Practical Strategies for Choosing among Incretin-Based Agents in Type 2 Diabetes, Part 2

For complete information and the Question #1 and Answer, please refer to PART 1 of this Case Study.

More recently, 3 large randomized controlled trials involving approximately 25,000 subjects with established T2DM, ACCORD (Action to Control Cardiovascular Risk in Diabetes), ADVANCE (Action in Diabetes and Vascular Disease Preterax and Diamicron Modified Release Controlled Evaluation), and VADT (Veterans Administration Diabetes Trial), showed nonsignificant decreases in cardiovascular events with intensive glucose lowering (i.e., lowering A1c levels to < 6.0% or ≤ 6.5% vs. lowering A1c levels to 7.3%-7.9%). In ACCORD, which had the objective of decreasing cardiovascular disease with interventions aimed at achieving A1c levels < 6.0% vs. < 7.9%, it showed that intensive glucose control is associated with an increased risk for all-cause mortality (P = .04). The exact mechanisms responsible for this increased mortality are unknown. By contrast, results from ADVANCE and VADT, both of which had different interventions and study populations than ACCORD, did not demonstrate excess mortality with intensive regimens that achieved A1c levels comparable with the 6.0%-6.5% achieved in ACCORD. The VADT trial reported no significant effect on rates of major cardiovascular events or microvascular complications; the ADVANCE trial reported reduced incidence of major macrovascular and microvascular complications (18.1% vs 20.0%, P = .01), but severe hypoglycemia was more common in the intensive-control group (2.7% vs 1.5%, P < .001).

Research data from these large recent studies of patients with T2DM have influenced the content of clinical guidelines. Both the ADA/EASD and the AACE/ACE guidelines concur that glycemic-lowering intervention in T2DM should be early and intensive. However, some differences exist in terms of both recommendations for A1c targets and in terms of their respective algorithms for managing hyperglycemia. The AACE/ACE guideline sets more aggressive target A1c levels (≤ 6.5%) than the ADA/EASD guideline (A1c < 7%). The VA/DoD guideline does not suggest single A1c targets for application to most patients; instead, stratification of target A1c based on the presence and severity of major comorbidities, physiologic age, and microvascular complications, is recommended. According to the VA/DoD guideline, the goal A1c level for patients with a life expectancy of more than 15 years who have no/minimal microvascular complications is 7.0%. For other patients with microvascular complications and/or comorbidities, a less stringent target of either < 8.0% (life expectancy 5-15 years) or < 9.0% (life expectancy < 5 years) is recommended.

Despite these differences, individualization of target A1c levels with consideration of risk-benefit ratio of required treatment, is a common feature of all 3 sets of guidelines. Specifically, the ADA/EASD guideline emphasizes that clinical judgment should be used when deciding the level of intensity applied to glycemic lowering for individual patients. The AACE/ACE guideline states that their recommended A1c level of ≤ 6.5% is the primary treatment goal, but must be tailored to numerous patient factors. Glycemic targets should be patient-specific and tailored to factors such as age, comorbidities, life expectancy, disease complications, burden of treatment, and patient preferences. In certain cases, this may result in less stringent A1c levels being acceptable, for example, an older patient with significant comorbidities.

In view of Mark’s current presentation, which of the following represents the most appropriate next step in management?

1. Stop glimepiride and add a thiazolidinedione (TZD)
2. Stop glimepiride and commence a glucagon-like peptide-1 (GLP-1) receptor agonist
3. Add basal insulin to his current regimen and reduce the dose of glimepiride
4. Initiate a dipeptidyl peptidase-4 (DPP-4) inhibitor and reduce the dose of glimepiride

Correct Answer 2:

The episodes of hypoglycemia in this patient most likely result from glimepiride, a drug in the sulfonylurea class for which hypoglycemia is a known AE. GLP-1 receptor agonists have a very low risk for hypoglycemia in the absence of sulfonylurea use; DPP-4 inhibitors also have low risk for hypoglycemia. Most patients taking GLP-1 receptor agonists will experience weight loss of 2-4 kg, while DPP-4 inhibitors are weight neutral. Because this patient is bothered by his recent weight gain, a GLP-1 receptor agonist would be a reasonable choice for his therapy. Insulin and TZDs, are also treatment options for combination therapy with metformin; however, they are both associated with weight gain as an AE, and insulin can cause hypoglycemia.

Hypoglycemia and/or weight gain are common AEs of some treatments for T2DM and cause treatment burden for patients and providers alike. The injectable GLP-1 receptor agonists and oral DPP-4 inhibitors have low rates of hypoglycemia in clinical trials and in addition do not produce weight gain, key AEs of non-incretin based therapies such as TZDs, sulfonylureas, and insulin.

