Atherosclerosis and the Cardiovascular Complications of Diabetes
Jorge Plutzky, MD
This year's American Diabetes Association (ADA) 61st Scientific Sessions seemed to offer proof of a trend evident at the American Heart Association meetings held in November 2000 -- endocrinologists and diabetologists seem as interested in atherosclerosis and cardiovascular complications as cardiologists are in diabetes and insulin resistance. Such interdisciplinary crossover seems well warranted given the emerging picture of atherosclerosis as a metabolic process, and of insulin resistance and/or diabetes as an important determinant of cardiovascular outcomes. The ADA Scientific Sessions may also have offered examples of another blurring interface -- namely the one between basic science and clinical medicine.
HOPE and Diabetes
Considerable interest continues to be expressed in the results of the Heart Outcomes Prevention Evaluation (HOPE) trial, especially as they relate to patients with diabetes. The HOPE trial examined the effect of the angiotensin-converting enzyme (ACE) inhibitor ramipril in a large cohort of patients with either known cardiovascular disease or diabetes and at least one other risk factor. In the study population as a whole, significant benefits were seen with a relative risk reduction in the primary end point (a composite of myocardial infarction [MI], stroke, or death from cardiovascular causes) of 22%.
However, what was of interest and frequently discussed at this year's ADA meeting were the benefits observed in the diabetic subgroup. These included a 25% overall reduction in cardiovascular events for the primary end point and an impressive 37% decrease in cardiovascular death, with benefits being apparent even after controlling for blood pressure (blood pressure changes were modest, as the study population was not very hypertensive). In fact, the study was ended early by the Data Safety and Monitoring Board.
Particularly intriguing was the observation that the incidence of new diabetes among treated patients was also significantly decreased. The basis for this effect is unclear but may involve some direct effect of the ACE inhibitor and perhaps some previously unrecognized influence of ACE on metabolic pathways. Of interest, similar data have been reported from some of the statin trials in which the incidence of new diabetes was also lower among treated patients. Again the possible mechanism underlying this effect is unknown, although the number of patients influenced and the rigor of these data may be less solid than the ACE inhibitor results.
There is no doubt that the advent of statin therapy has dramatically changed the scope, approach, and thinking regarding dyslipidemia and preventive cardiology. The ADA guidelines follows closely on the heels of the release of the Adult Treatment Panel (ATP) III, the latest version of the National Cholesterol Education Program (NCEP) guidelines regarding lipid therapy. In this important document, the study and treatment of diabetes and the metabolic syndrome receives considerable attention. First and foremost, this document embraces a position already adopted by the ADA -- that diabetes represents a risk equivalent for cardiovascular disease. Furthermore, the ATP III also identified people with the metabolic syndrome and its attendant associated cardiovascular risk as a subgroup of patients in whom aggressive treatment may be warranted.
One might consider the statin field to be saturated. Such arguments seem analogous to discussions that took place in the business world a few years ago as several new specialty beverages were being introduced to the market -- did the world really need another juice? Perhaps surprising, several of those drinks are now successful contenders for market share. Similarly, attention continues to be directed at the anticipated introduction of a new statin, rosuvastatin (Crestor). Preliminary data presented at the American College of Cardiology (ACC) meeting suggested that rosuvastatin might decrease low-density lipoprotein (LDL) levels to a degree at least comparable if not greater than atorvastatin (Lipitor), while providing an even greater increase in high-density lipoprotein (HDL) levels.
Additional data were presented at the ADA from a trial in which rosuvastatin was used to treat hypertriglyceridemic (fasting triglyceride level >/= 300 mg/dL and < 800 mg/dL) patients with doses ranging from 5-80 mg. Compared with placebo, triglycerides were decreased by 18% in the 5-mg group to 40% lower in the 80-mg group whereas HDL was increased by 4% with the 5-mg dose up to a maximum 18% higher with 20 mg (+15% with 40 mg, +10% with 80 mg).
Thiazolidinediones (TZDs) continue to receive considerable attention as one of the latest additions to the clinician's armamentarium.[7,8] Given their insulin-sensitizing ability, TZDs are a particularly appealing treatment for the insulin resistance syndrome. The TZDs have also been of interest because of their activity as peroxisome proliferator-activated receptor (PPAR)-gamma ligands. In terms of current clinical use, the 2 available TZDs -- pioglitazone (Actos) and rosiglitazone (Avandia) -- continue to try to distinguish themselves from each other. Both agents seem efficacious in terms of glucose lowering. Several abstracts compared and contrasted differences in the effects on lipids.[9-11] Given work from several labs demonstrating PPAR-gamma expression in the vasculature, the possibility of direct effects in vascular cells remains an intriguing one for further investigation. Several abstracts reported new PPAR-gamma agonists, some of which were non-TZDs, some of which may have dual PPAR-gamma and PPAR-alpha activity.[12-14] It will be interesting to see how many of these ultimately come to market.
