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Treatment of Diabetes Beyond Glycemic Control: Getting to the Heart of the Matter

Diabetes: A Vascular Inflammatory Disorder?

“It’s amazing that people with diabetes still do not see cardiovascular disease (CVD) as one of the major risks of the disease,” said Christopher Sadler, MA, PA-C, Physician Assistant, Diabetes and Endocrine Associates, La Jolla, CA. “Sit down with a patient after they are diagnosed and they worry about blindness, amputations, and renal failure. Very few mention CVD despite studies showing diabetes to be a cardiovascular risk equivalent.”

Data from Dr. Steven Haffner and his group first noted that diabetes was a CVD risk equivalent. For those with no diabetes and no prior history of myocardial infarction (MI), a patient’s risk for an MI was low. However, those with diabetes and no MI had a seven-year risk of heart attack equivalent to a person with no diabetes but a prior MI. Having diabetes alone was almost equivalent to having all three other widely recognized risk factors- hypertension, hypercholesterolemia and smoking (Haffner SM, et al. NEJM. 1998;339: 229).

Insulin resistance (IR) is seen long before hyperglycemia. As IR progresses, the patient may develop beta-cell failure. It is important to remember that many IR patients will not have diabetes but may still develop CVD.

National Cholesterol Education Program (NCEP) guidelines indicate that a person has metabolic syndrome if they exhibit three or more traits. These include abdominal obesity, measured as a waist circumference of greater than
35 inches for women and 40 inches for men, triglyceride levels of 150 milligrams per deciliter (mg/dL) or higher, blood pressure of 130/85 mm Hg or higher, a fasting blood sugar level of 110 mg/dL or higher, and a level of high-density lipoprotein (HDL) lower than 50 mg/dL for women and 40 mg/dL for men (Expert Panel on Detection, Evaluation, and Treatment of High Blood Choles-terol in Adults. JAMA, 2001;285: 2486).

“As we learn more about metabolic syndrome, we are seeing that these guidelines miss many people who are insulin resistant,” said Mr. Sadler. “If you measure insulin resistance using glucose clamps, you can have just one of the criteria and still be significantly IR. Someone who does not meet all the criteria for metabolic syndrome may still be at risk.”

IR induces a cycle where visceral adiposity causes IR, which increases adiposity. Dyslipidemia with high triglycerides, low HDL cholesterol, small-dense LDL cholesterol, inflammation, hypertension, altered vascular reactivity, impaired fibrinolysis, and development of type-2 diabetes all lead to increased risk of CVD through vascular inflammation and endothelial dysfunction (ED).

“When you have endothelial dysfunction, you end up with enhanced rates of atherosclerosis and proteinuria,” said Mr. Sadler. “That is why microalbuminuria is such a good marker for patients developing vascular and cardiovascular disease.”

Another sensitive indicator is C-reactive protein (C-RP). The Hoorn study looked at survival in patients with C-RP levels less than 2.8 mg/L and those greater than 2.8 mg/L. At one year there was already a significant separation between the two groups with an even wider gulf by year 5 (Jager A, et al. Arterioscler Thromb Vasc Biol. 1999;19:3071).

“So the question then becomes: What do we want to accomplish in our patients with type-2 diabetes?” asked Mr. Sadler. “First of all, we want to eliminate symptoms of hyper- and hypoglycemia. If we want to affect the risk for
eye, kidney, and nerve damage, then lowering glucose levels are critical.” (Table 1)

Results from the UK Prospective Diabetes Study (UKPDS) indicate that lowering blood pressure achieves almost as much risk reduction in microvascular complications as that seen in glucose control. Another study has shown that lowering LDL to < 70 mg/dL provided more protection compared to levels <100 mg/dL (Cannon C, et al. NEJM. 2004:350:15).

“I want to keep my patients as healthy as possible for years to come,” said Mr. Sadler. “This involves aggressive treatment of blood glucose and cardiovascular risk factors.”

Scope and Consequences of Cardiovascular Disease in Diabetes

For decades diabetes was looked upon as a metabolic disease defined by hyperglycemia with better glycemic control as the goal. As understanding of the disease process improved, there came the realization that effective treatment of type-2 diabetes requires combinations of therapy.

