In general, pharmacotherapy of diabetes should be individualized, since not all agents are equally appropriate for all patients. A variety of studies have demonstrated that adding a second antidiabetic agent to a first typically results in additional improvements in glycemic control.38-47 In the example here, a sulfonylurea was chosen because of its complementary mechanism of action with an insulin sensitizer. Since the patient had an elevated serum creatinine, metformin was not considered to be an appropriate choice. In addition, the combination of a glitazone with sulfonylurea therapy has been reported to achieve reductions in A1C40,48 at least comparable to those reported in analyses of the combination of a glitazone with metformin.40,45 TABLE 4 provides reported reductions in A1C that have been observed in clinical trials of various combination regimens in type 2 diabetes. Since these are not head-to-head comparisons of the various regimens, the data simply illustrate the range of A1C reductions that may be achieved with combination therapy. In this patient, glimepiride was chosen because of its weight neutral effect,49 potentially lower incidence of hypoglycemia,50,51 favorable effect on postprandial glucose (that may ameliorate cardiovascular risk),52-56 and once-daily dosing.
Given the progressive natural history of type 2 diabetes, and the fact that this patient currently requires a >2% A1C reduction, it is reasonable to anticipate that she will eventually need insulin to attain glycemic control. Recently, Riddle et al4 demonstrated that addition of a basal insulin (neutral protamine Hagedorn [NPH] or glargine) to existing oral agents reduced the A1C to <7% in the majority of patients with type 2 diabetes. Insulin glargine was associated with significantly less hypoglycemia than NPH insulin. This is an important consideration since hypoglycemia remains a major barrier to insulin therapy in type 2 diabetes.57 Sulfonylurea therapy should be maintained when insulin is initiated, as this combination has been demonstrated to be highly effective in improving glycemic control and is associated with a low incidence of hypoglycemia.3,33 In the current patient, the addition of basal insulin glargine would complement her other antidiabetic therapies. Insulin glargine would primarily normalize her FBG, while glimepiride controls PPG and rosiglitazone improves insulin sensitivity. Thus, this regimen would address the 2 most important defects in type 2 diabetes—insulin deficiency and insulin resistance.
Clinical trials have shown that combination therapy with oral agents and insulin, as well as with multiple oral agents, is effective.4,38,39 However, more long-term and comparative studies of these multiple-agent combinations are needed. It is important to set expectations with patients that gaining good control of diabetes frequently requires combination therapy with multiple agents with the ultimate goal of avoiding the onset of new complications or of delaying progression of existing complications.
TABLE 4
A1C reductions noted in clinical trials and reports of combination therapy for type 2 diabetes
| REGIMEN | A1C REDUCTION (%) |
|---|---|
| Sulfonylurea + metformin58 | ~1.7 |
| Sulfonylurea + glitazone40,48 | ~1.3 |
| Sulfonylurea + α-glucosidase inhibitor59 | ~0.9 |
| Metformin + meglitinide46 | ~1.4 |
| Metformin + glitazone40,45 | ~1 |
| Insulin + oral agents4 | Open to target |
Summary
The increased prevalence of obesity, metabolic syndrome, and type 2 diabetes in adolescents and adults is an ominous sign of more serious disease in the future. A concerted effort on the part of health care professionals to improve the care of patients with type 2 diabetes is needed to bring this burgeoning problem under better control. Diabetes is a recognized coronary risk equivalent; thus, a comprehensive multifactorial approach that rigorously addresses glycemia, as well as elevated BP and lipids, is recommended.
Most patients with type 2 diabetes will eventually require combination therapy with 2 or more agents to attain and maintain glycemic control.2,3 In particular, combinations of agents with complementary mechanisms of action (eg, an insulin sensitizer with a secretagogue) demonstrate greater improvements in glycemic control. Based on the progressive nature of diabetes, a principle in the pharmacotherapy of glucose control is that, in absence of untoward effects, if a given agent is secondarily unable to provide adequate glycemic control (ie, there was initial improvement in glucose control and then subsequent deterioration), additional agents—whether oral agents or insulin—should be added rather than substituted.
Disclosures:
Dr. Elasy has done consultation for Aventis Pharmaceuticals. Dr. Levy has received grants/research support from Aventis Pharmaceuticals, Eli Lilly and Co., Merck & Co., Novartis Pharmaceuticals, Novo Nordisk Pharmaceuticals Inc., and Pfizer Inc. He is a consultant and on the speaker’s bureau for Aventis Pharmaceuticals, Eli Lilly and Co., Novartis Pharmaceuticals, Novo Nordisk Pharmaceuticals Inc, Pfizer Inc, Takeda Pharmaceuticals America, Inc., Bristol-Myers Squibb Company, GlaxoSmithKline, and Wyeth-Ayerst Pharmaceuticals. Dr. Davis has received research grants from Aventis Pharmaceuticals, Eli Lilly and Co., and Bayer Pharmaceuticals Corporation.