Miglitol Reduced Cardiovascular Events, Hypoglycemia, and Weight Gain in Older Type 2 Diabetics
Abstract & Commentary
Synopsis: Treatment with miglitol offers older type 2 diabetic patients a useful and relatively safe therapeutic option for the treatment of their diabetes.
Source: Johnson PS, et al. J Clin Endocrinol Metab 1998; 83:1515-1522.
Selecting a hypoglycemic agent for the treatment of type 2 diabetes is not as "clear cut" as it may seem. Recent major reports from the United States1 and the United Kingdom2 support the effort to reduce blood glucose and HbA1c to as near the normal range as possible. This approach has resulted in the reduction of microvascular disease (blindness, renal failure, etc.) but not in a significant reduction in ischemic heart disease and stroke (macrovascular disease). When insulin and sulfonylurea preparations have been used, there has been weight gain and an increase in the number of cardiovascular risk factors.
The use of the alpha-glucosidase inhibitors, such as acarbose and miglitol, has gradually been increasing because they reduce postpyrandial blood glucose rises and do not cause hypoglycemia, which can be a significant problem in older patients.
Johnson and associates have published a one-year study to determine the safety, efficacy, and tolerability of the alpha-glucosidase inhibitor miglitol as compared to the sulfonylurea glyburide in the treatment of patients with type 2 diabetes who were older than 60 years of age and inadequately controlled by diet alone.
Four hundred diet-treated patients were randomized to receive either placebo tid (n = 101), miglitol 25 mg tid (n = 104), miglitol 50 mg tid (n = 102, or glyburide once daily, titrated based on fasting plasma glucose (n = 104) for a period of 56 weeks. They assessed efficacy based on HbA1c, fasting, and post-prandial glucose, insulin, and lipid levels as well as 24-hour urinary excretion of glucose and albumin.
At the one-year end point, HbA1c treatment effects (placebo-subtracted change in HbA1c from baseline) were -0.49% for miglitol 25 mg, -0.40% for miglitol 50 mg, and -0.92% in the glyburide group. Hypoglycemia occurred in 8% of the placebo group, 10% and 9% of the 25 mg and 50 mg miglitol group, and in 46% of the glyburide group. Weight gain was significantly greater in the glyburide-treated group (mean increase 5 lbs). Total cardiovascular events were reduced in the miglitol group, with 22% of the placebo group experiencing a cardiovascular event as compared to 18% on 25 mg miglitol, 17% on 50 mg miglitol, and 29% of those receiving glyburide.
Diarrhea, flatulence, and nausea were significantly more frequent in the miglitol group but were often temporary. There were no significant differences between treatment groups of discontinuation due to adverse events (6% placebo, 10% miglitol 25 mg, 12% miglitol 50 mg, and 6% glyburide). The most common reasons for discontinuation were hyperglycemia, diarrhea, and flatulence in the miglitol patients and cardiovascular events in the glyburide group.
Treatment failure was significantly lower in the glyburide group (2%) than in the other three groups—11% for placebo and miglitol 25 mg and 6% for miglitol 50 mg.
Treatment responders defined as patients who demonstrated a reduction in HbA1c from baseline to end point of at least 1% or whose end point was 7% or less were 33% of the miglitol 25 mg, 30% of the miglitol 50 mg, and 52% of the glyburide patients were responders.
Treatment with miglitol offers older type 2 diabetic patients a useful and relatively safe therapeutic option for the treatment of their diabetes.
COMMENT BY RALPH R. HALL, MD, FACP
It is important to note that despite a greater fall in HbA1c, the group tested with the sulfonylurea had a higher incidence of ischemic vascular disease. Thus, although the decline in HbA1c seems to be mirrored by a decline in microvascular disease, macrovascular disease may increase if there is increased weight gain and increased insulin levels.
There are not enough data at this time to indicate what the trade off is for a decrease in macrovascular disease vs. a potential for increase in microvascular disease. If one can obtain a maximum decrease in HbA1c in a segment of the population as this study suggests, it would be important to use a medication that was going to decrease the macrovascular disease as well as the microvascular disease to a minimum. Miglitol would then be an excellent choice for treating older patients whose blood glucose could be well controlled.
Previous studies have indicated that the 50 mg dose of miglitol was as effective as the 100 mg dose in reducing the blood glucose and HbA1c levels.3 The 50 mg dose had less side effects than the 100 mg dose.
Issues that need further exploration are how adding a sulfonylurea to miglitol or miglitol to a sulfonylurea will affect the incidence of ischemic vascular disease in those patients in whom monotherapy was not adequate. The UKPDS studies showed that adding metformin to sulfonylureas in patients not responding to a sulfonylurea alone increased the incidence of macrovascular disease. This occurred despite the lowering of the incidence of macrovascular disease in patients receiving monotherapy with metformin.
The safety of other agents, such as troglitazone, continues to be questioned. Troglitazone has been withdrawn from the British market and additional cases continue to be reported in the United States.4 It remains uncertain, as Vella and associates point out, whether adherence to the manufacturer and FDA will prevent fatal liver failure.
The use of the alpha-glucosidase inhibitors are attractive alternatives for those patients with older, mild type 2 diabetes. There also may be the potential for a decrease in macrovascular disease, as occurred in this study, since cardiovascular risk factors, such as weight gain and increased insulin resistance, do not occur.
References
1. Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-986.
2. UK Prospective Diabetes Study (UKPDS 34). Lancet 1998;352:854-865.
3. Johnston PS, et al. Diabetes Care 1994;17:20-29.
4. Vella A, et al. Ann Int Med 1998;129:1080.
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