Is Treatment of Insulin Resistance Beneficial Independent of Glycemia?
- Mayer B. Davidson, MD
- From the Clinical Trials Unit, Charles R. Drew University, Los Angeles, California
- Address correspondence and reprint requests to Mayer B. Davidson, MD, Director, Clinical Trials Unit, Charles R. Drew University,
1731 East 120th St., Los Angeles, CA 90059. E-mail: madavids{at}cdrewu.edu
The clinical definition of the Insulin Resistance or Metabolic Syndrome is shown in Table 1. Subjects who fulfill these criteria are at increased risk for cardiovascular disease (CVD). The criteria of the National
Cholesterol Education Program are more clinically relevant because those measurements are readily available. Although those
with impaired fasting glucose and/or impaired glucose tolerance (IGT) are at increased risk for the subsequent development
of type 2 diabetes (3), abnormal glycemia is not an independent predictor of cardiovascular disease once the other risk factors are taken into
account (4,5). Three recent randomized, controlled studies have shown that lifestyle intervention with diet and exercise can decrease
the development of type 2 diabetes in subjects with IGT (6–8). However, although exercise is associated with less CVD (9), the hypothesis that exercise decreases CVD has never been directly tested in a randomized, controlled clinical trial.
Insulin resistance, highly associated with visceral fat accumulation (10), characterizes the Insulin Resistance or Metabolic Syndrome. Furthermore, measured insulin resistance predicts CVD (11). In this issue of Diabetes Care, Shadid and Jenson (12) compare the effects of diet and exercise versus pioglitazone in insulin-resistant nondiabetic men and premenopausal women
with upper body obesity (i.e. visceral fat accumulation). Insulin sensitivity increased in both groups. Those given diet and
exercise showed weight loss and decreased visceral, subcutaneous, total body, and leg fat, whereas the subjects prescribed
pioglitazone had no change in subcutaneous and visceral fat and increased their weight and total body and leg fat. Although
the differences in fat and weight changes suggest different mechanisms, both approaches decreased insulin resistance. While
no one would argue with using diet and exercise to reduce insulin resistance, it is well recognized that the long-term effectiveness
of this lifestyle intervention is disappointing. This raises the question of whether pharmacological means to increase insulin
sensitivity would be beneficial and whether they should be considered.
Similar to the situation with lifestyle intervention, there are no studies currently available demonstrating a beneficial
effect on clinical cardiovascular end points after reducing insulin resistance by pharmacological means (although such trials
are in process). However, there are a number of reports of beneficial effects on risk factors for and surrogate end points
of CVD. All three glitazones raise HDL cholesterol levels (13–15) and change small, dense, more atherogenic LDL particles to larger, less atherogenic ones (16–18). Their effect on triglycerides is variable, with pioglitazone the most effective at lowering them and rosiglitazone the
least effective (13–15). The blood pressure-lowering effect of rosiglitazone is proportional to the drug’s effect on decreasing insulin resistance
(19).
In addition to the classical risk factors of dyslipidemia and hypertension for CVD, accumulating evidence has also implicated
prothrombotic and proinflammatory states, increased levels of certain endothelial cell molecules, and endothelial dysfunction
in the pathogenesis of CVD. Increased plasminogen activator inhibitor-1 levels, leading to impaired fibrinolysis and therefore
a prothrombotic state, are part of the Insulin Resistance Syndrome and were lowered by troglitazone (20–22) and rosiglitazone (19). C-reactive protein, a marker of the proinflammatory state, was also reduced by troglitazone (21,22), rosiglitazone (19,23), and pioglitazone (24), the latter having this effect even in patients who did not respond glycemically to the drug.
Early events in the pathogenesis of atherosclerosis involve the effect of oxidized and glycated LDL initiating the formation
of fat-filled macrophages or foam cells. This process involves triggering inflammatory responses by increased expressions
of cytokines and adhesion molecules, e.g., intracellular adhesion molecule (ICAM) and E-selectin, and the stimulation of monocyte
migration to the vessel wall by chemotactic factors, e.g., MCP (25). Troglitazone lowered E-selectin (26), ICAM (20), and MCP-1 (20) and rosiglitazone decreased E-selectin (27). One of the matrix-degrading metalloproteinases (MMP-9), which has been implicated in atherosclerotic plaque rupture, the
precipitating event in the acute coronary syndrome, was decreased in type 2 diabetic patients with CVD by troglitazone (22) and rosiglitazone (28).
Reducing insulin resistance also improved the morphologic, physiological, and clinical outcomes of CVD in type 2 diabetic
patients. Morphologically, intima-media thickness (IMT) of the carotid arteries correlates with the extent of coronary artery
atherosclerosis (29). Both troglitazone (30) and pioglitazone (31) decreased IMT within 3 months. Physiologically, endothelial dysfunction, which also characterizes atherosclerotic disease
in type 2 diabetic patients, was improved by troglitazone (32) and rosiglitazone but not by metformin (33). Furthermore, in type 2 diabetic patients, pulse wave velocity, a direct measure of arterial distensibility, which correlates
well with IMT (34), is a good marker of vascular damage (35), and predicts mortality (36), was decreased by pioglitazone (24), even in patients who did not respond glycemically to the drug. From a clinical perspective, rosiglitazone improved myocardial
blood flow measured by positron emission tomography scanning in type 2 diabetic patients with disease duration <8 years (37). Both the effects of troglitazone on endothelial dysfunction (32) and rosiglitazone on myocardial blood flow (37) were not significant in type 2 diabetic patients with longer durations of disease, suggesting that lowering insulin resistance
is more likely to prevent or delay CVD if it occurs early on. Finally, in type 2 diabetic patients in whom stents were placed
in their coronary arteries, the restenosis rate was markedly reduced by rosiglitazone compared with the control group in the
absence of a glycemic difference (38). Similarly, the minimal lumen diameter was significantly greater 6 months later in those given pioglitazone than in control
subjects, again with no difference in glycemia between the two groups (39).
Thus, there is a large amount of very suggestive evidence that reducing insulin resistance by pharmacological means may be
beneficial independent of a glycemic effect. However, there are at least two concerns that must be addressed before we can
embark on pharmacological therapy for the Insulin Resistance Syndrome; the duration of treatment and how to measure its effect.
When do we start pharmacological treatment? As soon as the Insulin Resistance Syndrome is identified? Only after age 30 years?
40 years? 50 years? Once started, how long should pharmacological treatment be given? Throughout a person’s lifetime? Up to
age 70 years? 80 years? Importantly, how do we judge its effectiveness? Most of the tests for insulin sensitivity are invasive
and not applicable to clinical medicine. A few rely on fasting insulin concentrations, but the insulin assay is not standardized
and, in some of them, the antibodies also cross-react with proinsulin and split products to varying degrees. Moreover, the
level assigned to insulin resistance is arbitrary. Should we use the highest decile? Quartile? Tertile? Above the median for
a “normal” population (whatever that may be)? These critical issues will need to be resolved before pharmacological treatment
for the Insulin Resistance Syndrome can be considered. At the moment, the evidence for a beneficial clinical effect rests
on surrogate end points and intermediate outcomes. If the ongoing clinical trials demonstrate a reduction in hard clinical
events, difficult decisions will need to be made.
Table 1—
Criteria for the Insulin Resistance or Metabolic Syndrome
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