More Aggressive Targets for LDL and Blood Pressure Slow Atherosclerosis, Reduce LV Mass in Diabetics

 Treating diabetic patients with high low-density lipoprotein (LDL) cholesterol and hypertension to lower-than-normal targets appears to produce regressions in atherosclerosis not seen in similar patients treated to standard target LDL and systolic blood-pressure levels, results from the Stop Atherosclerosis in Native Diabetics (SANDS) study suggest [1].

Writing in the April 9, 2008 issue of the Journal of the American Medical Association, Dr Barbara V Howard (Medstar Research Institute, Hyattsville, MD) and colleagues note that while the use of a surrogate end point — in this case, change in carotid intima media thickness (IMT) — is not a substitute for hard clinical events, the findings support the idea that an aggressive two-pronged approach may be particularly beneficial in diabetics. Importantly, the changes were seen in patients who had had no previous cardiovascular events.

The study looked exclusively at American Indian men and women with type 2 diabetes, hypertension, and dyslipidemia. According to Howard, this group was chosen because the LDL and blood-pressure targets have been previously validated in this population, while the carotid IMT and echocardiography measures have been shown to predict future events in this group. "We have also found over the years that studying American Indians with diabetes has been extremely relevant because this is a population that has classic type 2 diabetes; they’ve just had it longer, and so we know more about them," she said. "And now that there’s an epidemic all through the US, what we’ve learned has been very valuable."

Lower is better

Patients were randomized to drug treatment to reach the standard targets of 100 mg/dL or lower for LDL and 130 mm Hg or lower for systolic blood pressure (SBP) or to a more aggressive target of 70 mg/dL or lower for LDL and 115 mm Hg or lower for SBP.

Howard et al report that, while both groups were successfully treated to their respective LDL and SBP targets over 12 months and both experienced similarly low rates of cardiovascular events, only patients in the aggressive target group experienced regression of atherosclerosis by IMT. Likewise, patients in the aggressive target group also experienced greater decreases in left ventricular (LV) mass, as measured by echocardiography.

Changes by treatment targets

*Serious adverse events related only to BP drugs, not lipid-lowering drugs.

According to Howard, the atherosclerosis changes appeared to be linked to the LDL lowering, as other studies have shown, while the LV changes likely occurred in response to lower SBP.

"In our secondary analyses, we showed that the reduction in IMT was largely due to the LDL reduction. It’s hard to tease that out, but from the models we’ve set up it looks to us that the LDL drop is driving the reduction in atherosclerosis, and the blood-pressure change was largely responsible for the improvement in the size of the heart."

While the study implies that there are greater gains to be had by treating diabetics to even lower LDL and SBP goals, Howard emphasizes that only a small number of clinical events occurred even in patients treated to standard targets. "Our study suggests that treating even to the standard targets, which most diabetics don’t reach, is going to be very effective, although we need to look for longer, in more people, to be sure that the improvements that we saw in the neck vessels and in heart function will translate into lower events," she said. "The key is going to be cost/benefit. If, in fact, you could maintain that low rate of events in the standard group, that might be enough. In other words, if you control both their major risk factors, is it really worth the effort and money to go much lower? And is it worth the risks?"

In SANDS, rates of adverse events associated with drug therapy were higher in the more aggressively treated group, although rates of serious adverse events were no different. "There are some side effects, and you can’t know in advance if these would become more of a problem over time," she told heartwire.

The National Heart, Lung, and Blood Institute and the National Institutes of Health funded this study. Donations of pharmacologic agents were provided by First Horizon Pharmacy (Triglide), Merck and Co (Cozaar/Hyzaar), and Pfizer Inc (Lipitor). Some of the study authors have obtained funding. Other study authors have disclosed various financial relationships with Merck, Shering-Plough, the Egg Nutrition Council, General Mills, Pfizer, Bristol-Meyers Squibb, AstraZeneca, Kos, Reliant, Daiichi Sankyo, Bayhill Therapeutics, Boehringer Ingelheim, NovoNordisk, Takeda, Veralight, Amylin, Eli Lilly, GlaxoSmith Kline, Lifescan, sanofi aventis, Tethys Bioscience, Johnson & Johnson, Abbott, Merck Sharp & Dohme, and Novartis. The remaining study authors have disclosed no relevant financial relationships.