“The real challenge facing clinicians is not just achieving good control of blood glucose but sustaining those levels of control,” said David Kendall, MD, Chief of Clinical Services and Medical Director of the International Diabetes Center in Minneapolis, MN. “Multiple cardiovascular risk factors need to be addressed because they are so common in patients with diabetes.”

One key is that IR is a cluster of abnormalities. Dr. Kendall noted that someone with a blood glucose level greater than 100 mg/dL should also have his or her lipids and blood pressure followed. Similarly, patients with hypertension should be screened annually for diabetes and lipid abnormalities.

Data from the Nurses’ Health Study underscores the fact that this is a continuous process. Those entering the trial with diabetes were at a five-fold increase in risk for a cardiovascular event during the 20-year follow-up compared to someone without diabetes. Another group of patients who entered the trial without diabetes but developed diabetes during the follow-on period had a three-times higher risk for a cardiovascular event even before developing diabetes. Once diabetes developed, the risk was approximately the same as those who entered the study with diabetes (Hu FB, et al. Diabetes Care. 2002;25:1129).

“A continuum of cardiovascular risk exists in the metabolic syndrome and pre-diabetes that is likely associated with all these defects and not just IR,” said Dr. Kendall. “Based on the data available, we know that CVD risk had begun rising steadily long before diabetes developed.”

There are other indictors that are “hidden” according to Dr. Kendall. Among these are vascular inflammation, abnormal vessel behavior, and increased thrombotic risk. There is good evidence that IR plays at least some role in managing these factors.

One treatment for all of these conditions is weight loss and increased physical activity. Both are clearly insulin-sensitizing interventions with impacts on lipids, blood glucose, and blood pressure. In addition to these lifestyle changes, other important therapies should be considered.

The association between lower blood glucose (measured as Hemoglobin A1c (HbA1c)) and lower rates of micro-vascular disease is well established. But the relationship between blood glucose and CVD risk is different and it appears the lowest risk is only achieved with virtually normal blood glucose levels.

“An epidemiological analysis suggests that there is an impact of glucose alone on cardiovascular risk,” said Dr. Kendall. “If this relationship holds up, we’re likely going to have to normalize blood glucose to maximize benefit.”

Another concern is the dyslipidemias of diabetes. Although targeting LDL cholesterols over 100mg/dL has established benefits, it is not the most common lipid disorder in this group. Low HDL cholesterol and high triglycerides are more often seen clinically.

For example, data from the Framingham population indicates that a person with an LDL of 220 mg/dL and HDL of 85 mg/dL has one-third the risk of CVD as someone with a target LDL, but an HDL of 25 mg/dL (Castelli WP. Can J Cardiol. 1988;4 (Suppl A): 5A).

“This suggests that other components of lipid disorder are critical and may need to be targeted for intervention,” said Dr. Kendall. “Why, then do we talk about IR in this context?”

He says it is because insulin is not simply a glucose-regulating hormone. In patients with IR or diabetes, insulin’s signal tells the body to store the excess but the fat cells do not see the signal and think the body is starving. This causes the fat cells to liberate free fatty acids into the blood stream. The liver sees the increased fatty acid flux processing them into triglyceride-rich VLDL particles.

Through these mechanisms, IR can result in high free fatty acids and high triglycerides. In turn, HDL and LDL tend to fall. The lower LDL results in the formation of smaller and denser molecules through the action of lipases. Thus, all of the components of the lipid disorders seen in diabetes can be at least indirectly tied to IR. That would support the suggestion that targeting IR may improve the lipid disorder.

Hypertension and abnormal vascular behavior may be part of the same milieu. Two out of every 3 patients with diabetes also develops hypertension. It is the defining characteristic of metabolic syndrome.

“From the old Systolic Hypertension in the Elderly Program (SHEP) trial to the most recent Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), lowering blood pressure in diabetes works,” said Dr. Kendall. “This may be independent of the agents used since thiazides, calcium channel blockers, ACE inhibitors, and beta-blockers all demonstrated benefit.”

Dr. Kendall also stressed that about 80% of those with diabetes will need multiple-drug therapy to manage hypertension. The drug you start with may be less important than which combination you eventually use.

