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ORIGINAL ARTICLE

Effects of Oral Antihyperglycemic Agents in Modifying Macrovascular Risk Factors in Type 2 Diabetes

Harold E. Lebovitz, MD

Management of patients with type 2 diabetes should focus on decreasing the excess macrovascular disease with which it is associated as well as preventing or minimizing microvascular disease. Near-normoglycemic control can reduce microvascular disease. Reducing macrovascular disease requires concomitant management of the cardiovascular risk factors (components of the insulin resistance syndrome) associated with type 2 diabetes. The first phase of such treatment is to identify the effects that the various drugs used to treat the hyperglycemia are likely to have on these associated cardiovascular risk factors. Appropriate combinations of antihyperglycemic agents should be selected for specific patients to help achieve good glycemic control and produce beneficial, or at least nondetrimental, effects on cardiovascular risk.

Diabetes Care 22 (Suppl. 3):C41–C44, 1999

Type 2 diabetic patients suffer not only from the detrimental effects of hyperglycemia but also from the deleterious effects of a variety of other metabolic abnormalities associated with type 2 diabetes as part of the so-called insulin resistance syndrome (1). The impact of these other metabolic abnormalities on the cardiovascular system is perhaps even more important than that of hyperglycemia. The choice of therapeutic agents to treat the hyperglycemia, or indeed any other abnormality, in the type 2 diabetic patient should take into consideration the effect of those agents on these other metabolic abnormalities.

The most clearly defined cardiovascular risk factors include lipid and lipoprotein abnormalities, the procoagulant state, hypertension, and obesity. The purpose of this review is to examine the impact of the antihyperglycemic agents currently available on these and other possible cardiovascular risk factors.

The most difficult task in evaluating the effects of antihyperglycemic drugs on cardiovascular risk factors is to separate the specific pharmacological effects of the drugs from effects related to the improvement in glycemic control. For example, improved glycemic control reduces glycosuria, decreases calorie loss, and improves the anabolic state. Thus, some component of weight gain may be the result of improved metabolic control. Similarly, improved glycemic control decreases VLDL concentration, causing a decrease in serum triglycerides and total serum cholesterol (2). Changes in obesity can influence blood pressure and serum lipids (3). Studies designed to demonstrate a specific metabolic effect of an antihyperglycemic agent must be done in nondiabetic subjects or, if in type 2 diabetic subjects, in a design in which glycemic control is comparably improved with another agent of a different class.

EFFECTS OF SULFONYLUREA DRUGS ON CARDIOVASCULAR RISK— Concern about the effects of sulfonylurea drugs on the cardiovascular system have existed since 1970, when the University Group Diabetes Program stopped its study on the effects of antidiabetic treatments after 8.5 years because the tolbutamide-treated group showed a statistically significantly increased risk (P< 0.05) of sudden death compared with a placebo- or insulin-treated group (4). That study has been extensively criticized, reanalyzed, and compared with subsequent less extensive studies that have failed to show any increase in cardiovascular events in sulfonylurea-treated patients. The general consensus has been that the findings are unique to peculiarities of that study and not reflective of sulfonylurea treatment in general.

Some diabetologists, however, have continued to be concerned that there is some validity to the observations (5–7). Recent data on the biochemical mechanisms of sulfonylurea action have focused on whether there is indeed a possible physiological process that sulfonylureas might alter that could result in detrimental effects to the cardiovascular system (8,9).

It has been shown in the last several years that insulin secretion in the -cell is regulated by an ATP-sensitive potassium channel (K_ATP) in the plasma membrane (10). This channel is open in the basal state and pumps potassium ions out of the -cell. When plasma glucose rises and glucose transport into the -cell is increased through GLUT2, an increase in ATP results from mitochondrial metabolism of the glucose. The rise in ATP causes the membrane K_ATP to close. The plasma membrane depolarizes, and a voltage-dependent Ca²⁺ channel in the plasma membrane opens, allowing extracellular Ca²⁺ to enter the cell and increase the cytosolic Ca²⁺. The increase in Ca²⁺ causes the insulin granule to be secreted.

The K_ATP consists of two subunits: a channel pore-forming subunit (Kir6.2), which is an inwardly rectifying K⁺ channel with two transmembrane regions, and a sulfonylurea binding site (sulfonylurea receptor 1 [SUR1]) (11,12). Both subunits must be present for the channel to work. A sulfonylurea molecule binding to the SUR1 subunit closes the channel, stopping K⁺ efflux and facilitating Ca²⁺ influx, with a resultant increase in insulin secretion.

