THERAPEUTIC CONSIDERATIONS
Glucose-centric
Sonja’s glucose log demonstrates that her blood glucose values are at target with her current dose of extended-release metformin. Based on her glucose patterns and A1C, an agent of choice would be one that best directs its action on postprandial hyperglycemia. Fortunately, at this point in Sonja’s disease state, she should be able to achieve an A1C of < 7% with any of the noninsulin options.
However, when applying the glucose-centric approach, the proper course should be to use an agent that best addresses postprandial hyperglycemia. These agents include glucagon-like peptide 1 receptor agonists (GLP-1RA), dipeptidyl peptidase-4 inhibitors (DPP4i), sulfonylureas (SU), glinide, and α-glucosidase inhibitors (AGI) (see Table 2). Other agents would be less effective in addressing PPG.
Patient-focused
Since Sonja is young, has new-onset T2DM, is otherwise healthy, and has no overt complications from diabetes, her A1C goal should be < 6.5% and perhaps even < 6%, while minimizing the risk for hypoglycemia (see Table 3). However, she continues to be concerned with taking medications associated with any GI-related adverse effects.
The following are discussion points for Sonja regarding the agents approved as monotherapy or as monotherapy when metformin is contraindicated or not tolerated. Although all these classes have potential adverse effects, only GI intolerance and possibility for weight gain are covered here, since these directly pertain to Sonja’s choice of agent.
GLP-1RA (exenatide, liraglutide, exenatide extended-release, albiglutide, dulaglutide).7 This class, along with DPP4i, is also referred to as the incretins. The GLP-1RAs predominately target postprandial hyperglycemia and, to a lesser degree, fasting hyperglycemia—especially when used with the daily options of exenatide and/or liraglutide. The once-weekly options (exenatide extended-release, albiglutide, dulaglutide) have beneficial effects on both fasting and postprandial hyperglycemia.
Though GLP-1RAs are typically well tolerated, the most common associated adverse effects are nausea, which usually resolves in several weeks, and vomiting, which occurs infrequently. The GLP-1RAs are also one of two classes of diabetes medications associated with modest weight loss (the other is sodium glucose cotransporter-2 inhibitors [SGLT2i], to be discussed shortly). An additional benefit of GLP-1RA agents is that they are not associated with hypoglycemia, since they exert their effect in a glucose-dependent manner (ie, only when blood sugar is increased).
While Sonja is not averse to using an injectable agent, she is extremely hesitant to use any agent that may cause GI upset.
DPP4i (sitagliptin, saxagliptin, linagliptin, alogliptin).7 As previously stated, these are in the incretin class along with the GLP-1RAs. They help maintain physiologic levels of endogenous GLP-1, compared with the nearly eightfold pharmacologic level of GLP-1 from the injectable GLP-1RA. DPP4i agents are a physiologically appropriate choice for Sonja, because their effect is primarily on postprandial hyperglycemia. Since these medications also function in a glucose-dependent manner, they are not associated with hypoglycemia.
You explain to Sonja that while the DPP4i agents have a very low GI adverse-effect profile (compared with GLP-1RAs), they are not associated with weight loss but are considered weight neutral.
SU (glyburide, glipizide, glimepiride) and glinides (nateglinide, repaglinide).7 The SU class has a much longer half-life than the glinides and as a result affects both fasting glucose and PPG. The quicker-acting glinides improve PPG extremely well. However, because of the short duration of action, they must be dosed before each meal and sometimes before snacks as well. Since both of these classes stimulate insulin production, they carry a risk for hypoglycemia, but less than for the glinides.8
These agents are generally well tolerated, have a low GI adverse-effect profile, and can be associated with modest weight gain. But the risk for hypoglycemia means they may not be the optimal choice for Sonja.
SGLT2i (canagliflozin, dapagliflozin, empagliflozin).7 The mechanism of action for this class is rather unique in that it reduces re-absorption of glucose by the kidneys, resulting in increased urinary glucose output (glycosuria). This class has been shown to demonstrate modest weight loss. Since increased insulin secretion is not an effect of this class, it carries a very low risk for hypoglycemia.
While SGLT2i medications have a low GI adverse-effect profile, Sonja should be alerted to the associated increased urination, as it may impact her busy work schedule caring for patients.
TZD (rosiglitazone, pioglitazone).7 This is the most effective class for addressing insulin resistance, the key physiologic defect in T2DM. TZD is the only class that has demonstrated long-term A1C reductions (> 5 y).9 The drugs in this class are not associated with hypoglycemia and have a low GI adverse-effect profile. The most common adverse effects are weight gain and fluid retention, which are even more commonly observed in patients also taking insulin. Additionally, there is concern about increased risk for atypical fractures in women, particularly postmenopausal women.
Sonja should be made aware of this potential risk during her postmenopausal years, should she use one of these agents long-term. Currently, however, this would still be a viable option for her since she is early in the course of her disease and likely still has fairly good β-cell function.
AGI (acarbose, miglitol).7 This class is a good choice for directing therapy at postprandial elevations without hypoglycemia and is weight-neutral. Unfortunately, use of these agents has fallen out of favor since they are associated with significant GI adverse effects (ie, bloating, flatulence) and require multiple daily doses, with specific timing before each meal.
Insulin. Insulin is always an option for patients with diabetes, and it is the most effective and natural agent available. However, Sonja’s A1C and glucose pattern—consisting of mild postprandial elevations and near-target fasting glucose—suggest that she does not yet require this medication. Additionally, the risks for hypoglycemia and weight gain make this choice less desirable when other effective therapies are available.
After you have spent time discussing feasible options with Sonja, she decides that she would like to try a DPP4i. You agree and support her decision.
In your discussion, you also reiterate that T2DM is a progressive disease and that Sonja will likely need to use additional agents, possibly even insulin, in the years to come. You encourage her to strive for ongoing good dietary habits, exercise, and weight loss/maintenance, as these measures can lengthen the time before additional diabetes agents are needed.
To assist her with achieving these goals, you refer Sonja to a certified diabetes educator (CDE). The CDE, an integral member of the diabetes management team, will partner with Sonja to develop a plan to successfully implement these necessary lifestyle modifications.
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