The 2009 ADA/EASD Consensus Statement does not provide a definite next step when metformin no longer controls blood glucose, but instead it suggests several treatment options, which are broken into 2 tiers. Tier 1 add-on therapies to metformin are sulfonylureas and basal insulin, which are well-established therapies with known risks and long histories of use. Tier 2 add-on therapies include TZDs or GLP-1 receptor agonists, which are deemed as newer drugs with less information available on their long-term safety. Choices among these options are left to the discretion of the clinician. However, dual therapy with a GLP-1 receptor agonist and metformin is deemed an option if weight loss is a major consideration in T2DM management, as in the current patient case.

The 2009 AACE/ACE Consensus Statement deems the incretin-based therapies (GLP-1 receptor agonists or DPP-4 inhibitors) the most appropriate add-on therapy for patients inadequately controlled on metformin and with A1c levels of 7.6%-9.0%. Of the incretin-based therapies, the consensus statement gives preference to the GLP-1 receptor agonists because of their potential for weight loss, as well as greater effectiveness in reducing postprandial glucose (PPG) excursions relative to DPP-4 inhibitors. The lower position of TZDs as add-on therapy to metformin in the AACE/ACE clinical algorithm is due to the attendant risks for weight gain and fluid retention, congestive heart failure, and increased risk for fractures (a less common, but serious side effect of TZDs). Sulfonylureas and glinides are relegated to the lowest position for add-on therapy because of their greater risk for hypoglycemia.

GLP-1 receptor agonists have a low risk of causing hypoglycemia unless combined with a sulfonylurea. Product labeling for both currently available GLP-1 receptor agonists, exenatide and liraglutide, warn that the risk for hypoglycemia is increased when these agents are used in combination with a sulfonylurea. In 2 trials of twice-daily exenatide in which patients received a sulfonylurea (with or without metformin), mild to moderate hypoglycemia was much more frequent when sulfonylurea was part of background therapy.

Figure 2. Placebo-controlled trials of exenatide twice daily: incidence of hypoglycemia with background therapy.
From Buse JB, et al. Diabetes Care. 2004;27:2628-2635. Kendall DM, et al. Diabetes Care. 2005;28:1083-1091. DeFronzo RA, et al. Diabetes Care. 2005;28:1092-1100.

Clinical trials of exenatide 5 or 10 μg twice daily added to 1 or 2 oral antidiabetic drugs showed reductions in FPG and PPG concentrations, with average reductions in A1c levels of 0.4%-0.9% from baseline, and weight loss of 1.6-2.8 kg in studies up to 30 weeks. Once-daily liraglutide 0.6, 1.2, or 1.8 mg, combined with 1 or 2 oral antidiabetic drugs, reduced A1c by approximately 1.0%-1.5% and weight by 1-3 kg.

A positive effect on cardiovascular risk factors has been seen with long-term GLP-1 receptor agonist treatment. In an analysis of 314 patients who received exenatide in 3 30-week placebo-controlled trials and subsequently in 52 weeks of open-label uncontrolled extension studies (total 82 weeks), exenatide twice daily (in combination with metformin and/or sulfonylurea) produced significant improvements from baseline in diastolic blood pressure (-2.7 mm Hg), HDL-C (+4.6 mg/dL) and trigylceride levels (-38.6 mg/dL) (Figure 3). Other parameters (ie, systolic blood pressure, total cholesterol, LDL-C, and apolipoprotein B) also showed positive trends. It is not yet clear whether these beneficial changes in cardiovascular risk factors are direct effects of the GLP-1 receptor agonist or simply the result of weight loss. The latter possibility seems likely since in general, the greatest improvement in cardiovascular risk factors occurred in those with the greatest reduction in weight. Lipid parameters were improved independent of weight loss and across a range of A1c levels. In a meta-analysis of 6 pivotal 26-week clinical trials, liraglutide significantly improved total cholesterol, LDL-C, free fatty acid, and triglyceride from baseline (P < .01). With other therapies used in the trials that were analyzed, lipid levels did not all decrease significantly vs baseline. HDL-C levels were decreased from baseline with all therapies except for rosiglitazone.

Figure 3. Analysis of effects of exenatide over 82 weeks in patients with type 2 diabetes mellitus: mean change from baseline in lipid parameters and sitting blood pressure.
ApoB = apolipoprotein B; DBP = diastolic blood pressure; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; SBD = systolic blood pressure

From Blonde L, et al. Diabetes Obes Metab. 2006;8:436-447.