Enhanced glycemic control with combination therapy for type 2 diabetes in primary care

Abstract

Type 2 diabetes mellitus is an increasingly common medical problem for primary care clinicians to address. Treatment of diabetes has evolved from simple replacement of insulin (directly or through insulin secretagogs) through capture of mechanisms such as insulin sensitizers, alpha-glucosidase inhibitors, and incretins. Only very recently has recognition of the critical role of the gastrointestinal system as a major culprit in glucose dysregulation been established. Since glycated hemoglobin A(1c) reductions provide meaningful risk reduction as well as improved quality of life, it is worthwhile to explore evolving paths for more efficient use of the currently available pharmacotherapies. Because diabetes is a progressive disease, even transiently successful treatment will likely require augmentation as the disorder progresses. Pharmacotherapies with complementary mechanisms of action will be necessary to achieve glycemic goals. Hence, clinicians need to be well informed about the various noninsulin alternatives that have been shown to be successful in glycemic goal attainment. This article reviews the benefits of glucose control, the current status of diabetes control, pertinent pathophysiology, available pharmacological classes for combination, limitations of current therapies, and suggestions for appropriate combination therapies, including specific suggestions for thresholds at which different strategies might be most effectively utilized by primary care clinicians.

Figure 1

Relative contributions of postprandial and fasting hyperglycemia (%) to the overall diurnal hyperglycemia over quintiles of glycated hemoglobin A1C (HbA_1c). Adapted with permission from Diabetes Care 2003;26:881–885. Reproduced with permission from the American Diabetes Association. a=Significant difference was observed between fasting and postprandial plasma glucose (paired t test). b=Significantly different from all other quintiles (analysis of variance [ANOVA]). c=Significantly different from quintile 5 (ANOVA).

Figure 2

Natural history of type 2 diabetes. Upper panel: the dotted line represents the threshold for diagnosing impaired fasting glucose (IFG; 110 mg/dL). Lower panel: the dotted line represents a reduction in relative function by about 50%. Figure adapted with permission from Natural History of Type 2 Diabetes© 2010 International Diabetes Center, Minneapolis, MN, USA.

Figure 3

Median glycated hemoglobin A_1C (HbA_1c) levels in cohorts of patients followed up to 10 years by assigned treatment in the UK Prospective Diabetes Study (UKPDS) 34. Figure adapted with permission from DeFronzo et al., Annals of Internal Medicine; 1999. Table inset from Turner et al.

Figure 4

Suggested treatment algorithm for patients with type 2 diabetes mellitus, according to glycated hemoglobin A_1C (HbA_1c) level at presentation. Treatment should be adjusted every 4 weeks (6–8 weeks for thiazolidinediones [TZDs]) based upon degree of fasting blood glucose (FBG) attained. Adjust dosage q4w* based upon degree of FBG reduction attained. *q6-8w for TZDs.

Figure 5

American Diabetes Association and the European Association for the Study of Diabetes (ADA/EASD) consensus algorithm for the metabolic management of type 2 diabetes. Reinforce lifestyle interventions at every visit and check glycated hemoglobin A_1c (HbA_1c) every 3 months until HbA_1c is <7% and then at least every 6 months. The interventions should be changed if HbA_1c is 7%. ^aSulfonylureas other than glibenclamide (glyburide) or chlorpropamide. ^bInsufficient clinical use to be confident regarding safety. CHF=congestive heart failure; GLP-1=glucagon-like peptide-1. Copyright 2009 American Diabetes Association. From Diabetes Care 2009;32:193–203. Reproduced with permission from the American Diabetes Association.