The Role of Adipocytes in Glucose Homeostasis
The abstracts and presentations also included many important basic science presentations. Several intriguing areas may have future relevance for clinical diabetology and cardiovascular risk. Earlier this year, considerable excitement surrounded the publication of a seminal work by Mitchell A. Lazar, MD, PhD, and colleagues over their identification of resistin, a protein that appears to be involved in glucose homeostasis. Resistin impairs glucose tolerance and insulin action. Of interest, the research on resistin is an example of how the development of TZDs has influenced both basic science and clinical research, as investigators were working under the hypothesis that TZDs might sensitize patients to insulin by negatively regulating a specific gene target in adipocytes.
Working with Dr. Lazar, Dr. Claire Steppan, a postdoctoral fellow and first author of the first resistin article, presented additional data on resistin that provides more evidence for its antagonism of insulin. These findings may raise numerous clinically critical avenues of research and therapy, such as genetic syndromes in which increased resistin leads to diabetes, novel treatments that target resistin, upstream pathways that determine resistin expression, and assays for resistin that may offer insight into therapeutic responses.
Of interest, the other side of the resistin coin may be adiponectin, also known as Acrp30. In contrast to resistin, which is inhibited by PPAR-gamma activation, adiponectin is induced by PPAR-gamma ligands. Several interesting abstracts were presented regarding adiponectin. Kadowaki and his colleagues in Japan, who have made major contributions in the study of PPAR-gamma, found adiponectin to be increased in PPAR-gamma heterozygous-deficient mice who were protected from high-fat-diet-induced insulin resistance/diabetes.
In their studies, they were able to decrease triglycerides and improve insulin sensitivity by the administration of adiponectin in mice. Work by Scherer, Moller and colleagues also noted connections between adiponectin and insulin sensitivity, with induction of adiponectin in response to PPAR-gamma agonists. Such responses were not seen after PPAR-alpha or metformin. Both resistin and adiponectin circulate in the plasma.
Recently, Semenkovich and colleagues reported that crossing PPAR-alpha-deficient mice to LDL-receptor-deficient mice led to less, not more, atherosclerosis, despite numerous in vitro reports from many investigators, including ours, that might have predicted the opposite findings. A variety of studies have found PPAR-alpha regulation of target genes that would be expected to limit atherosclerosis and inflammation -- increasing adenosine triphosphate-binding cassette transporter 1 (ABC1; a regulator of HDL), decreasing the adhesion molecule, VCAM1, limiting interleukin-6, lowering endothelin 1, to name a few. At this year's ADA conference, Michele Guerre-Millo, PhD, working with Bart Staels, PhD, a major researcher in this area, reported similar findings as the Semenkovich results, at least in terms of insulin resistance. PPAR-alpha-deficient mice showed resistance to diet-induced diabetes/hyperglycemia. The mechanism of this PPAR-alpha-mediated protection from insulin resistance is not clear, nor is its relevance for humans. Thus far, clinical trials with PPAR-alpha-activating fibric acid drugs have not shown evidence for worsening glucose levels.
Atherosclerosis in Diabetes: Is it a Different Disease?
To come full circle, the fields of vascular biology, cardiology, and endocrinology all converge in the study of atherosclerotic plaque and its clinical sequelae -- plaque rupture. A pervasive research question relates to the possible existence of unique characteristics of diabetic atherosclerosis and MI that distinguish it from other forms of atherosclerosis or clinical events. In a well-attended session, which again underscores the shared interest in such topics, Robert H. Eckel, MD, invited Richard Nesto, MD, and me, 2 cardiologists, to discuss, if not debate, this issue.
