What, then, are the treatment options for patients with T2DM on dual oral therapy that experience loss of glycemic control? It is likely that postprandial hyperglycemia may contribute to a lack of HbA_1c control, especially when fasting plasma glucose levels are close but not at goal (Figure 3).^7,8 

Figure 4⁹ shows current treatment recommendations from the 2013 American Association of Clinical Endocrinologists Comprehensive Diabetes Algorithm for triple therapy, which in general highlights agents with a low risk of hypoglycemia and weight gain.¹⁰ Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are noted as “use with caution” because there is limited experience with them in clinical practice.⁹ Two of these inhibitors (canagliflozin and dapagliflozin) are approved for use in the United States. Both of these oral agents are associated with a low risk of hypoglycemia and some weight loss but carry risks of genitourinary infections. An unexplained adverse effect is an increased LDL-C level.⁹ 

α-Glucosidase inhibitors (AGIs) are oral antidiabetic drugs used for T2DM that work by preventing the digestion of carbohydrates in the gastrointestinal (GI) tract. These inhibitors lower postprandial glucose by inhibiting the gut enzyme that breaks down complex carbohydrates, thus delaying polysaccharide absorption. They are not associated with a risk of hypoglycemia. The HbA_1c-lowering effect of AGIs is modest, around 0.4% to 0.7%. Adverse effects such as bloating, flatulence, and diarrhea have limited the use of AGIs in the United States.⁹ α-Glucosidase inhibitors are more popular in Asia, and there are data directly comparing these agents with dipeptidyl peptidase-4 (DPP-4) inhibitors in Japanese patients with T2DM inadequately controlled on sulfonylurea therapy.¹¹ At 24 weeks of therapy, the HbA_1c reduction was almost identical between the groups (−0.091%, P=.47). As expected, GI adverse effects were more common with AGIs. 

Glucagon-like peptide-1 receptor agonists are peptides with substantial similarity to the native incretin hormone, GLP-1. Think of incretin as a hormone that increases the insulin. These receptor agonists stimulate insulin secretion from β cells of the pancreas through a G-protein receptor-mediated process that is regulated by the intracellular glucose level (ie, it is glucose dependent). Also, GLP-1 receptor agonists reduce glucagon secretion from α cells and slow gastric emptying.¹² 

Dipeptidyl peptidase-4 inhibitors increase endogenous GLP-1 and glucose-dependent insulinotropic polypeptide by inhibiting the enzyme (DPP-4) that breaks down the incretin hormones. The elevated level of GLP-1 increases insulin secretion in a glucose-dependent manner from β cells and reduces glucagon secretion from α cells in the pancreas.¹² 

Because the DPP-4 inhibitors rely on endogenous levels of incretin hormones, which may be reduced or impaired in patients with T2DM, and because GLP-1 receptor agonists provide exogenous concentrations of GLP-1, GLP-1 receptor agonists are inherently more effective in reducing HbA_1c levels.¹² This effect is supported by clinical trial data^13-16 and by a meta-analysis.¹⁷ The caveat is that GLP-1 receptor agonists must be given by subcutaneous injection and that higher levels of GLP-1 are also associated with other effects, such as nausea, which (not surprisingly) is dose dependent. 

Another feature of GLP-1 receptor agonist therapy is weight loss, which is independent of GI-related adverse effects. Weight loss is thought to be related to not only slowing of GI motility, but also to enhanced satiety signaling in the brain. Direct comparisons of GLP-1 receptor agonists vs DPP-4 inhibitors^13-16 show that GLP-1 receptor agonists are associated with greater HbA_1c reductions, likely a result of greater reductions in fasting plasma glucose levels, greater reductions in body weight, with similar risks of hypoglycemia but with more adverse effects (eg, GI distress). If patients experience mild to moderate nausea, they should be asked if it is truly nausea or perhaps satiety (a feeling of fullness). If it is troublesome, they might need to remain at lower doses, have their dose escalated gradually, or, in the case of exenatide twice daily, take it closer to meal time. Longer-acting agents have fewer GI adverse effects. 