Festa’s study found that the more components of metabolic syndrome seen in a patient, the more likely they were to have vascular inflammation and increased cardiac risk (Festa A. Circulation. 2000;102:42).

“Right now, it appears as though anything we do to reduce overall cardiac risk in diabetes is associated with reducing inflammatory risk,” Dr. Kendall noted.

Patients with diabetes or metabolic syndrome have increased levels of Plasminogen Activator Inhibitor -1 (PAI-1) which impacts on how fast clots are broken down. There is evidence that this is also seen in impaired glucose tolerance and pre-diabetes. Therapies used in the treatment of diabetes, such as the thiazolidinediones, the glitazones, and metformin, also lower levels of PAI-1.

“Ultimately, diabetes and the attendant cardiac risk may be tied to insulin resistance,” said Dr. Kendall. “However, treating IR by itself is not going to be some kind of golden bullet, since this is a multi-risk factor disorder.”

The one class of therapies that has very little evidence to support their use in cardiac disease is sulfonylurea. Dr. Kendall stressed that they are still effective glucose-lowering agents.

“We use these therapies for their glucose-lowering advantages and not for CVD risk reduction alone,” said Dr. Kendall. “I think as we have learned from ACE-Inhibitor, what we get from them beyond their primary effect may be critically important in determining CVD risk.”

 

Therapeutic Strategies for Cardiovascular Disease in Diabetes

In the recent past, it was generally thought that aggressive management of elevated glucose levels had minimal, if any, effects on improving outcomes for people with diabetes who presented with acute MI. The Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI) Trial was the first to show that aggressive management of hyperglycemia with IV insulin, glucose, and potassium could make a long-term difference in mortality.

DIGAMI enrolled type-2 diabetic patients who were being managed for acute MI and randomized them to either intensive treatment with insulin or standard diabetic care. Those entering the treatment arm were followed with tight control of blood glucose levels for a year (Malmberg K, et al. Eur Heart J. 1996; 17:1337).

At the end of the trial, there was a 27% reduction in one-year mortality in the treatment cohort. The Kaplan-Meier plots found an increasing separation in the two group’s mortality throughout the year.

“Clearly cardiovascular disease progression is amenable to treatment even in diabetics with acute heart attacks,” said Robert Henry, MD, Professor of Medicine at the University of California-San Diego. “Even the relatively simple technique of using glucose and insulin in the coronary care unit had a large impact on long-term cardiovascular mortality.”
This was followed by the UKPDS, which demonstrated a reduction of risk for microvascular and other complications for every 1% decrease in HgA1c. This was the first evidence that good glycemic control in type-2 diabetes had important effects on vascular events in chronic settings (Stratton IM, et al. BMJ. 2000;321:405). (Table 1)

The Steno-2 trial looked at all major CVD risk factors known at the time and how maximal efforts to treat known classic risk factors compared to conventional treatment. One hundred and sixty patients were entered into the study. Half were treated aggressively for blood pressure, lipids, glucose, and were also helped to stop smoking, put on a low-fat, low-calorie diet, and followed for 8 years. The other groups were treated using conventional protocols.

At the end of 8 years, there was a 50% reduction in a composite of the primary endpoints including cardiovascular death, nonfatal MI, non-fatal cerebrovascular accident, amputation or peripheral vascular disease, coronary artery bypass grafting or percutaneous coronary angioplasty. One cardiovascular event was prevented for every 5 patients who entered the treatment arm (Gaede P, et al. NEJM. 2003; 348:383).

“While clearly showing that aggressive treatment can make a big difference, this data also shows that it doesn’t appear to be enough by itself,” said Dr. Henry. “Even after this intensive intervention, there was still a two-fold increased risk of CVD and it looks as though there is still risk factors we aren’t treating.”

He suggests that at least one of these factors may be insulin resistance.

As IR develops, the pancreas may be able to produce enough insulin to overcome, or at least compensate for it. This leads to relatively normal glucose tolerance, but may contribute to the development of metabolic syndrome, which by itself is linked to a two-fold increase of CVD.

