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Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder that affects almost 24 million Americans. Healthcare providers often do not initiate and/or intensify therapy appropriately during patient visits, which may be due, in part, to a lack of understanding of the new diabetes medications. This review focuses on means by which primary care nurse practitioners (NPs) might evaluate the utility of pharmacologic agents based upon their relation to the pathogenesis of T2DM.The evidence used in developing this review included evidence-based reviews, clinical trials, cohort studies, position statements, and guidelines. The authors obtained relevant reports through a computerized search of the literature using PubMed, MEDLINE, and other search engines and scanning syllabi from national and international meetings on the subject of type 2 diabetes.Medications used to manage T2DM utilize different pharmacologic approaches. These include stimulating insulin production, reducing hepatic gluconeogenesis, slowing polysaccharide digestion, and increasing insulin sensitivity in muscle, liver, and fat to achieve euglycemia.Patients with T2DM should be treated to their lowest targeted glycemic goals as soon as they are diagnosed as safely and as rationally as possible. NPs in primary care practice can facilitate more effective diabetes management.