||Globally, cardiovascular events are the major cause of morbidity and mortality in patients with diabetes. The good news is that the major complications of diabetes have declined substantially during the past two decades, with a 68% decline in rates of myocardial infarction and ~50% decline in stroke and amputations.1 This is likely the result of a combination of better access to care, health promotion efforts, and advances in treatment. However, obesity and diabetes continue at epidemic rates: some 24 million adults in the United States have diabetes;2 the number of patients with diabetes worldwide soared to some 382 million in 2013; and cases are projected to reach 592 million by 2035.3 Thus, the task of improving CVD outcomes in patients with diabetes will continue to remain a major challenge.
Elevated LDL-cholesterol (LDL-C) and hypertension are the key risk factors for atherosclerotic cardiovascular disease (ASCVD), including coronary disease and stroke. Efforts to improve their control have been a major focus during the past 20 years, thanks to the evolution and application of cholesterol and blood pressure guidelines in the US and elsewhere. Recently, the AHA (American Heart Association) and ACC (American College of Cardiology) published their revised guidelines on cholesterol management, and the JNC 8 panel published their revised blood pressure guidelines. Although both documents based their recommendations strictly on the basis of strong evidence from clinical trials, strong controversy has arisen.
The cholesterol guidelines are a significant departure from the past and provide an increased emphasis on the use of statins rather than any other cholesterol-lowering drug not proven to reduce CVD events. They recommend a more intensive therapy, even in primary prevention, for those at risk with or without diabetes and provide an updated risk calculator based on longitudinal data from several population cohorts. The lack of evidence for the CVD benefit of combining statins with other cholesterol-lowering drugs, including ezetimibe and bile acid sequestrants, was also reviewed recently by Gudzune et al.4 Another major change is that these recommendations provide no defined goals for LDL-C or non-HDL-C, if sufficiently intensive statin therapy is used.
In the new blood pressure guidelines, the JNC 8 panel recommends a less intensive approach compared to those used in the past. Specifically, a more liberal systolic blood pressure goal has been recommended for those ≥ 60 years of age without diabetes or renal disease, which is different from that recommended by other major blood pressure guidelines from the American and International Societies of Hypertension, and others, including some of the authors of the JNC-8 itself.5
The impact and projections of the new cholesterol and blood pressure guidelines to the US population is discussed in the articles reviewed in this issue; in summary, these extrapolations find that some 13 million additional adults in the US are candidates for statin therapy, especially men > 60 years, and that some 13.5 million adults previously considered not at blood pressure goal by JNC 7 criteria would now be considered at goal.
One of the issues that has emerged recently is the impact of statin therapy on the development of diabetes. The risk is relatively small as reported in several studies and meta-analyses and mainly affects those already at increased risk for or have pre-diabetes; the risk/benefit ratio favors the use of statins even in those who develop diabetes. The largest meta-analysis of 17 trials is summarized in this issue (Navarese et al); it suggests that the risk of diabetes may be less pronounced with less potent statins, such as pravastatin, compared to than with more potent statins, such as rosuvastatin. The latter is, however, recommended by the new cholesterol guidelines as a preferred statin for those at the highest risk of CVD. Further, the interactions of specific statin molecules with the mechanisms of diabetes development remain incompletely understood.
The final topic discussed in this issue has to do with the residual CVD risk in patients treated with statins. It is well recognized that despite intensive statin therapy, many patients, particularly those with diabetes and metabolic syndrome, remain at considerable residual risk of subsequent CVD events. In the past, we have been using fibrate drugs and niacin to improve the dyslipidemia (characterized by high triglycerides and low HDL-C) often encountered in patients with type 2 diabetes — with limited evidence of their benefits in such patients. In the ACCORD-lipid study, addition of fenofibrate in patients treated with statins resulted in possible, but inconclusive, benefit in the that patient subgroup.6 The AIM-HIGH trial discussed here (Boden et al) randomized patients with diabetes and/or metabolic syndrome and with pre-existing CVD and low HDL-C to extended-release niacin or placebo. These patients were all optimally treated with intensive therapy to a LDL-C goal of < 70 mg/dl. In this setting, the addition of niacin resulted in no cardiovascular benefit despite the significant increase in HDL-C. Similar lack of benefits with niacin were recently reported in another larger trial (HPS2-THRIVE).7 These findings have raised the possibility that HDL-C as a static measure may not be very helpful in determining the functionality of HDL, and point to a need to develop drugs that might directly improve HDL function. Thus, it appears that intensive statin therapy should remain the mainstay of lipid management in our armamentarium.
1. Gregg, EW, Li, Y, Wang, J et al. Changes in Diabetes-Related Complications in the United States, 1990–2010. N Engl J Med. 2014;370: 1514-1523.
2. Selvin E, Parrinello CM, Sacks DB, Coresh J. Trends in prevalence and control of diabetes in the United States, 1988–1994 and 1999–2010. Ann Intern Med. 2014;160:517-525.
3. The IDF Diabetes Atlas, 6th edition.
4. Gudzune, KA, Monroe, AK, Sharma, R et al. Effectiveness of Combination Therapy With Statin and Another Lipid-Modifying Agent Compared With Intensified Statin Monotherapy A Systematic Review. Ann Intern Med. 2014;160:468-476.
5. Wright JT Jr, Fine LJ, Lackland DT, Ogedegbe G, Dennison Himmelfarb CR. Evidence supporting a systolic blood pressure goal of less than 150mmHg in patients aged 60 years or older: the minority view. Ann Intern Med. 2014;160:499-503.
6. The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362:1563-74.
7. Armitage J. HPS2-THRIVE: randomized placebo-controlled trial of ER niacin and laropiprant in 25,673 patients with pre-existing cardiovascular disease. Presented at: American College of Cardiology Annual Scientific Sessions; March 9, 2013; San Francisco, CA.