The K_ATP is also present in the myocardium, vascular smooth muscle cells, and brain (13–15). In the myocardium and vascular smooth muscle cells, the K_ATP is closed during basal conditions. In hypoxic and ischemic states, the K_ATP opens. For the myocardium, this results in increased extracellular K⁺ and decreased intracellular Ca²⁺. The result is a shortening of the action potential duration, with a decrease in Ca²⁺ entry into the cell during the plateau phase. This can lead to decreased contractility and reduced energy consumption. The intracellular loss of K⁺ and extracellular K⁺ increase is potentially arrhythmogenic. The net effect of opening the K_ATP, therefore, may be myocardial-protective but is also arrhythmogenic. Sulfonylureas in appropriate concentrations prevent the K_ATP from opening and could block both the myocardial protection and the arrhythmogenic potential. In vascular smooth muscle, the K_ATP plays an important role in regulating vascular tone. Opening this channel (secondary to decreases in ATP) leads to vasodilatation. Sulfonylurea drugs interfere with the vasodilatory responses to ischemia and hypoxia by preventing the K_ATP from opening. In coronary ischemia, it is thought that opening K_ATP in the arterial smooth muscle cell and the decrease in intracellular Ca²⁺ are major determinants of hypoxic and ischemic vasodilatation. Glibenclamide has been shown to interfere with this process in experimental studies in dogs.

Experimental studies of K_ATP modulation, as described above, suggest that sulfonylurea treatment in humans could cause changes in cardiovascular responses to hypoxia and ischemia. These changes would depend on whether the in vivo binding of the particular sulfonylurea to the K_ATP of myocardial and vascular smooth muscle cells is sufficient to cause an effect. This is currently unknown. Some data suggest that some sulfonylureas, such as glimeperide, have significantly lower binding to myocardial and vascular smooth muscle cell K_ATP than others, such as glyburide (glibenclamide). The clinical significance of these observations needs to be explored.

Known clinical effects of sulfonylureas on cardiovascular risk factors in type 2 diabetic patients are summarized in Table 1. The two most striking effects of sulfonylureas are the increase in body weight and the increase in plasma insulin levels. The 4.0 to 5.0 kg increase in body weight is probably not due to a decrease in energy loss through decreased glycosuria, as several studies, including the U.K. Prospective Diabetes Study, have shown that type 2 diabetic patients treated to the same degree of glycemic control with metformin or acarbose do not show the weight gain (16,17). Hyperinsulinemia, which is characteristic of sulfonylurea therapy, is of significance if it is related to the weight gain or if plasma insulin is an independent risk factor for coronary artery disease. This latter issue is quite controversial, and no definitive answer is currently forthcoming.

The effects of sulfonylureas in improving plasma lipid and lipoprotein levels appear to be secondary to improved glycemic control. In studies comparing sulfonylurea treatment of type 2 diabetic patients to insulin treatment, comparable glycemic regulation with insulin gives greater improvement in decreasing VLDL levels and triglycerides than sulfonylurea treatment (18).

A consistent independent effect of sulfonylureas on fibrinogen, plasminogen activator inhibitor 1, and platelet aggregation in type 2 diabetic patients has not been shown. Similarly, although suggestions have been made that sulfonylurea drugs increase blood pressure, no consistent data support this contention. Weight gain, however, may be associated with an increase in blood pressure.

EFFECTS OF METFORMIN ON CARDIOVASCULAR RISK— Table 2 summarizes the most important effects of metformin on factors that might influence the development of cardiovascular disease in type 2 diabetic patients. Metformin consistently is not associated with weight gain, even though it lowers glycosuria significantly. In the 9-year follow-up of the obese type 2 diabetic group in the U.K. Prospective Diabetes Study, the change in mean weight in the metformin group compared with the diet-treated controls was a 2 kg less weight gain (diet: 3 kg increase from year 0; metformin: 1 kg increase) (16). Campbell and Howlett (19), in comparing sulfonylurea versus metformin treatment in nine randomized trials, found a 4-kg weight differential between them (–1.2 kg for metformin vs. +2.8 kg for sulfonylurea) despite comparable improvement in glycemic control. The Biguanides and Prevention of Risks in Obesity (BIGPRO) Study, which examined the effect of 1 year of treatment on nondiabetic subjects with an increased waist-to-hip ratio with metformin versus placebo, showed a mean weight loss on metformin of 2.0 kg compared with 0.8 kg in the placebo-treated group (20). A study of 10 obese type 2 diabetic subjects found that metformin decreased fat mass and not lean body mass (21).

The effects of metformin on plasma lipids and lipoproteins are modest reductions in plasma triglycerides and LDL cholesterol. In a study of several hundred patients who were poorly controlled on glyburide and then randomized to either remain on glyburide or be switched to metformin, plasma triglycerides and LDL cholesterol decreased 4–5% on metformin, even though glycemic control was unchanged (22). Type 2 diabetic patients in whom insulin and metformin treatment resulted in equal improvement in glycemic control had statistically significantly better improvement in plasma LDL cholesterol (decreased) and HDL cholesterol (increased) with metformin (23). Metformin has its most dramatic effect in decreasing plasma VLDL levels (24). Metformin added to sulfonylurea-treated patients decreases postprandial concentrations of triglyceride-rich particles of intestinal origin. Some recent studies have focused on the effect of metformin in decreasing lipolysis and lowering plasma free fatty acids (25). A summary of the effects of metformin on lipid and lipoprotein metabolism in type 2 diabetic patients is that they are consistent with a modest reduction in the atherogenic profile.

