Glucose-lowering treatment regimens should be tailored to patients’ specific risk factors, but should largely include a foundation of metformin, researchers reported.
In a systematic review and network meta-analysis (NMA) of over 450 trials spanning 21 antidiabetic therapies, the greatest reduction in HbA1c levels was seen when insulin and certain GLP-1 receptor agonists were added to metformin, reported Apostolos Tsapas, MD, MSc, PhD, of the University of Thessaloniki in Greece, and colleagues.
Not surprisingly, adding other agents including sulfonylureas, basal-bolus insulin therapy, as well as premixed insulin on top of metformin were all tied to a higher chance of a severe hypoglycemic event, the group wrote in Annals of Internal Medicine.
In drug-naive patients, all glucose-lowering agents besides DPP-4 inhibitors were as effective as metformin at lowering HbA1c levels.
“[T]he use of metformin as first-line treatment of drug-naive patients at low cardiovascular risk seems justified,” the authors noted.
This reinforces the current guidelines from the American Diabetes Association, recommending metformin as the preferred first-line pharmacologic treatment for adults with type 2 diabetes.
When drug-naive patients were stratified by cardiovascular risk, those at low risk for heart events didn’t see any significantly different outcomes on mortality rate or vascular events between glucose-lowering agents.
Among low-cardiovascular-risk patients already on metformin therapy, no add-on agents yielded any significant benefit in terms of vascular outcomes. For these patients, “choice among available agents should be based on their effect on other efficacy and safety outcomes because of lack of difference in vascular outcomes,” the group suggested.
However, for those at high cardiovascular risk already on metformin, there was a significant reduction in all-cause mortality when adding oral semaglutide (Rybelsus), empagliflozin (Jardiance), liraglutide (Victoza), extended-release exenatide (Bydureon), or dapagliflozin (Farxiga) to their metformin regimen.
And those at a higher risk for heart events also saw a significant reduction in cardiovascular death when oral semaglutide, empagliflozin, or liraglutide were added to metformin. The odds of having a stroke were slashed with subcutaneous semaglutide (Ozempic) or dulaglutide (Trulicity) adjunctive to metformin.
Not surprisingly, adding one of the SGLT-2 inhibitors — canagliflozin, dapagliflozin, or empagliflozin — on top of metformin cut the risk of heart failure hospitalization and end-stage renal disease. The fourth SGLT-2 inhibitor, ertugliflozin (Steglatro), was not included, since its cardiovascular outcomes trial VERTIS-CV was just completed.
However, certain second-line agents did come with added risks, as subcutaneous semaglutide increased the risk for diabetic retinopathy, while canagliflozin increased the risk for amputation. This isn’t much of a surprise, as canagliflozin carries a boxed warning for lower limb amputation risk, stemming from the results of the CANVAS clinical program. On the other hand, incidence of amputation was reduced with adjunctive liraglutide.
“For patients at increased cardiovascular risk receiving metformin-based background therapy, the optimal choice between specific GLP-1 RAs and SGLT-2 inhibitors should be based on the cardiovascular profile of individual agents and guided by patients’ personal preferences and therapeutic priorities,” the researchers recommended.
However, “[g]iven the lack of pertinent evidence,” Tsapas and colleagues noted they failed to reach a conclusion about the “optimal” initial treatment for high-cardiovascular-risk drug-naive patients.
The analysis included 453 randomized trials with an intervention period spanning a minimum of 24 weeks. Including a total of 21 antidiabetic interventions from nine drug classes, all trials tested glucose-lowering agents in adults with type 2 diabetes.
Although the inclusion of a large number of trials was certainly a strength of the analysis, accompanying editorial authors Christine Lee, MD, MS, and William Cefalu, MD, both of the National Institutes of Health in Bethesda, Maryland, said “[l]ow confidence in estimates from networks of trials of initial drug therapy does not allow for answering whether any of the newer diabetes medications will be better initial monotherapy agents than metformin for lowering glycemia or reducing the risks for mortality and cardiovascular disease.”
The editorialists also noted the most of the randomized clinical trials included were conducted among patients already at high cardiovascular risk, leaving less room for comparison between agents for those at low cardiovascular risk.
“To facilitate more robust and consistent NMAs for comparative effectiveness research that can inform individualized care, clinical trials should attempt to enroll a more heterogeneous patient population that includes the full range of cardiovascular risk and diabetes duration and should try to categorize these factors similarly,” Lee and Cefalu suggested.
The study was funded by the European Foundation for the Study of Diabetes, supported by an unrestricted educational grant from AstraZeneca.
Tsapas reported grants from the European Foundation for the Study of Diabetes during the conduct of the study, and relationships with Boehringer Ingelheim and Novartis. Other study authors also reported disclosures.