The editorialists note that despite longstanding recommendations from ACP and other organizations to use metformin as first-line treatment for type 2 diabetes, one study found that among insured patients, only about half were using metformin during 2003 to 2013, and its use rose only slightly during that time.
Concern about lactic acidosis likely played a role in the underuse. "The change in the metformin contraindication to an estimated glomerular filtration rate of 30 mL/min/1.73 m2 or less will expand metformin access to many patients with chronic kidney disease who may benefit," Dr Fradkin and Dr Rodgers write.
Dr. Damle said, "Metformin has been standard of care for over a decade.... I don't think there's much question about that, but it may need to be adopted more than it already is."
Indeed, a separate paper also published January 3 in the Annals highlights the benefits of metformin specifically in patients with type 2 diabetes and other conditions that had previously been considered contraindications for metformin use, including chronic kidney and liver disease with hepatic impairment and congestive heart failure.
Moreover, whereas there are fewer contraindications to metformin now, a few still remain, including decreased tissue perfusion, hemodynamic instability, advanced liver disease, and acute unstable congestive heart failure.
Second-Line Oral Therapy: SGLT2s and DPP-4s Favored
The second recommendation, to consider adding a sulfonylurea, a thiazolidinedione, an SGLT2 inhibitor, or a DPP-4 inhibitor to metformin to improve glycemic control when a second oral therapy is deemed necessary, was graded as "weak," with moderate-quality evidence.
ACP recommends "that clinicians and patients select among medications after discussing benefits, adverse effects, and costs." A table is provided that lists expected benefits, harms, and clinical considerations for each of the oral drug classes, and a second table focuses on comparative efficacy, adverse effects, and costs for add-on therapies to metformin.
Sulfonylureas, although inexpensive and used for many years, are associated with increased risk for hypoglycemia and weight gain. The evidence also does not include information on switching from sulfonylureas to other second-line agents, but for patients who are currently receiving them and achieving good glycemic control without adverse effects, "keeping them on this drug may be reasonable."
The SGLT2 inhibitors are favored over sulfonylureas as an add-on to metformin therapy in terms of cardiovascular disease (CVD) mortality, hemoglobin A1c levels, weight, systolic blood pressure, and heart rate, and are favored over DPP-4 inhibitors as an add-on to metformin therapy in terms of weight and systolic blood pressure.
However, the SGLT2 inhibitors are also associated with an increased risk for genital mycotic infections.
The DPP-4 inhibitors are favored over sulfonylureas for long-term all-cause mortality, long-term CVD mortality, and CVD morbidity; over the thiazolidinedione pioglitazone for short-term CVD morbidity; and over sulfonylureas or other thiazolidinediones because of less weight gain.
On the down side, the FDA has warned that the DPP-4 inhibitors saxagliptin and alogliptin may increase the risk for heart failure, especially in patients who already have heart or kidney disease.
Dr. Damle told Medscape Medical News, "Use of SGLT-2 inhibitors is favored as second-line therapy in terms of...cardiovascular mortality, weight loss, and systolic blood pressure. I think this will reinforce to practicing internists to use them more, probably even a little more frequently than DPP-4 inhibitors."
He continued, "I think this will reaffirm what people are doing in practice, but perhaps not doing as widely as needed to bring A1c under tight control for patients in whom tight control is appropriate."
However, he also said that the difference between SGLT2 inhibitors and DPP-4 inhibitors combined with metformin is "more than marginal but still not so compelling that we need to recommend one over the other. I think the choice of DPP4 or SGLT2 will be very individual, and somewhat experienced-based."
In addition, he noted that for both classes, "The results are not so impressive that costs should not be a consideration.... So you will have to weigh the costs vs benefits of some of these expensive drugs such as SGLT2is and DPP4is."
Dr Fradkin and Dr Rodgers point out that although pills are generally preferred over injections, the use of insulin and injectable GLP-1RAs is increasing, facilitated by newer pen devices and once-weekly and combined formulations. "Patients therefore should be offered the full range of options for therapy," they advise.
Indeed, Dr Damle said ACP may decide to include injectables in its next guidelines, although of course that would mean getting into all the different insulin regimens. "We want to use as many oral agents as possible to maximize efficacy before going to injectable form."
To address the lack of long-term, head-to-head comparator studies needed to inform treatment guidelines, the National Institute of Diabetes and Digestive and Kidney Diseases has launched the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) study, which compares the four commonly prescribed drug classes added with metformin.
The primary outcome is relative effectiveness in maintaining glycemic control over time, but the study will also assess effects on weight, cardiovascular risk factors, microvascular complications, cognitive function, safety, adverse effects, tolerability, quality of life, and cost. Patient-specific phenotypic, physiologic, and genotypic differences will also be explored.
In addition, Dr Fradkin and Dr Rodgers write, "Because [type 2 diabetes] is a progressive disease with worsening metabolic control, requiring additional glucose-lowering therapies over time, an important strength of the GRADE Study is the planned average 4- to 5-year follow-up of participants and its standardized approach to treatment intensification."
The guidelines were funded by the ACP. One coauthor reports receiving grants, personal fees, and nonfinancial support from Informed Medical Decisions Foundation and Healthwise, both nonprofits, outside the submitted work. One coauthor reports personal fees from Takeda Pharmaceuticals speakers' bureau before 2015, outside the submitted work. The other authors, Dr Fradkin, and Dr Rodgers have disclosed no relevant financial relationships.
Ann Intern Med. Published online January 3, 2017