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Treatment of Diabetes with Metformin and Insulin



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Am Fam Physician. 2000 Feb 15;61(4):1119.

Type 2 diabetes (formerly known as non–insulin-dependent diabetes) is more common among persons who are obese. Dietary modification and weight loss improve glycemic control in these patients. However, the addition of pharmacologic therapy is often needed to obtain tight glycemic control. Because sulfonylureas have a high rate of failure, the use of other oral agents or insulin is often necessary. Overweight patients who are insulin resistant often require high dosages of insulin. These high dosages can cause weight gain, making glycemic control more difficult. Avilés-Santa and associates performed a randomized, double-blind, placebo-controlled trial to evaluate the efficacy of combining metformin with insulin in the treatment of patients with poorly controlled type 2 diabetes.

Metformin decreases hepatic glucose output and improves peripheral insulin sensitivity, which results in improved glycemic control in patients with type 2 diabetes. With the use of metformin, blood lipid abnormalities, particularly hypertriglyceridemia, improve, and weight loss is often reported. These beneficial effects make the combination of metformin and insulin an attractive treatment that allows patients to avoid weight gain while achieving glycemic control.

For inclusion in the trial, patients must have been treated with at least 50 units of insulin per day for at least two years and have a hemoglobin A1c level of 8 percent or higher at the time of enrollment. Patients with a serum creatinine concentration greater than 1.5 mg per dL (130 mmol per L), elevated hepatic enzyme levels or renal disease were excluded from the study. Forty-three patients were randomized to receive metformin or placebo in addition to their current insulin therapy (at least two doses per day) and were followed for 24 weeks. Metformin was started at a dosage of 500 mg per day and increased gradually over eight weeks to the maximum dosage of 2,500 mg per day. The dosages of insulin were modified throughout the study to achieve better glycemic control.

While glycemic control improved in both groups, the hemoglobin A1c levels were 10 percent lower in the metformin group than in the placebo group. Patients in the placebo group had a significant increase in daily insulin dosages and a 3.2 kg (7 lb, 6 oz) increase in average body weight compared with those in the metformin group, who had no increase in daily insulin requirements and a 0.5 kg (1 lb, 2 oz) increase in average body weight. Side effects of metformin versus placebo are listed in the accompanying table.

Incidence of Adverse Effects

Side effect Metformin group* Placebo group†

Nausea

7

4

Abdominal pain

1

0

Diarrhea

9

4

Hypoglycemia

3

3

Hunger

1

1

Bloating

1

1

Anorexia

1

0


*—N = 21 patients.

†— N = 22 patients.

Reprinted with permission from Avilés-Santa L, Sinding J, Raskin P. Effects of metformin in patients with poorly controlled, insulin-treated type 2 diabetes mellitus. Ann Intern Med 1999;131:182–8.

Incidence of Adverse Effects

View Table

Incidence of Adverse Effects

Side effect Metformin group* Placebo group†

Nausea

7

4

Abdominal pain

1

0

Diarrhea

9

4

Hypoglycemia

3

3

Hunger

1

1

Bloating

1

1

Anorexia

1

0


*—N = 21 patients.

†— N = 22 patients.

Reprinted with permission from Avilés-Santa L, Sinding J, Raskin P. Effects of metformin in patients with poorly controlled, insulin-treated type 2 diabetes mellitus. Ann Intern Med 1999;131:182–8.

The authors conclude that adding metformin to an intensified insulin regimen results in a reduction of hemoglobin A1c level that is 11 percent lower than that achieved with insulin therapy alone, with less total insulin used, a less complicated insulin regimen and no increase in the incidence of hypoglycemia or weight gain.

Avilés-Santa L, et al. Effects of metformin in patients with poorly controlled, insulin-treated type 2 diabetes mellitus. Ann Intern Med. August 3, 1999;131:182–8.



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