SGLT-2i, GLP-1 agonists tied to better survival in T2D
SGLT-2* inhibitors and GLP-1** agonists were associated with better survival compared with DPP-4*** inhibitors or control (placebo or no treatment) in patients with type 2 diabetes (T2D) who were inadequately controlled on metformin, according to a large network meta-analysis of 236 randomized trials.
“International guidelines recommend escalation to either SGLT-2 inhibitors or incretin-based treatments in people with T2D not achieving target glycaemic control with metformin,” the researchers stated. [Am Fam Physician 2017;95:40-43; https://www.nice.org.uk/guidance/ng28]
Noting that a lack of comparative clinical and cost-effectiveness among the three glucose-lowering drug classes may lead to uncertainty regarding the optimal treatment pathway, the researchers continued, “When no head-to-head trial exists, network meta-analysis can be used to estimate the effect.”
“Of the three classes tested, SGLT-2 inhibition may be preferred over the incretin-based therapies based on their association with lower mortality and their favourable adverse event [AE] profile,” they added.
The network meta-analysis included 176,310 patients with T2D in 236 trials which compared either SGLT-2 inhibitors, GLP-1 agonists, or DPP-4 inhibitors with each other or with control (comprising either a placebo or no treatment). [JAMA 2018;319:1580-1591]
Participants who received SGLT-2 inhibitors or GLP-1 agonists had a significantly lower risk of all-cause mortality compared with DPP-4 inhibitors (HRs, 0.78 and 0.86 for SGLT-2 inhibitors and GLP-1 agonists, respectively), as well as compared with control (HRs, 0.80 and 0.88, respectively).
Similarly, both SGLT-2 inhibitors and GLP-1 agonists were associated with significantly reduced risk of cardiovascular (CV) mortality compared with DPP-4 inhibitors (HRs, 0.79 and 0.85 for SGLT-2 inhibitors and GLP-1 agonists, respectively) and control (HRs, 0.79 and 0.85, respectively).
“SGLT-2 inhibitors and GLP-1 agonists ... [were associated with] reduced all-cause and CV mortality, with no difference between the two,” according to an accompanying multimedia.
Furthermore, SGLT-2 inhibitors were associated with additional CV benefits of significantly lower rates of heart failure (HR, 0.62, 95 percent Crl, 0.54–0.72) and myocardial infarction (HR, 0.86, 95 percent Crl, 0.77–0.97) compared with control.
No significant differences were observed between DPP-4 inhibitors and control in terms of the rates of all-cause mortality (HR, 1.02) and CV mortality (HR, 1.00).
With regard to safety, risk of AEs leading to study withdrawal was greater in participants treated with GLP-1 agonists compared with SGLT-2 inhibitors (HR, 1.80) and with DPP-4 inhibitors (HRs, 1.93). The majority of the AEs reported in the GLP-1 agonist group were related to the gastrointestinal tract. On the other hand, SGLT-2 inhibitors were linked with a higher risk of genital infections based on safety data from CV outcome trials; while DPP-4 inhibitors were associated with a greater risk of acute pancreatitis.
“Careful treatment selection may be necessary to minimize these outcomes in at-risk patients,” advised the researchers.
Limits of meta-analysis as an estimate
“To date, no randomized clinical trials with mortality or CV outcomes have directly compared the efficacy of these three classes,” they wrote. Therefore, the current findings have to be interpreted within the limitations of the meta-analysis.
One of the limitations was that clinical efficacy and safety was analysed by drug class instead of by individual drug type. “Although this substantially increases power to detect treatment effects, there is a key assumption that within-class treatments are interchangeable,” according to the researchers.
In addition, the availability and quality of data included in the analysis were variable. Also, patient characteristics which may influence the relative efficacy of the treatments were assumed to be similar among the various treatment groups.
“It will be important to test these three classes against and in addition to metformin monotherapy for CV outcomes to better determine treatment algorithms,” the researchers added.