Individualizing Treatment of Hyperglycemia in Type 2 Diabetes
Journal of Clinical Outcomes Management. 2017 January;24(1)
References
Initiate Treatment with Metformin
There is strong consensus that metformin is the preferred drug for monotherapy due to its long proven safety record, low cost, weight-reduction benefit, and potential cardiovascular advantages [4,16]. As long as there are no contraindications, metformin should be recommended concurrent with lifestyle intervention at the time of diabetes diagnosis. The recommendation is based on the fact that adherence to diet, weight reduction, and regular exercise is not sustained in most patients, and most patients ultimately will require treatment. Since metformin is usually well-tolerated, does not cause hypoglycemia, has a favorable effect on body weight, and is relatively inexpensive, potential benefits of early initiation of medication appear to outweigh potential risks.
The U.S. Food and Drug Administration (FDA) recently relaxed prescribing polices to extend the use of this important medication to patients who have mild–moderate, but stable, chronic kidney disease (CKD) [28]. Metformin is recommended as first-line therapy and should be used unless it is contraindicated (ie, estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m 2)[4,7,29].
Add Additional Agent(s) as Needed to Achieve Goal
Other than metformin, evidence is limited for the optimal use of the burgeoning array of available agents, especially in dual or triple combinations [6,30]. Research is now starting to focus more on what the ideal number and sequence of drugs should be. The Glycemic Reduction Approach in Diabetes (GRADE) study, which will compare long-term benefits and risks of the 4 most widely used antihyperglycemic medications in combination with metformin, is now underway [31,32]. The 4 classes being studied are sulfonylurea, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and a basal,
long-acting insulin. From a practical standpoint, investigating all possible combinations in diverse patient populations is not feasible. Physicians therefore must continue to rely on clinical judgment to determine how to apply trial data to the treatment of individual patients.
Eleven classes of non-insulin medications are currently approved for treating hyperglycemia in T2DM [4]. Within each class, numerous agents are available. Six of these classes (ie, α-glucosidase inhibitors, colesevelam, bromocriptine, pramlintide, meglitinides, and thiazolidinediones) are not used frequently
because of their modest efficacy, inconvenient frequency of administration, and/or limiting side effects. The 4 most commonly used non-insulin antihyperglycemic drug classes that can be added to metformin or used if a patient cannot tolerate metformin include the sulfonylureas, DPP-4 inhibitors, GLP-1 receptor agonists, and sodium-glucose cotransporter-2 (SGLT-2) inhibitors. Because T2DM is a progressive disease, many patients eventually may require insulin to achieve their glycemic goals. The primary characteristics of commonly used non-insulin agents are summarized in Table 4 [4,6,29,30,33–37] and the properties of FDA-approved insulins are summarized in Table 5 [37,38].
Consider Effects on A1C
There is a paucity of high-quality, head-to-head comparison trials evaluating the ability of available agents to achieve recommended glycemic targets. This is important because the glucose-lowering effectiveness of individual medications is strongly influenced by baseline characteristics such as A1C, duration of diabetes, and previous therapy. With these limitations in mind, the relative glucose-lowering effectiveness of commonly used agents is shown in Table 4. When used as monotherapy, A1C reductions of approximately 1% to 1.5% are achieved with metformin, sulfonylureas, and GLP-1 receptor agonists [6,30,34,35,39]. DPP-4 inhibitors and SGLT-2 inhibitors have more modest glucose-lowering efficacy, with A1C reductions of approximately 0.5% to 1% [6,30,34,35,39]. Larger effects may be seen in individuals with higher baseline A1C and those who are drug naïve. Insulin is the most effective glucose-lowering agent—it can reduce virtually any level of A1C down to the normal range, with hypoglycemia being the only limiting factor. When a patient has uncontrolled hyperglycemia on metformin monotherapy, or if there is a contraindication or intolerance to metformin, clinicians should consider the potential glucose-lowering effects of other available options and should choose an agent that conceivably could bring a patient close to meeting their treatment goal.
Add Additional Agent(s) as Needed to Achieve Goal 