If GI adverse effects are severe, the possibilities of gastroparesis or pancreatitis (if abdominal pain is severe, radiating, or accompanied by vomiting) should be considered. Incretin-based therapies are not recommended in patients with gastroparesis. Individuals with T2DM are at an increased risk of pancreatitis independent of treatment provided. Also, because of concerns regarding postmarketing cases of pancreatitis in individuals taking incretin-based therapies, therapy should be discontinued and other treatment options considered if pancreatitis is suspected.^18-20 

Incretin-based therapies are associated with a low risk of hypoglycemia because they work only when glucose levels are elevated. Incretin-based therapies are also associated with a low risk of weight gain, and in the case of GLP-1 receptor agonists, may be associated with weight loss that ranges from 1 to 4 kg, as well as improvement in markers of cardiovascular risk factors.⁹ These agents are also associated with robust HbA_1c lowering (0.8% to 2.0%).⁹ 

Insulin is well known to be the most potent glucose-lowering agent for treating patients with diabetes.²¹ Its efficacy is limited only by the risk of hypoglycemia, which also requires the need for self-monitoring of blood glucose levels by patients. Patient concerns that limit the use of insulin include its propensity to cause weight gain. Although its route of administration by injection is often cited as a barrier, the use of pen devices and the availability of very small needles have largely alleviated this concern.^22,23 

Direct comparisons of basal insulin with DPP-4 inhibitors in patients with glycemia uncontrolled on metformin showed that the mean reduction in HbA_1c levels was greater for patients on insulin glargine (−1.72%) than for those on sitagliptin (−1.13%), with a mean difference of −0.59% (P<.0001). Not surprisingly, the estimated rate of all symptomatic hypoglycemic episodes was greater with insulin than with the DPP-4 inhibitor (4.21 vs 0.50 events per patient-year; P<.0001).²⁴ Comparisons of sitagliptin with the investigational very-long-acting basal insulin degludec showed no differences in nighttime hypoglycemic rates between agents but greater improvements in HbA_1c reduction and fasting plasma glucose levels. However, degludec resulted in higher overall hypoglycemia rates and greater weight gain.²⁵ Overall, DPP-4 inhibitors are less effective than insulin in reducing HbA_1c levels but are associated with less hypoglycemia and less weight gain. 

In comparisons of GLP-1 receptor agonists and insulin, comparable rates of HbA_1c lowering can be achieved without increased risks of hypoglycemia and without weight gain—even with some potential for weight loss.²⁶ A meta-analysis²⁷ showed that GLP-1 receptor agonists are associated with a greater reduction in postprandial glucose than insulin. Despite a similar decrease in HbA_1c level, the risk of hypoglycemia was 35% lower (P=.001) with GLP-1 receptor therapy compared with insulin. In addition, GLP-1 analogs cause a statistically significant decrease in systolic blood pressure compared with insulin.²⁷ However, a significantly higher number of GI adverse events were reported with the GLP-1 group compared with insulin. The number of GI adverse events can be minimized with appropriate dose titration and patient counseling (especially in the case of exenatide twice a day—take it 0 to 60 minutes prior to a meal; more time before the meal increases the likelihood of nausea). 

A systematic review and meta-analysis recently evaluated the comparative safety and efficacy of available classes of antihyperglycemic therapies in patients with T2DM inadequately controlled with metformin and sulfonylurea combination therapy. 

Insulins (basal, biphasic, bolus), DPP-4 inhibitors, GLP-1 receptor agonists, and thiazolidinediones (TZDs) all produced statistically significant reductions in HbA_1c levels in combination with metformin and a sulfonylurea (−0.89% to −1.17%), whereas meglitinides and AGIs did not (Table 2).²⁸ Biphasic insulin, bolus insulin, and TZDs were associated with weight gain (1.85-5.00 kg), whereas DPP-4 inhibitors and AGIs were weight-neutral and GLP-1 receptor agonists were associated with modest weight loss (Table 2).²⁸ Severe hypoglycemia was rare across all treatments; regimens containing insulin were associated with increased hypoglycemia relative to comparators.²⁸ 

Thiazolidinediones have been accepted treatment options for many years, but recently they have been the subject of greater scrutiny. These agents reduce insulin resistance in skeletal muscle and other tissues. Adverse effects such as weight gain and fluid retention, which may contribute to chronic edema or heart failure, and adverse metabolic effects on bone, which may increase risk of fracture, have limited the use of TZDs. However, of note, in November 2013, the FDA announced lifting some prescribing and dispensing restrictions for rosiglitazone that were put in place in 2010.²⁹ 

Pioglitazone is the only other TZD available for general use. Pioglitazone has many positive attributes, including HbA_1c lowering of 0.7% to 1.2%, low hypoglycemia risk, and possible cardiovascular benefits. The reported association of pioglitazone and bladder cancer is an unresolved issue. The benefits and risks of pioglitazone should be weighed when considering it for long-term management of T2DM.⁹ 

