Treating ß-Cell Dysfunction: Reducing Cardiovascular Risk in Type 2 Diabetes

At a symposium held in conjunction with the American Association of Clinical Endocrinologists annual meeting in Chicago, Illinois, three leaders in endocrinology presented series of presentations involving appropriate treatment of ß-cell dysfunction and how it can help in the treatment of diabetes and in reducing the cardiovascular risk in diabetes. Topics included the pathophysiology ß-cell dysfunction, the relationship between HbA1C and cardiovascular risk in diabetes, and the use of combination therapy to treat this multi-pathological disease.

This program was supported by an unrestricted educational grant from Pfizer Inc.

Back to ß-Cell Dysfunction: The Foundation of Type 2 Diabetes

A major concern with type 2 diabetes is the number of complications that develop in these patients, such as blindness, end stage renal disease, non-traumatic amputations, and cardiovascular disease, stated Mary Ann Banerji, MD, associate professor of endocrinology, State University of New York, Health Science Center of Brooklyn, Brooklyn, New York. To decrease the risk of developing these complications requires that we fully understand the pathophysiology of type 2 diabetes and to use appropriate treatments to attenuate the development of both diabetes and the complications associated with diabetes.

ß-Cell Deficiency
Although insulin resistance is a feature of obesity and type 2 diabetes, hyperglycemia does not occur without insulin deficiency and ß-cell dysfunction. In type 2 diabetes, one of the first defects is a decrease in the insulin response to intravenous glucose stimulation. Risk factors that lead to this are unclear but include a family history of diabetes, diet and so forth. For example, first degree relatives of persons with type 2 diabetes have significantly lower first and second phase insulin response to intravenous glucose stimulation. Some individuals are insulin sensitive while others are insulin resistant. Thus at this early stage, the primary etiology of type 2 diabetes appears to be heterogeneous. Among Pima Indians who are very insulin resistant, the development of hyperglycemia was associated with a precipitous decline in insulin response. Dr. Banerji stressed that while persons with established diabetes were usually both b-cell deficient and insulin resistant, only beta cell deficiency was essential to develop the hyperglycemia of type 2 diabetes.

Another important observation that was stressed by Dr Banerji was the myth of hyperinsulinemia in type 2 diabetes. Relative to the amount of insulin which is required to maintain normal blood glucose, persons with type 2 diabetes are insulin deficient. “If you look at the insulin response in obese insulin resistant persons with diabetes, it is lower than that in obese insulin resistant non-diabetic controls,” stated Dr. Banerji. That is, relative to their increased need for insulin to maintain blood glucose, type 2 diabetes is an insulin deficient state.

ß-Cell Recovery and ß-Cell Preservation
The UKPDS showed that in type 2 diabetes, ß cell function is 50% at the time of diagnosis (Figure 1). Despite the UKPDS treatment policy with either a sulfonylurea or metformin, ß-cell function continued to decline over the 6-year observation period. What is needed is a better understanding of when to begin intensive treatment to preserve ß-cell function and what treatment to use.

One possible approach to preserve beta cell function is to develop a treatment program that reestablishes glycemic/metabolic control, thereby restoring ß-cell function. Such remissions have been demonstrated in patients with blood glucoses over 300 mg/dL who are initially hospitalized and treated with fluids; within one year they are able to discontinue their anti-diabetic medications and maintain normal HbA1C levels on their own modest diets.

In a follow- up of normoglycemic patients, Dr. Banerji found the median duration of remission was over 3 years (39 months). “This is a very substantial period of time for maintaining complete euglycemia off of all pharmacologic agents having first presented with severely high glucoses,” said Dr. Banerji.
In an attempt to further prolong this remission period, a comparison of remission rates in 3 groups was performed: no treatment, placebo, and low-dose sulfonylurea (glipizide). The results found that glipizide significantly prolonged the remission rate (Figure 2). How this sulfonylurea improves remission is unclear. Dr. Banerji speculated that sulfonylureas may replace a ligand that is low or missing in type 2 diabetes. Whether or not other agents such as metformin, thiazolidinediones, or other insulin secretagogues can also mimic remission remains to be seen.

