Clinical inertia is unfortunately all too common in diabetes management, at both the primary care and specialist levels.1 As a diabetes specialist, I am constantly astonished by how long patients referred to me have been exposed to chronic hyperglycemia without some escalation in their therapy. As Khunti et al point out in this issue, there is a sobering six-year lag time between maximal doses of three oral antidiabetic drugs and initiation of insulin therapy. Given the increasing number of antidiabetic agents currently available and the lack of clear consensus recommendations among professional societies, in can be challenging for the clinician to decide how best to sequentially intensify pharmacotherapy in patients with uncontrolled type 2 diabetes. Several principles, many of which have been outlined in this issue, can help guide the clinician to intensify therapy in a timely manner.
First of all, metformin should be the cornerstone of any diabetes regimen (unless contraindicated), given the fact that it is really the only medication in the diabetes armamentarium shown to have a beneficial effect on cardiovascular disease outcomes.2 As Hirst et al (reviewed in this issue) demonstrated, the clinically meaningful effect of metformin is not fully realized until a dose of 1,500 mg or higher is used. Therefore, barring any contraindications or side effects, metformin should be maximized (2,000 to 2,500 mg daily), with consideration of the ER formulation in those patients with GI intolerability. Metformin should be adjusted based on the eGFR, not serum creatinine, and it should be continued whenever possible in patients receiving insulin to improve insulin sensitivity.
If patients are still not at goal A1C after maximal metformin doses for three months, a second agent should be started. Several factors play into the decision to add a second glucose-lowering agent, including the glucose-lowering effect, convenience, side effects, effect on weight, hypoglycemia risk, cost, and availability of long-term outcome data. Currently 11 classes of commercially available noninsulin glucose-lowering medications are available in the United States, and it can be increasingly challenging for clinicians to understand the rationale behind choosing a particular medication. The fact that professional society recommendations differ with respect to choice of second-line agents illustrates the complexities of diabetes management and calls for greater research to clarify effective intensification strategies. Currently, the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) place priority on incretin-based therapies, with GLP-1 receptor agonists being the first-line medication after metformin.3 On the other hand, The American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) guidelines provide less specific advice on the choice of a second agent, recommending five treatment options after metformin.4
To help guide the clinician in selecting a second or third line medication to intensify glycemic control, several key articles published in this field over the last two years are reviewed in this issue. The meta-analysis of 39 random control trials (RCTs) by Liu et al compares the glycemic efficacy and risk of hypoglycemia and weight gain of commonly used medications as add-on therapy to diabetes. This study showed that the GLP-1 agonists are the most effective agents as add-on therapy to metformin.
Given their clinical efficacy and increasing use in clinical practice, clinicians need a greater understanding of the effectiveness and side effects of the individual GLP-1 agonists when used in combination with oral glucose lowering medications or insulin. As Buse et al (reviewed in this issue) show, liraglutide is slightly more effective than once-weekly extended-release exenatide, while the latter is better tolerated from a gastrointestinal standpoint. Both of these GLP-1 agonists are effective when added to oral anti-hyperglycemic medications. The prandial effect of GLP-1 agonists can be augmented by the addition of a basal insulin, as shown by DeVries et al (reviewed in this issue). In their study, the addition of basal insulin to metformin and liraglutide provided meaningful glycemic lowering effect.
As an endocrinologist, I am frequently referred patients who have failed maximal doses of three glucose-lowering medications and who have clearly reached a state of insulin deficiency. Many of these patients have gone years without transitioning to insulin, with various untoward consequences on their health. The reasons for this delay have been the subject of several studies. Limitations to starting insulin by primary care physicians or specialists include, among other things, lack of time required to train patients, lack of clear guidelines and definitions, lack of support (certified diabetes educators), and lack of motivation by the patient.5 While many primary care physicians understand how to start basal insulin, in my experience, there appears to be a knowledge gap in understanding how and when to initiate insulin or how to adjust insulin doses in patients on intensive basal-bolus insulin regimens. As the reviewed article by Testa et al demonstrates, a basal-bolus insulin regimen, while more burdensome for the patient, may be associated with greater glycemic efficacy and, consequently, greater patient satisfaction compared to premixed insulins, especially in patients with long duration of diabetes Physicians need a good understanding of insulin actions to guide therapeutic adjustments in insulin doses. Empowering patients to make small dose changes based on their self-monitored blood glucose readings will lead to more timely attainment of glycemic targets and conceivably greater patient satisfaction.
1. Shah BR, Hux JE, Laupacis A, Zinman B, van Walraven C. Clinical inertia in response to inadequate glycemic control: do specialists differ from primary care physicians? Diabetes Care. 2005;28:600-606.
2. Selvin E, Bolen S, Yeh HC, et al. Cardiovascular outcomes in trials of oral diabetes medications: a systematic review.Arch Intern Med. 2008;168:2070-2080.
3. Tamez-Perez HE, Proskauer-Pena SL, Hernrndez-Coria MI, Garber AJ. AACE Comprehensive Diabetes Management Algorithm 2013. Endocrine Practice. Endocrine practice: official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2013;19:736-737.
4. Inzucchi SE, Bergenstal RM, Buse JB, et al.Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35:1364-1379.
5. LaSalle JR, Berria R. Insulin therapy in type 2 diabetes mellitus: a practical approach for primary care physicians and other health care professionals. J Am Osteopath Assoc. 2013;113:152-62.