The bile acid sequestrant colesevelam had as its first indication an adjunct to statin therapy for decreasing LDL-C levels in patients with elevated cholesterol levels. It also is indicated as adjunct therapy to other glucose-lowering agents for patients with T2DM. It lowers glucose modestly (HbA_1c reductions of 0.4% to 0.6%) through an unknown mechanism. Colesevelam does not cause hypoglycemia or increase hypoglycemia risk when used with other agents. Increased triglyceride levels can be problematic for some patients. The major adverse effect is GI intolerance, which limits its use.⁹ 

The quick-acting formulation of the dopamine receptor agonist bromocriptine mesylate has glucose-lowering properties and reduces HbA_1c levels by about 0.5% through unknown mechanisms of action. Bromocriptine QR (quick-release) formulation needs to be given shortly after waking. Nausea and orthostasis can be treatment-limiting adverse effects, and bromocriptine QR should not be used in patients who are taking antipsychotic drugs.⁹ 

Currently, 3 GLP-1 receptor agonists are available. Exenatide is available in 2 formulations: a short-acting drug that needs to be administered twice daily 0 to 60 minutes before meals with a dose-escalation schedule, and exenatide extended release, which is administered once weekly on the same day each week with no dose escalation. Liraglutide, a once-daily drug with a structure most similar to that of human GLP-1, does not need to be given with regard to mealtime. The short-acting exenatide has the most profound effects on postprandial glucose levels, whereas both of the longer-acting agents affect both fasting and postprandial glucose levels and reduce HbA_1c levels more than short-acting exenatide (as shown in clinical trials).^30-34 Both longer-acting agents are also associated with less nausea than shorter-acting exenatide. All 3 agents are relatively comparable with regard to their weight-loss profiles.³⁵ 

The US Food and Drug Administration (FDA) requires new drugs for T2DM to demonstrate cardiovascular safety. An analysis of 58 trials that included more than 10,000 patients receiving GLP-1 receptor agonists and more than 7000 patients receiving comparator GLP-1 agonists do not seem to show any increased risk of cardiovascular events with this class of drugs. Overall, the odds ratio for cardiovascular events with GLP-1 receptor agonists was 0.52 (95% confidence interval [CI], 0.27-0.99) compared with placebo and 0.84 (95% CI, 0.52-1.36) with active controls.³⁶ Data from clinical trials exploring their antihyperglycemic effects have suggested beneficial effects on some cardiovascular risk factors, notably systolic blood pressure³⁷ and some aspects of lipid profiles.³⁸ Specific cardiovascular outcome trials are ongoing, but to my knowledge no results are yet available. 

The role of medical nutritional therapy and physical activity as part of T2DM self-management should never be neglected and requires constant reinforcement with the patient and positive coaching. For example, data show that regardless of what diet is used (eg, Zone, Ornish, South Beach), it is the nutritional program that a patient can persist with that will have the greatest success.^39-42 Recent evidence continues to support the use of the Dietary Approaches to Stop Hypertension diet in managing risk factors for T2DM⁴³ and has recently been shown to be of specific benefit in women with gestational diabetes.⁴⁴ New nutritional guidelines from the ADA focus on overall eating patterns without recommending any one form of diet while reviewing the evidence for several popular eating plans.⁴⁵ The American College of Sports Medicine and the ADA have issued a joint position statement on exercise and T2DM that may be useful.⁴⁶ In general, the ADA recommends that adults perform at least 150 minutes per week of moderate-intensity aerobic physical activity (at 50%-70% of maximum heart rate), spread over at least 3 days per week with no more than 2 consecutive days without physical activity.³ 

The middle-aged patient who is not at HbA_1c treatment goal is probably not achieving blood pressure or lipid goals either, and thus presents the osteopathic physician with a clinical challenge. Attention to the ABCs (HbA_1c, blood pressure, and cholesterol levels) of T2DM is therefore needed to protect the patient from the devastating effects of microvascular and macrovascular complications. Data show that blood pressure, cholesterol, and glucose may be the rank order of protection that is most important. Thus, the choice of a glucose-lowering agent for treatment intensification in patients whose glycemic levels are not well controlled with monotherapy or dual therapy should take into account some of the cardiometabolic aspects of therapy. 

Severe hypoglycemia has also been shown to aggravate cardiovascular risk in patients with T2DM in whom aggressive blood glucose-lowering strategies were attempted.⁴⁷ Incretin-based therapies, which are associated with effective glucose lowering without adverse risk of hypoglycemia, may be rational approaches to treatment intensification in middle-aged patients. For patients in whom an HbA_1c reduction of 1% or more is needed or in whom weight loss is desirable, GLP-1 receptor agonists may be especially beneficial.