A few studies suggested that metformin treatment would lower blood pressure. These studies were uncontrolled and could not be confirmed in randomized placebo-controlled trials. The large clinical trials of metformin treatment in type 2 diabetes failed to show any blood pressure lowering effect of metformin. A more detailed analysis of blood pressure responses to angiotensin II or norepinephrine infusions have shown no effect of metformin treatment.

Metformin treatment does modify the procoagulant state in type 2 diabetes. It has a specific effect in decreasing plasminogen activator inhibitor 1 levels in type 2 diabetic patients (26). Metformin decreased plasminogen activator inhibitor 1 antigen levels in the centrally obese nondiabetic patients in the BIGPRO study (20).

The effects of metformin in decreasing insulin resistance and plasma insulin levels are related to its mechanism of antihyperglycemic action. The implications of these reductions in cardiovascular risk are speculative, as noted previously.

EFFECTS OF TROGLITAZONE ON CARDIOVASCULAR RISK— Troglitazone is the only approved drug of a new class of antidiabetic drugs, the thiazolidinediones. It acts primarily by binding to a peroxisome proliferator-activated receptor and activating transcription of a large number of genes (27). Some of these genes code for proteins that are involved in adipose tissue differentiation and fatty acid metabolism. In addition to improving insulin action on muscle glucose metabolism, troglitazone has been reported to exert many effects that are independent of its antihyperglycemic actions (Table 3).

The most dramatic of these effects are those associated with lipid metabolism. Troglitazone causes a mild increase in weight gain during effective monotherapy (28), but a larger weight gain is seen when troglitazone is given in conjunction with sulfonylureas (2.5–6.0 kg) (29) or insulin (3.5 kg) (30). These estimates of weight gain are derived from 6-month studies. Troglitazone treatment reduces plasma triglycerides 15–20% and increases plasma LDL cholesterol and HDL cholesterol 10–15% (30–32). Preliminary studies suggest that troglitazone increases plasma lipoprotein(a).

Some studies measuring blood pressure suggest that troglitazone may decrease diastolic blood pressure by several millimeters of mercury (30–32). Other studies, however, failed to find any effect on blood pressure (33). Recent data show that plasminogen activator inhibitor I levels are significantly reduced by 400 mg troglitazone daily (34,35).

Available present studies do not allow a clear picture of what to expect for the long-term effects of troglitazone on cardiovascular events in type 2 diabetic patients.

EFFECT OF -GLUCOSIDASE INHIBITORS ON METABOLIC FACTORS OTHER THAN GLYCEMIC CONTROL— -Glucosidase inhibitors act primarily on the gastrointestinal tract. Effects on weight would not be expected, because the drugs do not cause malabsorption (carbohydrate in the colon is metabolized to short-chain fatty acids) (34). No effects on blood pressure have been observed.

Other than a reduction in postprandial hyperglycemia and insulinemia, the only other significant effects noted with -glucosidase inhibitors are modest decreases in postprandial plasma triglyceride levels and a rise in plasma glucagon-like peptide 1 (36).

CONCLUSIONS— Each class of antihyperglycemic agents has a spectrum of activities concerning the various metabolic factors of the insulin resistance syndrome. These effects should be considered when designing a treatment program for type 2 diabetic patients. A treatment program should consider: 1) the magnitude of effect on glycemic regulation; 2) the mechanism of antihyperglycemic action; 3) the profile of effects on other components of the insulin resistance syndrome; and 4) the likelihood and nature of possible severe side effects, such as hypoglycemia, lactic acidosis, or liver toxicity.

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From the Division of Endocrinology and Metabolism, State University of New York, Health Science Center at Brooklyn, Brooklyn, New York.

Address correspondence and reprint requests to Harold E. Lebovitz, MD, Division of Endocrinology and Metabolism, SUNY Health Science Center at Brooklyn, 450 Clarkson Ave., Box 1205, Brooklyn, NY 11203.

Received for publication 6 July 1998 and accepted in revised form 21 December 1998.

H.E.L. has received honoraria or consulting fees from and has served on advisory panels of Bayer, Pharmacia-Upjohn, SmithKline Beecham, Novo Nordisk, Knoll, Bristol-Myers Squibb, Novartis, Hoechst, and Amylin; has been paid for serving on the speaker's bureau for Parke-Davis; and has received research support from SmithKline Beecham, Merck, Novo Nordisk, and Bristol-Myers Squibb.

Abbreviations: BIGPRO, Biguanides and Prevention of Risks in Obesity; K_ATP, ATP-sensitive potassium channel; SUR1, sulfonylurea receptor 1.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

This article is based on a presentation at a conference organized by the Indiana University Diabetes Research and Training Center. The conference and the publication of this article were made possible by an unrestricted educational grant from Eli Lilly and Company.

Copyright © 1999 American Diabetes Association
Last updated: 3/99
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