The question was posed as follows: Coronary death in diabetes: plaque or nonplaque? I was asked to support the "plaque" position while Dr. Nesto argued against it. In reviewing the related literature, I was surprised by how little this issue has been thoroughly addressed. Certainly, all standard texts argue that diabetic atherosclerosis is by and large no different from typical atherosclerosis, representing instead just more severe disease that occurs earlier. Because we know that the vast majority of MIs are caused by plaque rupture, it might seem logical that similar processes are at work in diabetes. Another argument is a therapeutic one -- if those interventions that decrease cardiovascular mortality and MIs in nondiabetics have the same effects in diabetics, they are likely working on similar lesions. Most beneficial therapies, such as statins, are thought to work through plaque stabilization. In fact, in most trials, patients with diabetes enjoy the same if not greater benefits than patients without diabetes. Another line of arguments that surprisingly has not been explored takes the position that many first, fatal MIs occur in patients with undiagnosed diabetes. Certainly, both diabetes and first, fatal MI are common events. Six percent of the population is diabetic, but perhaps another 12% are undiagnosed. Because approximately 50% of patients with diabetes have had an MI before their disease is diagnosed, it seems likely that many cases of sudden death, or fatal MI, are occurring in patients with undiagnosed diabetes.
Dr. Nesto offered equally compelling data. He suggested that the real challenge was to survive an MI. A large and growing database suggests that interventions may favorably improve the chances of surviving an MI and thus, many argue that for coronary death, the issues may focus much more on preserving myocardial function, decreasing ischemia, and limiting arrhythmia than on any specific factor related to the plaque itself. As is often the cause in such debates, both positions have validity. Most MIs are likely caused by plaque rupture, but subsequent cardiovascular events are greatly influenced by interventions that preserve myocardial function and viability. Taken together, both positions establish the potential benefits from aggressively addressing atherosclerosis and cardiovascular risk both before and after an acute event. No doubt, the basic science and clinical work presented at the 61st Sessions of the ADA will continue to provide further insights on how we can best do so.
Diabetes, the Heart, and the Kidney
Michael Jones, MD, FACP
The 61st Scientific Sessions of the American Diabetes Association (ADA) was characterized by the large number of symposia, state-of-the-art lectures, and abstracts relating to the cardiovascular and renal complications of diabetes. In addition, the close link between the 2 complications was emphasized in many presentations. It is clear that diabetic nephropathy and cardiovascular morbidity and mortality are major issues for those with diabetes and those providing care. Several presentations described the scale of the problem and some new experimental and clinical studies, but also highlighted the fact that we have not always been successful in implementing what we already know to be effective treatment.
Cardiovascular Mortality and Morbidity
Cardiovascular mortality rates are higher in people with diabetes. In a cross-sectional study, Nichols and Brown demonstrated that the prevalence of cardiovascular disease was 28.7% in people with diabetes, compared with 16.3% in a control group of similar age and sex, an increase of 76%. The presence of cardiovascular complications had a major economic impact, more than doubling healthcare costs across all age groups. A subgroup analysis of the Treat Angina with Aggrastat (tirofiban) and determine Cost of Therapy with an Invasive or Conservative Strategy -- Thrombolysis In Myocardial Infarction (TACTICS-TIMI 18) trial by Jurkovitz and colleagues confirmed that people with diabetes and acute coronary syndromes (ACS) are almost twice as likely to die, suffer myocardial infarction (MI), or be rehospitalized with ACS within 6 months. On a more positive note, they demonstrated that an intensive strategy of early catheterization and revascularization resulted in a 27% reduction in the end points described above that was not seen in a much larger group of patients without diabetes. This intensive strategy was cost-neutral, presumably as a result of improved outcomes. This study, like the Hypertension Optimal Treatment (HOT) study and the Scandinavian Simvastatin Survival Study (4S), demonstrated that although people with diabetes have the highest cardiovascular event rates, they also benefit the most from interventions.
Cardiovascular Mortality and Morbidity in Diabetic Nephropathy
People with diabetes and nephropathy have an even higher burden of cardiovascular disease. In the Kelly West Lecture, Professor John H. Fuller discussed the marked increase in mortality in patients with micro- and macroalbuminuria compared with those with normal urinary albumin excretion. Cardiovascular mortality rates appear to increase as diabetic kidney disease progresses to the stage when serum creatinine starts to climb. In a prospective study of Pima Indians with type 2 diabetes, Williams and colleagues described a mortality rate that was 5.7 times higher in men and 7.5 times higher in women with diabetes and renal impairment compared with those with type 2 diabetes without renal insufficiency.
Nishimura and colleagues indicated that the 20-year cumulative incidence of end-stage renal disease (ESRD) decreased in type 1 diabetes from 9.1% in a cohort diagnosed between 1965 and 1969 to 4.5% in a cohort diagnosed between 1975 and 1979. However, the 20-year cumulative incidence of ESRD was much higher in blacks (22.5%) compared with whites (5.2%). Patients with ESRD treated with dialysis had a particularly high 5-year mortality of 70%, whereas those who received a renal transplant fared much better, with a 5-year mortality of 20%.