Dr. Banerji speculated that sulfonylureas may replace a ligand that is low or missing in type 2 diabetes or they may enhance the function of the sulfonylurea receptor (SUR), a KATP channel which is an integral component of physiological insulin release. Whether or not other agents such as metformin thiazolidinediones or other insulin secretagogues can also prolong remission remains to be seen.

Conclusion
Dr. Banerji ended her presentation by saying that ß-cell dysfunction is present at the time of a clinical diagnosis of hyperglycemia but early intensive treatment can reverse ß-cell dysfunction, decrease complications and in some cases, induce remission.

Level of Glycemia and Cardiovascular Risk: Is There a Continuous Relationship?

Kay Tee Khaw, professor of clinical gerontology at the University of Cambridge in Cambridge, England, began her presentation by asking, “Why do diabetics get cardiovascular disease and what is the basic mechanism?” Whether it is hyperinsulinemia or hyperglycemia is still debatable but the growing consensus it that hyperglycemia is linked both directly and indirectly to increased risk of cardiovascular disease.

As with hypercholesterolemia and hypertension, which were once thought to be a dichotomous condition in terms of cardiovascular risk, impaired glucose metabolism can be considered as a continuum with the worse the condition, the higher the cardiovascular risk. Unfortunately, the traditional measurements for diabetes, blood glucose levels, display a large day to day variance. A better marker for cardiovascular risk in diabetes patients may be glycated hemoglobin (HbA1C) which is a marker of blood glucose levels over several weeks. In a community-based study, HbA1C was measured in 4,000 middle-aged men from the general population. These people were divided into 5 groups: 1) persons with known diabetes, 2) newly diagnosed diabetes or undiagnosed diabetes with HbA1C> 7%, 3) persons without diabetes with HbA1C< 5%, 4) persons without diabetes with HbA1Cbetween 5–5.5%, and 5) persons without diabetes with HbA1C between 5.6–6.9%. Persons with known diabetes had higher mean levels of the classical cardiovascular risk factors: blood pressure, cholesterol, and systolic blood pressure. Persons with diabetes had increased total and cardiovascular disease mortality compared to persons without diabetes. There appeared to be a continuous relationship between HbA1C level and mortality throughout the whole range of HbA1C even at levels below the threshold used for the diagnosis of diabetes (i.e., no threshold effect). More surprising, when diabetes was included with HbA1C as well as all the classical risk factors (age, systolic blood pressure, body mass index, cholesterol, cigarette smoking status) diabetes status was no longer an independent risk factor for mortality or for cardiovascular disease. Instead, “the increased risk that diabetics have for cardiovascular disease or for total mortality indeed seems to be totally mediated by their HbA1C level,” stated Dr. Khaw. In this study, a 1% increase in HbA1C correlated to a 30% increase in both total and cardiovascular disease mortality (BMJ 2001;322:15–18) (Figure 3). What is most striking about the relationship between HbA1C and mortality is that there is no specific threshold but that the relationship is continuous. As such, while many clinicians focus on the extremely high levels of HbA1C in phase 3 diabetes to illustrate the increased mortality risk, “we can’t just consider people who have diabetes, we also have to consider large numbers of people who have HbA1C above optimum levels at least in terms of risk,” said Dr. Khaw.

Figure 3 also suggests that the majority of the mortalities occur at only slightly elevated HbA1C since they make up the majority of the population. Therefore, clinicians need to begin educating patients with slightly elevated HbA1C that they are at risk. Even a small decrease (i.e., 0.1%) can greatly reduce mortality risk (5–10%). Several diet behavioral interventions such as physical activity or diet may influence HbA1C levels. For example, high intake of fruit and vegetables, as indicated by plasma vitamin C levels, may be associated with lower HbA1C levels and also decreased cardiovascular risk. An increase of plasma vitamin C by 20 mmol, which can be achieved by increasing daily intake by about 50 gram fruit and vegetables daily, is associated with a lowering of mortality risk of about 20%.

