What is the best medical therapy for new-onset type 2 diabetes?

Oral agents are commonly prescribed for patients with diabetes mellitus type 2 when diet and exercise fail. Options for initiating therapy include sulfonylureas, metformin (Glucophage), α-glucosidase inhibitors, thiazolidinediones, and nonsulfonylurea secretagogues (repaglinide [Prandin] and nateglinide [Starlix]). A systematic review with 31 placebo-controlled randomized trials (total n=12,185 patients) evaluated changes in HbA _1c with monotherapy using 5 different classes of oral agents (TABLE). Except for the α-glucosidase inhibitor acarbose (Precose), which was less effective, all agents typically reduced HbA_1c by 1% to 2%. However, in an additional 19 out of 23 randomized head-to-head studies (total n=5396) included in the same systematic review, all classes showed equal efficacy. Head-to-head studies are difficult to compare since hypoglycemic medications may reach peak effects at different times. An RCT compared glimepiride (Amaryl), pioglitazone (Actos), and metformin over 12 months of use by 114 patients with diabetes. There was no difference among the groups in overall HbA_1c reduction. However, glimepiride decreased HbA_1c rapidly over 1 month and reached a nadir at 4 months. Pioglitazone did not reduce HbA_1c until 6 months and reached its nadir at 7 to 9 months. Metformin produced an intermediate response. A meta-analysis of head to head studies involving α-glucosidase inhibitors included 8 trials comparing acarbose with sulfonylureas. In pooled results, sulfonylureas trended towards greater HbA _1c reduction but did not reach significance (additional HbA _1c decrease 0.4%; 95% confidence interval [CI], 0%-0.8%). A meta-analysis of head-to-head studies involving metformin showed equal efficacy compared with injected insulin (2 trials, 811 participants), α-glucosidase inhibitors (2 trials, 223 participants), and non-sulfonylurea secretagogues (2 trials, 413 participants). In 12 trials with 2067 patients, metformin decreased HbA_1c more than sulfonylureas did (standardized mean difference [SMD] -0.14; 95% CI, -0.28 to -0.01). In 3 trials with 246 patients, metformin also produced greater HbA_1c decreases than thiazolidinediones (SMD -0.28; 95% CI, -0.52 to -0.03). In the United Kingdom Prospective Diabetes Study (UKPDS), metformin improved diabetes-related outcomes and all-cause mortality in obese patients (relative risk of mortality=0.73; 95% CI, 0.55-0.97; P=.03; number needed to treat [NNT]=19). A systematic review with 22 RCTs (total n=7370), ranging in length from 12 weeks to 3 years, compared 2 oral agents with a single oral agent or placebo. Combinations of oral agents produced statistically significant additional improvement in HbA_1c in 21 of 22 studies. The magnitude of this effect across the studies was on the order of a 1% change in HbA_1c, although the data were not subject to a formal meta-analysis. Inhaled insulin may expand the list of initial therapies for type 2 diabetes. A 12-week manufacturer-sponsored RCT with 134 patients (mean HbA_1c=9.5) compared inhaled insulin with rosiglitazone (Avandia). More patients using inhaled insulin achieved an HbA_1c <8.0 (82.7% vs 58.2%; P=.0003); however, inhaled insulin produced more adverse effects, including cough and hypoglycemia.