The American College of Physicians has recommended metformin as first-line therapy for type 2 diabetes and advises consideration of four class options for oral pharmacologic treatment if a second agent is required.
Amir Qaseem, MD, head of the ACP Clinical Guidelines Committee, and colleagues published the new recommendations online January 3 in the Annals of Internal Medicine. The American Academy of Family Physicians has endorsed the guidelines.
The recommendations on oral medications for type 2 diabetes updates the group's 2012 guideline. Since 2002, the US Food and Drug Administration (FDA) has loosened previous restrictions on metformin use, and new information has become available about the sodium-glucose cotransporter-2 (SGLT2) and dipeptidyl peptidase-4 (DPP-4) inhibitor classes. Sulfonylureas and thiazolidinediones are also addressed, but are less favored as second-line options.
"A lot has changed in 4 years. It's an evolving story right now," ACP President Nitin S. Damle MD, told Medscape Medical News.
Although the document essentially reflects the approach many clinicians are already taking to treat type 2 diabetes, it does add reinforcement regarding expanded use of metformin and also clearly lays out the pros and cons of each of the various second-line agents.
However, as with the 2012 guideline, the new recommendations only addresses oral agents, so they do not include insulin or glucagon-like peptide-1 receptor agonists (GLP-1RAs).
In addition, because it is based on a systematic review of comparative effectiveness research, it also does not include data from the recent cardiovascular outcomes trials mandated by the US Food and Drug Administration in 2008 for new diabetes drugs. Those trials were designed to assess cardiovascular safety rather than comparative effectiveness, Dr. Damle explained.
Of the studies that were included, one limitation is that "study lengths generally were 1 year or less, whereas diabetes is a chronic, progressive disease requiring lifelong treatment," write Griffin P. Rodgers, MD, director of the National Institute of Diabetes and Digestive and Kidney Diseases, and Judith E. Fradkin, MD, director of the institute's Division of Diabetes, Endocrinology, and Metabolic Diseases, Bethesda, Maryland, in an accompanying editorial.
Thus, Dr Fradkin and Dr Rodgers note, the evidence provided in the ACP document is strongest for intermediate outcomes (eg, hemoglobin A1c, weight, and blood pressure) and for harms (eg, hypoglycemia, heart failure, and gastrointestinal adverse effects): "The information on intermediate outcomes and harms is presented clearly and may help inform shared decision making," they write.
Wider Metformin Use Urged
The recommendation to use metformin as first-line treatment for type 2 diabetes in conjunction with lifestyle modification was graded as strong, based on moderate-quality evidence. Overall, metformin is effective in reducing blood glucose levels, is associated with weight loss and fewer hypoglycemic episodes, and is less expensive than other diabetes medications.
In April 2016, the FDA loosened its previous restrictions on the use of metformin in patients with moderate chronic kidney disease (estimated glomerular filtration rate, 30-60 mL/minute per 1.73 m2), based on data showing that those individuals are not at significantly elevated risk for lactic acidosis. Now, the contraindication remains only for those with severe chronic kidney disease (<30 mL/minute per 1.73 m2).
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.
Ann Intern Med. Published online January 3, 2017.
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