EVIDENCE-BASED ANSWER
Combination therapy using insulin plus metformin (Glucophage), a sulfonylurea, or both produces glycemic control comparable with using insulin alone, but there is less weight gain when metformin is used (strength of recommendation [SOR]: B, based on systematic review of randomized controlled trials [RCTs] with some heterogeneity). Combination therapy using insulin and pioglitazone (Actos) reduces glycosylated hemoglobin (HbA1c) more than either insulin alone or adding pioglitazone to a sulfonylurea, but results in more weight gain (SOR: A, based on RCT). Using insulin glargine (Lantus) in combination therapy produces fewer nocturnal hypoglycemic events than using neutral protamine Hagedorn (NPH) insulin, while producing equivalent HbA1c reduction (SOR: B, based on RCT).
When the HbA1c is high (above 9.0% to 9.5%) on 1 or 2 oral agents, beginning combination therapy is more effective than adding another oral agent (SOR: B, based on subpopulation analysis in RCTs).
CLINICAL COMMENTARY
Educate patients from the time of diagnosis that insulin is not a failure
Vincent Lo, MD
San Joaquin General Hospital, French Camp, Calif
Combination therapy for patients with type 2 diabetes is a safe and effective stepping stone between oral therapy and insulin therapy. Unfortunately, significant barriers remain to getting insulin started when oral agents alone are insufficient. Patients often do not understand the common need for insulin therapy as type 2 diabetes advances, and some physicians continue to use the threat of insulin as a punitive incentive to promote patient compliance. It is little wonder that many patients perceive a physician’s eventual recommendation for insulin therapy as a personal failure. Patients are also concerned about the discomfort, inconvenience, and risk of insulin injections. Physicians should focus on educating their patients from the time of diagnosis that insulin is not a failure, but just another tool that will help them achieve their blood sugar goals.
Evidence summary
A systematic review evaluated beginning combination therapy (adding insulin to oral medication) compared with switching to insulin alone in patients with type 2 diabetes mellitus with inadequate glycemic control on oral medication.1 Twenty RCTs studied a total of 1811 patients; glycemic control was the primary outcome measure. Oral medication comprised either sulfonylureas (75%), metformin (4%), or both (21%). Individual studies used different insulin dosing schedules and statistical measures. However, overall, combination therapy provided glucose control comparable with insulin alone. In only 1 small, low-quality study did insulin plus metformin reduce HbA1c more than other combination therapy regimens or insulin alone. Ten studies reported a trend toward less weight gain with combination therapy that included metformin. Fourteen studies found the same incidence of hypoglycemic episodes in combination therapy and insulin alone.
Three later RCTs of overweight patients with inadequate control on oral agents (HbA1c >7% on a sulfonylurea, metformin, or both) also compared beginning combination therapy with switching to insulin alone (with 70/30 or NPH insulin twice daily). In one study with 64 patients followed for 12 months, HbA1c fell by 0.14% less (nonsignificant) in the combination therapy group (bedtime NPH plus sulfonylurea and metformin) than in the insulin alone group (70/30 twice daily).2 The combination therapy group gained significantly less weight than the insulin-alone group (1.3 kg vs 4.2 kg; P=.01).
In the second study of 261 patients, the combination therapy group (glimepiride [Amaryl] plus bedtime NPH) had a significantly higher HbA1c after 9 months than 2 groups using insulin alone (twice daily 70/30, and twice daily NPH insulin) (8.9% vs 8.3% and 8.4%).3 Mean weight gain was similar in all 3 groups but only a minority of patients reached a target HbA1c of 6.5%. In the final study of only 16 patients, HbA1c after 6 months improved significantly and equally in both groups (baseline: 8.3%, combination therapy final: 6.8%; insulin alone final: 7.0%). However, the combination therapy group gained significantly less weight.4
An open-label RCT with 341 patients who were inadequately controlled on metformin compared beginning combination therapy (biphasic insulin aspart 30/70 [Novolog Mix 70/30] and metformin) with switching to insulin alone (biphasic insulin aspart 30/70).5 A third group added a second oral medication (sulfonylurea and metformin). After 16 weeks, patients taking combination therapy had a significantly lower HbA1c than those on insulin alone (treatment difference 0.39%, P=.007).
Overall, combination therapy and 2 oral medications reduced HbA1c by the same amount, but combination therapy reduced HbA1c more in a subpopulation of patients with HbA1c >9.0% at baseline (treatment difference 0.46%, P=.027). The group on insulin alone weighed significantly more (4.6 kg, P<.001) at the end of the trial than the group taking 2 oral medications.
An open-label RCT of 756 patients with inadequate glycemic control (HbA1c >7.5%, mean 8.6%) on either 1 or 2 oral agents (70% taking both metformin and a sulfonylurea) compared combination therapy using bedtime insulin glargine with combination therapy using morning NPH.6 Each group titrated insulin doses to achieve a target fasting glucose ≤100. By 24 weeks, both groups had equivalently reduced HbA1c (mean HbA1c=6.96% with glargine, and 6.97% with NPH; P=NS), but fewer patients experienced nocturnal hypoglycemia with glargine than with NPH (33.2% vs 26.7%, P<.05).