The other scenario occurs when the pancreas cannot keep up with the severe degree of IR and beta-cell insufficiency results in both hyperglycemia and metabolic syndrome. The pivotal role of IR in the genesis of type-2 diabetes, combined with estimates that as many 25% of the 35 million non-diabetic people with metabolic syndrome will convert to type-2 diabetes during their lifetime, makes IR a major focus of treatment.

“Clearly the most effective form of therapy for such individuals is weight loss and lifestyle modification as obesity, in particular visceral obesity, is strongly associated with IR,” noted Dr. Henry. “Unfortunately, this is a very difficult therapy to maintain long-term. Thus, we also need to look at insulin sensitizers (IS).”

Metformin is a modest insulin sensitizer that has many benefits, including significantly lowering of HgA1c and beneficial effects on lipids. Additionally, there are numerous CV risk factor benefits that result from metformin use.

Another group of medications useful in IR are the glitazones. This class works by a unique mechanism of action that involves binding through the nuclear receptor PPAR gamma onto defective genes that regulate the transcription and translation of proteins in those with type-2 diabetes and metabolic syndrome. These actions have effects on IS, cholesterol, triglycerides, lower LDL density, and free fatty acids.

Overall, this group of medications results in increases of up to 20% in HDL cholesterol. However, despite the benefits of increased “good cholesterol”, those with very low HDL cholesterol often continue to be at high-risk for macrovascular events even if HDL is increased. This occurs because many non-cholesterol risk factors for CVD exist.

Numerous CVD risk factors have been shown to be improved by the glitazones. Pioglitazone has been shown to have a measurable impact on the thickness of the intima of the carotid, probably related to reduced vascular inflammation. Treatment results in significant reductions in this measure at three and six months versus placebo (Koshiyama H, et al. J Clin Endocrinol Metab. 2001;86:3452).

Sidhu studied rosiglitazone in 92 patients with metabolic syndrome and documented coronary artery disease. They were randomized to either rosiglitazone or placebo and followed for nearly a year. In the placebo group, there were progressive increases in the intima media thickness while no significant increase occurred in the treatment arm (Sidhu JS, et al. Arterioscler Thromb Vasc Biol. 2004;24:930).

Research by Takagi and others enrolled diabetic patients who were having a stent placed for cardiac ischemia. They were then randomized to either troglitazone or control. There were significant benefits seen in terms of intima medial thickness and intima index in the treatment group (Takagi T. J Am Coll Cardiol. 2000;36:1529).

“We are starting to get more compelling data that the glitazones have significant cardiovascular benefits,” noted Dr. Henry. “It appears as though the glitazones may act directly on the liver to reduce glucose production, lower IR in skeletal muscles so insulin can work better, and probably have a direct and indirect beneficial effect on vascular tissue.”
However, it is also of interest that the glitazones appear to have an effect on adipose tissue with a significant amount of their impact being mediated through alterations in adipose tissue secretory products.

The mechanism may be related to the class’s impact on a newly discovered hormone known as adiponectin, which is only produced in adipose tissue. Unlike other hormones, the greater the mass of adipose tissue, the lower the levels of the hormone. It has also been established that adiponectin rapidly accumulates underneath the epithelium of an injured vessel wall and may be protective against the inflammatory process.

“Unlike other peptide hormones, adiponectin appears to protect from IR, type-2 diabetes and premature CVD,” noted Dr. Henry. “So, for the first time we have identified a hormone that is produced in fat where levels are lower as obesity increases.”

There are currently only two methods to significantly increase adiponectin in circulation. The first is weight loss, related to the inverse relationship between the hormone and changes in adipose tissue mass.

The other is use of the glitazones. Both pioglitazone and rosiglitazone have been shown to increase low adiponectin levels in diabetes by two- to three-fold. There are also indications that metformin may have an additive effect in disease prevention when combined with the glitazones, although metformin has no effect on adiponectin levels. (Bajaj M, et al. Diabetes. 2003;52(Suppl 1):A139).

“The glitazones, together with compounds like metformin, as well as weight loss and exercise, can reduce IR and have beneficial effects across a wide variety of parameters,” said Dr. Henry. “Hopefully we will be able to use these compounds in the foreseeable future to delay and prevent the development of both diabetes and premature cardiovascular disease.”

 

 

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