The Link Between Renal Disease and Cardiovascular Disease in Diabetes
Professor Fuller discussed the results of EURODIAB, linking cardiovascular and renal complications and describing how features of the metabolic syndrome -- hypertriglyceridemia, raised low-density lipoprotein (LDL)-cholesterol levels, low high-density lipoprotein (HDL)-cholesterol levels, high body mass index (BMI), and waist-hip ratio -- were risk factors for the development of diabetic kidney disease, just as they are risk factors for cardiovascular disease.
In the Edwin Bierman Lecture, Maria Lopes-Virella, MD, PhD, described how abnormalities in lipid subfractions, particularly oxidized LDL, interact with antibodies to activate T- and B-lymphocyte-modulated immune responses leading to macrophage activation and release of cytokines and adhesion molecules. As a result of the release of cytokines such as tumor necrosis factor (TNF)-alpha, C-reactive protein (CRP) is increased, linking subtle lipid abnormalities and immune and inflammatory responses. In a subset of 100 patients from the Diabetes Control and Complications Trial (DCCT), Professor Lopes-Virella had demonstrated that in patients with microalbuminuria:
These changes are associated with increased activation of immune and inflammatory responses.
These findings have therapeutic implications. The HMGCoA-reductase inhibitors, such as statins, reduce major histocompatibility complex class II (MHC-II) receptor expression in macrophages. As a result, the initiation of inflammatory and immune processes should be reduced, supporting the notion that statins may have a role beyond their effect on cholesterol levels and explaining why they have been shown to reduce inflammatory markers such as CRP. In addition, there may be a role for agents such as chloroquine and hydroxychloroquine, which are known to reduce lysosomal function and therefore LDL processing by macrophages, and in theory decrease cytokine secretion, immune cell recruitment, and activation.
What Can Be Done to Reduce Cardiovascular Disease in Diabetes?
In his presidential address, the current ADA president, Robert S. Sherwin, MD, reflected on the current state of diabetes care and research. While recognizing that "glucose matters," he stressed the need for cardiovascular risk management, early intervention, and prevention. There is much that can be done and the 61st Scientific Session of the ADA had clearly moved beyond glucose centricity.
Fibrates and Cardiovascular Disease
Marja-Riitta Taskinen, MD, presented data from the Diabetes Atherosclerosis Intervention Study (DAIS). This randomized, controlled trial of 418 people with type 2 diabetes from 11 centers in North America and Europe studied the effect of micronized fenofibrate vs placebo on coronary atherosclerosis in type 2 diabetes. Subjects with mild dyslipidemia underwent angiography at baseline and after a mean duration of 3 years. Fenofibrate treatment resulted in a 10% decrease in total cholesterol, a 7% increase in HDL, and a 20% to 30% reduction in triglycerides. Compared with placebo-treated participants, these lipid changes were accompanied by a 40% reduction in coronary artery lumen diameter and coronary artery stenosis, reflecting localized coronary artery disease and a 25% reduction in mean segment diameter, and reflecting more diffuse disease, though the latter did not reach statistical significance.
The study was not powered for clinical end points. Nevertheless, there was a trend toward lower levels of myocardial infarction, mortality, and revascularization, with a 23% reduction in people who received fenofibrate.
Although this value failed to reach statistical significance, it was of the same order of magnitude as that observed in larger studies such as Cholesterol and Recurrent Events Trial (CARE), Long-term Intervention with Pravastatin in Ischemic Disease (LIPID), and Veterans Affairs-High-Density Lipoprotein Intervention Trial (VA-HIT). It was concluded that treatment with fenofibrate reduced coronary artery disease in:
In the same well-attended session, Sander Robins, MD, presented data from VA-HIT, including data from a subanalysis of patients with type 2 diabetes. This is a randomized controlled trial of gemfibrozil vs placebo in people with normal LDL and low HDL levels. The main finding was a 22% reduction in cardiovascular events, including myocardial infarction and death from coronary heart disease. Twenty-five percent of the 2531 men in this study had a history of diabetes with an additional 6% detected on entry into the study, a much higher proportion than studies such as CARE and 4S. People with diabetes in the study had twice the rate of cardiovascular events of those without diabetes. However, the people with diabetes also gained more from intervention with a fibrate, as demonstrated by a 41% risk reduction in cardiovascular events compared with 23% in the entire study group.
It was suggested that for people with diabetes and modestly increased or normal LDL levels, fibrates were a more effective treatment than statins, especially if HDL levels were low. However, we will have to wait until the Lipids in Diabetes Study (LDS) results for a definitive answer, and it may be that combination treatment will be required.
