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Combining rosiglitazone, metformin, and insulin aspart
improved glucose metabolism in obese type 2 diabetic patients compared
with mixed insulin alone, according to the results of a open-label,
randomized trial published in the December issue of Diabetes Care.
Which of the following would not be a benefit
of the above triple therapy?
1. Improved peripheral insulin sensitivity
2. Improved hepatic insulin sensitivity
3. Improved glycemic control
4. Improved weight control
Triple therapy addresses three pathophysiological components of type
2 diabetes: reduced insulin secretion and insulin resistance in skeletal
muscle and in the liver. In triple therapy, insulin aspart (a rapid-acting
insulin analog) is used to address reduced insulin secretion, metformin
is used to improve hepatic insulin sensitivity, and rosiglitazone is
used to improve peripheral insulin sensitivity. The authors hypothesize
that compared with insulin therapy alone, triple therapy can produce
better outcomes in
HbA1c levels, insulin dosage required, number of hypoglycemic episodes,
and diurnal profiles of glucose.
Type 2 diabetes is caused by reduced insulin secretion and insulin resistance
in skeletal muscle and liver," write Mikael Kjær Poulsen,
MD, from Odense University Hospital in Denmark, and colleagues. "There
has been a tradition for many years to use only one antidiabetic drug
at a time, and most patients are still treated with either insulin secretagogues
or insulin alone. However, these drugs have only a minor effect on cardiovascular
events and mortality, whereas metformin, which improves insulin sensitivity,
is able to reduce the risk of myocardial infarction and reduce the mortality
rate."
For six months, 16 obese type 2 diabetic outpatients receiving human
NPH or MIX (regular + NPH) insulin twice daily either received triple
therapy or continued their NPH or MIX insulin twice daily. Triple therapy
consisted of insulin aspart, a rapid-acting insulin analog, at meals;
metformin, which improves hepatic insulin sensitivity; and rosiglitazone,
which improves peripheral insulin sensitivity. Algorithms directed adjustment
of insulin doses in both groups.
In the triple therapy group, mean HbA1c decreased from 8.8% to 6.8%
(P < .01) without occurrence of severe hypoglycemic events, and insulin
sensitivity improved in both skeletal muscle and liver. Postprandial
hyperglycemia was infrequent. The diurnal profile of serum insulin was
characterized by fast and high peaks without the need to increase insulin
dose. Triple therapy was not associated with significant weight gain
or impairment in plasma lipids, blood pressure, or safety parameters
other than hemoglobin.
Although the insulin dose was increased by 50% in the control group,
there was no change in HbA1c levels, 24-hour blood glucose levels, or
insulin sensitivity.
"These results strongly indicate that normalization of the three
major pathophysiological defects of type 2 diabetic subjects, namely
peripheral insulin resistance, hepatic insulin resistance, and reduced
insulin response following meals, can significantly improve glucose
metabolism," the authors write. "Triple therapy seems a promising
treatment for hyperglycemia in type 2 diabetic subjects, but long-term
studies are necessary. However, if these results are confirmed, diabetes
complications may be dramatically reduced."
Novo Nordisk provided insulin aspart, GlaxoSmithKline provided rosiglitazone,
and Merck provided metformin. Novo Nordisk and GlaxoSmithKline provided
honoraria for speaking engagements to three of the study authors. The
Clinical Institute, University of Southern Denmark; Bernard Rasmussen
and wife Meta Rasmussen's foundation, Overlægerodets Legatudvalg;
Den Almindelige Danske Lægeforening's science foundation; Novo
Nordisk, Denmark; and GlaxoSmithKline, Denmark, supported this study.
Diabetes Care. 2003;26:3273-3279
Pearls for Practice
Triple therapy addresses both reduction in insulin secretion and insulin
resistance (liver and peripheral) in obese patients with insulin-requiring
type 2 diabetes.
Triple therapy over six months results in improved HbA1c levels, diurnal
glucose profile, and insulin sensitivity than therapy with insulin alone,
with no increase in hypoglycemic episodes. Long-term trials are pending.
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