Type 2 Diabetes (T2DM) is an increasing epidemic, with an incidence of 7.8% of the US population. It was ranked the 7th leading cause of death in 2006 and is responsible for heart disease, stroke, blindness, nephropathy, neuropathy, and loss of limb.1 While the clinical goals for treatment are directed toward glycemic control, the primary objective is to prevent both microvascular and macrovascular morbidity and mortality. Although studies have consistently shown that tighter glycemic control prevents microvascular complications, there are surprisingly few studies that have directed study design toward macrovascular outcomes. Therefore, the benefits of improved glucose control on mortality remain to be proven definitively in T2DM. Choice of therapy to treat T2DM is thus currently dependent on glycemic control, theoretical mechanistic advantages, and practitioner or patient preference.
Metformin is often a first-line agent for T2DM and is recommended as such by the American Diabetes Association and European Association consensus statement.2 Metformin works primarily to decrease the production of glucose and lower fasting glycemia, but has also displayed metabolic and anti-inflammatory properties.3,4 Of all the oral hypoglycemic medications, metformin has demonstrated the most evidence toward prevention of complications. Metformin has also shown equal glucose-lowering effects in both obese and non-obese patients compared to insulin secretagogues.5 Theoretically, however, secretagogues or insulin may be the preferred therapy for non-obese patients, as they tend to have a more pronounced insulin secretion deficiency and less insulin resistance than obese patients. Moreover, an observational study confirmed that repaglinide, a short-acting secretagogue, has similar cardioprotective effects as metformin.6 The follow-up study to the UKPDS trial also demonstrated reduced cardiovascular outcomes and mortality with both metformin (33% and 27%, respectively) and insulin or insulin secretagogues (15% and 13%, respectively) in a combined group of non-obese and obese patients.7
Over time, many patients will fail oral hypoglycemic agents and insulin may be necessary to control the disease. It is generally preferred to add insulin to oral therapy rather than completely replace it. Combination with a secretagogue is dependent on pancreatic beta cell function but can be used as adjunct therapy in some patients. Combination with metformin or a thiazolidinedione, however, retains insulin sensitizing utility. The UKPDS Trial demonstrated that intensive treatment with metformin and insulin reduces cardiovascular disease in obese patients.8 However, there is no current evidence to confer the same for non-obese patients, although several guidelines presume so. The question remains, then, whether non-obese patients who are started on a secretagogue should remain on them when initiating insulin or change the oral hypoglycemic agent to metformin.
A randomized, double blind trial was recently conducted to determine whether insulin plus metformin has a similar glucose lowering potency in non-obese patients with T2DM as a combination of insulin plus an insulin secretagogue.9 The study was conducted at a single center in Denmark and recruited a total of 133 patients.
Patients had a BMI ≤ 27 with T2DM, defined as age onset of diabetes > 40 years, fasting serum C peptide ≥ ...