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Combination therapy in diabetes

Type 2 diabetes is a long term and mostly lifelong disorder characterized by resistance to insulin action in the liver, the muscles and the fat cells in the body. It is also characterized by progressive reduction in the ability of the body to produce insulin, abnormalities of intestinal functioning, satiety and weight control. These abnormalities lead to elevated blood sugar levels, obesity, cholesterol abnormalities, hypertension, heart and blood vessels abnormalities and damage to the kidneys, the nerves and the retina of the eyes.

As a result of its multi-factorial causation, control is often difficult to achieve and oftentimes requires the use of multiple medications that have different mechanisms of action and will thus produce synergistic effects. Long-term use of a single medication to control blood sugar levels will thus ultimately end in failure. Most professional societies involved in diabetes care have thus emphasized the need for systematic and progressive use of combinations of various types of blood sugar lowering medications.

Metformin is often the preferred first line medication. As the disease progresses however, it will be necessary to combine it with additional medications. It is also known that a time will come when combination of oral medications will also no longer be able to keep the blood sugar levels at bay, at such times one or more injections will be required. The choice of combination therapy to be undertaken will need to take cognizance of factors such as duration of the disease, complications that are present, life expectancy, risk of hypoglycaemia, the patient's personal preferences and capacity for self-care, social support and financial capabilities.


In Type 2 diabetes, there is often concurrent insulin deficiency and insulin resistance. The progressive nature of the disease leads to loss of efficacy of single drugs used in therapy within three years of use. Hence, early use of combination therapy which should include an agent that enhances insulin availability (insulin or sulfonylurea) with one that enhances insulin sensitivity in the target tissues (metformin or pioglitazone) will be advised. Metformin acts primarily by improving the sensitivity of the liver to effects of insulin while pioglitazone acts principally by increasing the responsiveness of the muscles and fat cells to insulin. Hence, combined use of Metformin and Pioglitazone has additive effects.

One of the advantages inherent in the use of combination therapy is that the side effects of each drug become minimized as smaller dosages of each drug are then required. Hence, blood sugar control is improved while side effects are minimized. For example, the maximum daily dose of Metformin is usually 2, 000 mg at which dose significant side effects occur in the intestines. When the dose is lowered to 1, 000mg per day, about 70% of its blood sugar lowering effects will still occur but with significant reduction in the abdominal discomfort, diarrhoea, nausea and vomiting associated with the higher dosage. Hence, use of sub-maximal doses of two drugs can achieve not only a greater reduction in blood sugar levels but also experience of fewer side effects.

Oral agents can also be combined with injections such as insulin.
The continued use of Metformin when insulin is started is quite desirable as lower doses will then be required thus reducing the episodes of hypoglycaemia. Additionally, the concurrent use of insulin and Metformin reduces significantly the weight gain that will have been associated with the use of insulin alone. Beyond improving blood sugar levels, use of combination therapy can assist in other areas. The ability of Metformin to limit weight gain is well recognized.

Combination of Metformin with Glibenclamide (Daonil) or Glimepiride (Amaryl) or with Pioglitazone (Actos) is commonly used. So also is the combination of Metformin with the relatively newer DPP-IV Inhibitors (Vildagliptin, sitagliptin).

To attain the goal of good blood sugar control, the effectiveness of treatment can be optimized by the use of combination therapy.

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