk factors, the addition of pharmacologic therapy to ongoing lifestyle modification to reach a target goal of an LDL cholesterol level lower than 100 mg per dL is recommended.5
A recent evidence-based guideline6 from the American College of Physicians recommends that lipid-lowering therapy should be used for all patients with type 2 diabetes and known coronary artery disease. It also recommends that statins should be used for primary prevention against macrovascular complications in all patients with type 2 diabetes and other cardiovascular risk factors.
The National Cholesterol Education Project (NCEP) Adult Treatment Panel III guideline7 recommends that patients with diabetes and cardiovascular disease should initiate statin therapy regardless of baseline LDL cholesterol levels. For patients in this high-risk group, statins are a therapeutic option to achieve a low LDL cholesterol level (i.e., lower than 70 mg per dL [1.8 mmol per L]).7 This recommendation is endorsed by the ADA.7 However, for patients with diabetes who have no known cardiovascular disease and an LDL cholesterol level lower than 116 mg per dL, NCEP recommends that initiation of a lipid-lowering medication should be an option based on the clinical judgment of the physician.7
Evidence from recent clinical trials has given physicians a new opportunity to reduce cardiovascular morbidity and mortality in patients with type 2 diabetes. For patients with type 2 diabetes, there is compelling evidence for aggressive lipid lowering in addition to tight blood pressure and glycemic control with statin therapy. A recent cost-effectiveness study based on a cardiovascular disease life-expectancy model with the assumed benefit of statin therapy from the Scandinavian Simvastatin Survival Study8 suggests that among men and women with diabetes but no cardiovascular disease, lipid therapy with a statin is likely to be as cost-effective as treating individuals with cardiovascular disease who do not have diabetes. The study estimated the cost ranges from $5,063 to $23,792 per year of life saved.9 Although more evidence is needed to support a universal recommendation of statin therapy for all patients with type 2 diabetes and without clinical cardiovascular disease, it is clear that most patients with diabetes probably benefit to some extent from lipid-lowering therapy.