Treatment of Type 2 Diabetes with a Combination of Two Insulin Sensitizers. Increased Efficacy and Fewer Side-effects

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US Cardiology 2004;2004:1(1)

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Thiazolidinediones (TZD) and metformin lower cardiac risk factors, as do serum glucoses, and are therefore the best choice for initial therapy of type 2 diabetes. To choose between metformin and a thiazolidinedione is difficult because of the many benefits of both drugs. In most cases, a combination of metformin and a TZD is chosen, and this article describes the rationale for this decision.

The basic principle of combination therapy is that with smaller doses of two drugs there is greater efficacy and fewer side-effects than with a large dose of either drug used as monotherapy. In the case of the addition of metformin to a TZD or vice versa, because of their different sites of action (liver with metformin and muscle with the TZD), it will result in a decrease in the hemoglobal (Hb) A1c that will be greater than that achieved by monotherapy with a larger dose of either drug. Perhaps of more importance is that, at lower doses, the side-effects of metformin (anorexia, nausea, and diarrhea) and TZDs (weight gain, edema, and dilutional anemia) are much less. Around 30% of patients initiated on metformin will develop gastrointestinal symptoms,and 3% will have to discontinue the drug. Of the remaining 27%, the majority will only tolerate metformin at less than the maximum dose of 2,500mg daily (usually one gram or less).

Both metformin and TZDs lower cardiac events. This is important with type 2 diabetes, which has been described as a cardiac condition characterized by hyperglycemia and is a cardiac risk equivalent i.e., a 20% chance of a cardiac event over 10 years. Metformin lowers total low-density lipoproteins (LDL) and triglycerides, and TZDs variably lower triglycerides and raise total high-density lipoprotein (HDL). Of more importance is that by suppressing the activity of hepatic lipase, TZDs have been shown to increase the size of both the HDL and LDL particles.1The larger LDL particle is less atherogenic and the larger HDL particle (HDL2) is the only HDL particle, which is cardioprotective. Furthermore, the smaller HDL3 particle in addition to being less cardioprotective, is also more easily broken down by the liver, accounting for the low total HDL seen with insulin resistance. Therefore, insulin sensitizers used in combination can, even at lower doses by their effects on the lipid profile, provide a further lowering in cardiac risk and are complementary to the statins which most type 2 diabetic patients will be or should be utilizing.2

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