Source

1. Howard BV, Roman MJ, Devereux RB, et al. Effect of lower targets for blood pressure and LDL cholesterol on atherosclerosis in diabetes: The SANDS randomized trial. JAMA. 2008;299:1678-1689.

Clinical Context

Statins have previously been demonstrated to improve important outcomes among patients with type 2 diabetes. Sever and colleagues compared atorvastatin 10 mg daily vs placebo among 2532 patients who had type 2 diabetes, and their results were published in the May 2005 issue of Diabetes Care. They observed participants for 3.3 years. During this period, atorvastatin reduced the composite rate of major cardiovascular events and procedures vs placebo. However, atorvastatin failed to promote a significant difference vs placebo in the risks for coronary events, stroke, or peripheral artery disease as individual endpoints.

Some research has suggested that treating patients with diabetes to lower targets for blood pressure and lipid levels can reduce the risk for cardiovascular events. The SANDS explores this issue.

Study Highlights

• Patients eligible for study participation were 40 years or older and had a diagnosis of type 2 diabetes. All participants were American Indian and had an LDL cholesterol level of at least 100 mg/dL and an SBP of 130 mm Hg or more. Patients with significant heart failure, SBP greater than 180 mm Hg, or significant elevation of serum liver transaminase levels were excluded from participation.
• Participants were randomized to a group with a goal SBP of 115 mm Hg or less plus a goal LDL cholesterol level of 70 mg/dL or less (aggressive treatment group) or a goal SBP of 130 mm Hg or less plus a goal LDL cholesterol level of 100 mg/dL or less (standard treatment group). Clinicians followed specific treatment algorithms to help subjects achieve these goals.
• The main outcome of the study was the common carotid artery IMT, which has been associated with the risk for future cardiovascular events. Secondary endpoints included LV mass, as measured by echocardiography, and clinical cardiovascular events. Outcomes were measured at 18 and 36 months.
• 548 patients underwent randomization. The mean SBP was 5 mm Hg lower in the aggressive vs standard treatment groups. Otherwise, baseline characteristics were similar between treatment groups.
• The mean age of participants was 56 years, and 66% were women.
• 21% of subjects were smokers.
• Both groups generally achieved their treatment goals. Among subjects in the aggressive treatment group, mean levels of LDL cholesterol during the last 12 months of the trial were 72 mg/dL, and SBP levels were 117 mm Hg. The respective mean LDL cholesterol and SBP levels in the standard treatment groups were 104 mg/dL and 129 mm Hg.
• Mean body mass index and fasting blood glucose levels remained similar between study groups during the trial.
• Mean carotid IMT increased slightly during the trial in the standard treatment group but regressed slightly in the aggressive treatment group (0.038 vs –0.012 mm, respectively), yielding a significant difference between groups.
• Participants in the aggressive treatment group also experienced improved outcomes vs the standard treatment group in carotid arterial cross-sectional area.
• LV mass decreased in the both treatment groups, but this reduction was greater in the aggressive treatment vs the standard treatment groups.
• Primary cardiovascular events occurred in 11 subjects in the aggressive treatment cohort and 8 subjects in the standard treatment cohort. This difference was not significant.
• Subgroup analysis based on age and disease characteristics did not alter the main outcomes of the study.
• Aggressive treatment of high LDL cholesterol levels appeared to be more effective in improving carotid IMT, whereas aggressive treatment of SBP appeared to be more effective in improving LV mass.
• Longer duration at the treatment goal in the aggressive treatment group was associated with improved carotid IMT values.
• Rates of adverse events from blood pressure medications were higher in the aggressive treatment (38.5%) vs the standard treatment (26.7%) groups.

Pearls for Practice

• A previous trial of atorvastatin vs placebo among patients with diabetes found that active treatment reduced the risk for a composite of major cardiovascular events and procedures but not the individual elements of this composite outcome.
• In the current study, aggressive treatment of high LDL cholesterol levels and high SBP among adults with type 2 diabetes improved carotid IMT, carotid arterial cross-sectional area, and LV mass vs standard treatment. However, the rate of clinical cardiovascular events was similar between groups.