Conclusion
It has been well established that persons with established diabetes have increased risk of cardiovascular disease. It is now apparent that people with even mildly elevated HbA1C have increased cardiovascular risk, whether they are diabetic or not. We need to consider how we can also reduce cardiovascular risk in the large numbers of people with mildly elevated HbA1C through changes in life-style or other means.

Combination Therapy

The UKPDS found that most of type 2 diabetes patients were unable to achieve a HbA1C below 7% with mono-therapy. With diet alone, less than 10% of the patients achieved their goal. Similar poor outcomes were seen with sulfonylurea (20%), insulin (20%), and metformin (7%). In the clinical setting, similar percentages have been observed. Part of the problem with using mono-therapy is that hyperglycemia can have multiple causes and multiple interventions are required, stated Vivian Fonseca, MD, FACE, director of the Diabetes Program and professor of medicine at Tulane University Medical Center, New Orleans, Louisiana. Defective ß-cell secretion, insulin resistance, excess glucose intake, and inadequate hepatic glucose production are just four examples that combine to create hyperglycemia.

The two most important abnormalities are ß-cell dysfunction and insulin resistance, and each are driving the other. Therefore, Dr. Fonseca concluded, “if you’re going to get patients into remission or at least good glycemic control, you’re going to need to address both these abnormalities and that’s where combination therapy comes in.”

Combinations Tested
Combination therapy in the United States is a fairly new concept and the first report using combination therapy was in 1995, when Dr. Fonseca examined patients who had failed on glyburide and were either continued on glyburide, switched to metformin, or given glyburide and metformin. Of the three groups, only the combination therapy was effective. As a result of this report, combination therapy has now become more popular and Dr. Fonseca quickly summarized some of the recent combination therapies that are or have undergone clinical trial. For example, the combinations of repaglinide and metformin, pioglitazone and metformin, rosiglitazone and sulfonylurea, and pioglitazone and a sulfonylurea have all proven to be more effective than the monotherapy in these trials.

Unfortunately, combination therapy is usually begun only when monotherapy has failed. Therefore, “we need to rethink our current treatment paradigm,” stated Dr. Fonseca. The current paradigm is diet and exercise, followed by monotherapy, followed by combination therapy. This transition can span years and as each treatment eventually fails, the patient is exposed to hyperglycemia and increased risk of microvascular/macrovascular complications. We need to consider a new paradigm of trying not to let the blood sugar go too high by rapidly moving on to combination therapy or maybe even starting with combination therapy to induce remission. This concept has been explored by many in the pharmaceutical industry and the first combination that has recently become available is Glucovance which is a combination of glyburide and metformin. In a recent trial, the superiority of Glucovance over either agent alone was confirmed in regard to fasting glucose, weight gain, and triglycerides levels. With that being said, Dr. Fonseca cautioned the audience by saying that there are some limitations with this combination. In this study, 11% of the patients developed hypoglycemia since glyburide is a very potent sulfonylurea. Therefore, Dr. Fonseca said “it may be difficult for some patients as an initial therapy to put up with and may impede their ability to achieve remission or very tight glycemic control.”

One combination that may be safer is glipizide (Glucotrol-XL) and metformin. In a trial of patients given either Glucotrol-XL (initial dose 5 mg, titrated to 20 mg) or metformin (initial dose 850 mg, titrated to 2,250 mg). After 6 weeks, if their fasting glucose was still above 140, they were eligible for the combination therapy. As expected, the combination was found to be superior to monotherapy reducing HbA1C by 2.5%, without changing body weight, abdominal fat, intra-abdominal fat, or subcutaneous fat.

As the disease progresses, insulin therapy will eventually be required. Fortunately, insulin in combination with several oral agents has been shown to be superior to monotherapy. There are a variety of combinations used, including many of the insulin analogs with metformin, glitazone, sulfonylureas, meglitinide, and alpha-glucosidase inhibitors. For example, bedtime NPH plus daytime glipizide is effective, and in patients who have supper as their large meal, the use of suppertime 70/30 plus morning glimepiride is an appropriate combination.

Conclusion
Type 2 diabetes is a progressive disease involving progressive ß-cell dysfunction and concomitant insulin resistance. “As a result combination therapy is going to be what’s needed for most patients,” concluded Dr. Fonseca.