Zachary T. Bloomgarden, MD, MACE: There are about 11 different classes of drugs that are available for treatment of diabetes. Both the ADA (American Diabetes Association) and the AACE (American Association of Clinical Endocrinologists) guidelines for managing diabetes focus on the use of a subset of those drugs—metformin, sulfonylureas, the SGLT2 (sodium-glucose cotransporter-2) inhibitors, DPP-4 (dipeptidyl peptidase-4) inhibitors, the GLP-1 (glucagon-like peptide-1) receptor activators, and the thiazolidinediones. The other drug that’s commonly used, and is included in both of the algorithms, is insulin itself. So the question is, how does one use these drugs in treating the individual with diabetes?
Both of these documents show a lot of understanding of the complexities of diabetes care. But the ADA algorithm suggests to start with metformin; then, essentially there’s no specific guidance given as to whether to use insulin, sulfonylureas, thiazolidinediones, GLP-1 receptor activators, DPP-4 inhibitors, or the SGLT2 inhibitors.
That’s a little bit of an oversimplification because the ADA guideline does say that if cost is an issue, one should use the less expensive drug—such as the NPH (neutral protamine Hagedorn) insulin or the sulfonylureas. If hypoglycemia is an issue, one should avoid those drugs and, rather, use the other drugs in the classification scheme.
In contrast, the AACE algorithm comes out and says, “Here are the drugs that we think of as most effective, and here’s how they should be used.” The AACE algorithm has suggested [that] yes, starting with metformin is reasonable, it’s economical, it’s effective, it’s not associated with hypoglycemia, and it’s not associated with weight gain. But then, in add-on [therapy], [the AACE guidelines suggest that] we should strongly consider 3 classes of drugs—probably appearing as the best at the current time. The DPP-4 inhibitors, perhaps, are least effective in the AACE algorithm because of their lesser effect in lowering blood sugar. However, they’re recognized to be the best-tolerated of the drugs, with, essentially, no side effects in the vast majority of individuals.
The SGLT2 inhibitors are considered quite potent. They are more potent than the DPP-4 inhibitors, particularly with individuals who have greater degrees of hyperglycemia—let’s say an A1C (glycated hemoglobin) above 8% when they’re already on metformin. They have some side effects, though; they cause urinary frequency. In certain individuals, genital tract or urinary tract infections are seen. There may be risk in some individuals of dehydration, although this doesn’t seem to be a major problem.
Then there are the GLP-1 receptor agonists, which are probably the most potent drugs we have for lowering blood sugar. Like the DPP-4 and SGLT2 inhibitors, they are not intrinsically associated with hypoglycemia—clearly very desirable. Like the SGLT2 inhibitors, they are associated with some degree of weight loss. And especially with the longer acting GLP-1 receptor activators, these drugs give the most potent degree of glucose lowering. So, they’ve been shown to be equally potent, or even a bit more potent, to a single dose of insulin glargine in controlling glycemia.