Medical Education Library

Glucose-lowering effects of incretin-based therapies

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  • Glucagon-like peptide (GLP-1) agonists and dipeptidyl peptidase (DPP-4) inhibitors effectively lower blood glucose levels in a glucose-dependent manner, which results in a low incidence of hypoglycemia
  • Reduction of glycosylated hemoglobin is greater with GLP-1 agonists (up to 1.5%) than with DPP-4 inhibitors (up to 0.9%), as is reduction of postprandial glucose (PPG)
  • GLP-1 agonists and DPP-4 inhibitors vary in dosing (frequency, route of administration), contraindications, and requirement for dose adjustments with renal impairment
  • GLP-1 agonists are emphasized in the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) 2009 guidelines and the American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) 2009 consensus statement

The authors received editorial assistance from the Primary Care Education Consortium and WriteHealth, LLC in the development of this activity and honoraria from the Primary Care Education Consortium. They have disclosed that Dr Campbell is on the advisory board for Daiichi-Sankyo and the speakers bureau for Eli Lilly and Co; Dr Cobble is on the advisory board for Abbott Laboratories, AstraZeneca, and Eli Lilly and Co and speakers bureau for Abbott Laboratories, AstraZeneca/Bristol Myers Squibb, Eli Lilly and Co, GlaxoSmithKline, and Novo Nordisk Inc; Dr Reid is on the advisory board and speakers bureau for Amylin Pharmaceuticals, Medtronic, Novo Nordisk Inc, and sanofi-aventis; and Dr Shomali is on the advisory board for Novo Nordisk Inc and speakers bureau for Amylin Pharmaceuticals, Eli Lilly and Co, sanofi-aventis, and Takeda Pharmaceuticals.


The selection of glucose-lowering therapies is dependent on many factors, including stage of disease progression, comorbidities, and previous treatments, as highlighted in the 3 cases. Other factors include an agent’s efficacy in lowering blood glucose levels, side effects and tolerability, safety, convenience and ease of use, and cost, as well as a patient’s current glycosylated hemoglobin (A1C) level. The mechanisms of action of concurrent glucose-lowering therapies also should be considered, since using therapies with complementary mechanisms is desirable.1 This article will focus on efficacy factors, while nonglycemic factors, including safety and tolerability, will be discussed in the next article in this supplement (“Safety, tolerability, and nonglycemic effects of incretin-based therapies”). Among these many factors, 2 concerning efficacy deserve discussion at this point.

First, the magnitude to which a pharmacologic option typically lowers blood glucose varies from 0.5% to 3.5% as either monotherapy or combination therapy (FIGURE 1).1-3 According to the AACE/ACE 2009 recommendations, monotherapy is appropriate if the initial A1C level is 6.5% to 7.5%, while dual therapy is appropriate if the A1C level is 7.6% to 9.0%. If the A1C level is >9.0%, however, combination (dual or triple) therapy is required.4,5 In contrast, the ADA/EASD 2009 consensus statement provides more general options. These treatment recommendations are based on landmark trials that show the risk of microvascular and, perhaps, macrovascular complications are decreased substantially.

The second factor to consider is the effectiveness of each agent in lowering both fasting plasma glucose (FPG) and PPG. As demonstrated by Monnier et al, at an A1C level of approximately 8% to 8.5%, FPG and PPG contribute equally to the A1C level.6 At A1C >8.5%, the contribution of FPG increases and PPG decreases. Conversely, at A1C <8%, the contribution of PPG increases and FPG decreases. Thus, the increasing predominance of PPG as patients gain better glycemic control suggests that an agent that effectively lowers both FPG and PPG is needed to achieve the target glycemic goal of ≤7%.

The correlation between PPG and cardiovascular risk is also worth mentioning here. A number of studies have linked elevated PPG levels to increased cardiovascular risk,7-10 and 2 studies have shown PPG to be more predictive than FPG for cardiovascular risk.11,12 One recent study, NAVIGATOR, sought to explore this connection further but could not provide definitive results.13,14 While the study found that 5 years of nateglinide provided no protection against progression of cardiovascular disease in patients with impaired glucose tolerance and cardiovascular disease (or risk factors), it also revealed a paradoxical increase in PPG levels in patients taking the drug. Research on this issue will no doubt continue. The agents that provide the greatest reduction in PPG are insulin, GLP-1 agonists, and pramlintide.4 Of course, benefits of glycemic control must be weighed against potential adverse effects of each agent, as will be discussed in the next article.

FIGURE 1 Range of A1C lowering by class of glucose-lowering agent as monotherapy or by lifestyle modification1-3

AGI, α-glucosidase inhibitor; DPP-4 I, dipeptidyl peptidase-4 inhibitor; GLP-1 A, glucagon-like peptide-1 agonist.
a Adapted to include sitagliptin and saxagliptin.
b Adapted to include exenatide and liraglutide.


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