Angiotensin II (AII)-Receptor Antagonists and Diabetic Nephropathy
Results from 3 recent trials on diabetic nephropathy were presented to a full house. The Reduction in renal Endpoints in NIDDM with the AII Antagonist Losartan (RENAAL) was presented by Barry M. Brenner, MD. This study of 1513 patients was carried out in 29 countries at a total of 250 centers to ensure an ethnically diverse population. The participants were a high-risk group with significant albuminuria (> 300 mg/24 hr) and raised creatinine (1.3-3.0 mg/dL), and were randomized to receive either 100 mg of losartan or placebo. On average, participants required 3.5 different antihypertensive medications to control their blood pressure. The primary end point of end-stage renal failure (ESRF), doubling of serum creatinine and/or death was reduced by 16% in the actively treated group.
This was due to a 25% to 28% reduction in renal outcomes with no effect on mortality. The differences remained significant after adjustment for the 3-mmHg difference in blood pressure between groups. In this study, which lasted 3.4 years, 16 patients were treated for every episode of ESRF prevented. If these data are extrapolated to the whole of the United States, treatment with losartan and tight blood pressure control, with an average of 3-4 additional blood-pressure-lowering agents, would save $3.1 billion from reduced costs of ESRF management.
The Irbesartan Diabetic Nephropathy Trial (IDNT) was reviewed by Lawrence G. Hunsicker, MD. In this study 1715 patients with type 2 diabetes, significant proteinuria, and creatinine of 1-3 mg/dL were randomized to receive 300 mg irbesartan, 10 mg of amlodipine, or placebo. There was a significant 20% reduction in the primary end point of doubling of creatinine, ESRF, and death in the irbesartan-treated group that was not observed in the placebo or amlodipine groups. Again this difference was due almost entirely to a 20% to 30% reduction in renal end points. Treatment of 15 patients for 2.6 years was required to prevent an episode of ESRF in this study.
Both of these studies therefore established the efficacy of AII receptor antagonists in people with type 2 diabetes and nephropathy. In both studies there were few serious side effects, in particular few incidences of a sudden rise in serum creatinine and less than 2% developed hyperkalemia.
In the final talk in this session, Professor Hans-Henrik Parving described the Irbesartan in patients with type 2 diabetes and Microalbuminuria (IRMA-II) study. In this study, patients with type 2 diabetes, persistent microalbuminuria, and normal serum creatinine were randomized to receive either irbesartan 150 mg or 300 mg a day, or placebo in addition to other therapies to maintain blood pressure at or below 135/85 mmHg. Patients who received 300 mg of irbesartan experienced a 70% reduction in the progression to diabetic nephropathy. Such individuals had a mean reduction in urinary albumin excretion of 54% and were nearly twice as likely to regress to normoalbuminuria compared with placebo-treated patients. Irbesartan was safe and well tolerated and preserved glomerular filtration rate (GFR). Treatment of only 10 patients was needed to prevent the progression of microalbuminuria to overt diabetic nephropathy in 1 patient.
The take-home messages from the AII-receptor antagonists trials are:
Room for Improvement in Initiating Interventions
A number of abstracts suggested that the current level of initiating proven interventions was less than ideal. In Northern California, for example, the rate of lipid screening had improved from 20% to 46% annually. Although this had been associated with a reduction in mean cholesterol levels from 144.7 to 124.7 mg/dL, less than 50% of people were having a regular cholesterol check. Similar data were reported by Chowdhury and colleagues, with 51% of their cohort receiving a lipid assessment; however, only 20% had a "renal assessment." A Canadian group presented similar data, with only 15% of their patients being screening for renal complications of diabetes. On a more positive note, Grover and colleagues estimated the possible benefits of a more aggressive policy of lipid-lowering therapy with statins, suggesting that people with diabetes should be regarded as having the same cardiovascular risk as a secondary-prevention group. This being the case, appropriate lipid-lowering therapy would be expected to increase life expectancy by up to 3.5 years in men and 2.4 years in women with diabetes, resulting in 15 million person-years of life across the United States.
Don't Forget Glucose
The Cochrane Collaborative Group revisited the effect of intensive blood glucose control on cardiovascular disease in type 1 diabetes. Studies to date have been too small or of too short duration to detect a significant effect on cardiovascular outcomes in type 1 diabetes. In a meta-analysis of 4 different studies, there were over 10,000 patient-years of data. Analysis revealed a 66% reduction in cardiovascular events in those receiving intensive therapy (P < .0001). However, the number needed to treat 100 patient-years to prevent 1 event was much higher than that required in the studies of type 2 diabetes described above.
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