Published online Nov 15, 2020. doi: 10.4239/wjd.v11.i11.540
Peer-review started: August 13, 2020
First decision: September 16, 2020
Revised: September 29, 2020
Accepted: October 19, 2020
Article in press: October 19, 2020
Published online: November 15, 2020
Currently, not much is known on the efficacy, safety and potential cardiometabolic benefits of combination therapy, including sodium/glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like-1 receptor agonists (GLP-1RA), in the treatment of patients with type 2 diabetes (T2DM) with poorly controlled glycemia. Separately, both drug classes have proven cardiovascular (CV) benefits, mainly in secondary and some also in primary prevention. Moreover, both drug classes improve glycemic control by not enhancing the risk of hypoglycemia and having additional beneficial effects on body weight, making them a preferred option for treating obese/overweight patients with T2DM.
Data on using combination therapy are still modest. The analyses of results coming from randomized controlled trials (RCTs) suggest improvements of glycemic control as well as in CV surrogate markers when GLP-1RAs are added on top of SGLT-2i. Interestingly, glycemic improvements when both drugs are given simultaneously might not be additive. Moreover, data from real-life clinical practice with mentioned drug classes not always follow the results of RCTs. The question of the right timing for the mentioned agents in the course of the disease and if their effect is durable still remains open.
The aim was to investigate whether the efficacy of GLP-1RA and SGLT2i combination observed in randomized controlled trials translates into therapeutic benefits during routine clinical practice and 12 mo follow-up. In addition, the efficacy of simultaneous vs sequential initiation approach was also compared. The primary study endpoint was the proportion of participants with hemoglobin A1c (HbA1c) < 7.0% and/or 5% bodyweight reduction. Secondary outcomes included changes in fasting plasma glucose (FPG), prandial plasma glucose (PPG), low-density lipoprotein cholesterol (LDL) cholesterol, estimated glomerular filtration rate (eGFR) and CV incidents assessment over a follow-up period.
This retrospective and prospective multi-centric cohort study included 200 T2DM Caucasian patients with long-standing, poorly controlled T2DM prescribed both SGLT-2i (empagliflozin, dapagliflozin) and GLP-1RA (liraglutide, dulaglutide) between January 2016 and April 2019. Patients were identified from electronic medical records and served as a source population. The index visit was the one where either SGLT-2i was prescribed to already present GLP-1RA (1), GLP-1RA was prescribed on top of already present SGLT-2i therapy (2), or both agents were prescribed simultaneously on top of background glucose-lowering agents (3).
Patients who started simultaneous therapy had poorer glycemic control, higher FPG and body mass index (BMI) values than the other two groups. There was a statistical significance in the reduction of HbA1c in all three groups. However, no difference was achieved in the reduction depending on the specific therapy group, meaning that simultaneous or sequential intensification does not make a difference in this population of patients. A significant reduction of body weight, defined as a loss of 5% or more, was predominantly achieved in the simultaneous therapy group. No difference was observed in our patients in the incidence of CV events, whether it was three points mild autonomous cortisol excess or heart failure, which may be a reflection of short follow-up time or a small number of events. No differences in eGFR were noted, which was expected given that SGLT-2i are still indicated in patients with eGFR over 60 mL/min; thus, all our patients had normal kidney function. Only small proportion of patients (32.3%) achieved composite outcomes defined as HbA1c < 7% and 5% weight loss, which deviates significantly from the results of available RCTs promising more favorable results, which emphasizes the problem of clinical inertia and poor adherence, especially related to side effects. However, these results could be mainly a reflection of Croatian health reimbursement policy since GLP-1RAs were reimbursed in patients with BMI above 35 kg/m2 and after the failure of two anti-diabetic agents, while SGLT-2i prescription was possible in case of BMI above 27 kg/m2 with obligatory co-payment preventing physicians from initiating therapy in the earlier course of the disease. Only 18.2% of patients attained composite outcome defined as HbA1c below 7% with 5% weight loss and less stringent target of LDL cholesterol < 2.5 mmol/L highlighting a significant problem of nonadherence and sub dosage of statin therapy.
Simultaneous use of both drugs in everyday clinical practice is mainly reserved for patients with the highest degree of dysglycemia (including HbA1c, FPG, and PPG). SGLT-2i are commonly used early in the disease course when FPG is still in range or only slightly elevated. GLP-1RA and SGLT-2i, when added sequentially to the other or simultaneously, decrease the HbA1c and reduce the BMI, but weight loss and glucose-lowering potential are not additive in case of their simultaneous use. In terms of metabolic control, the combination of these two drugs has positive effects, although it is not clear whether simultaneous or sequential intensification makes a difference. In these obese, poorly regulated patients with long-standing diabetes, both options seem to be equally effective, although the real question is whether the results would have been different if we had the opportunity to start the therapy earlier. It was also not possible to assess the most significant benefit of this combination and its effects on CV complications and kidney function.
The next step would be to monitor patients treated with this particular combination in earlier stages of the disease and through a longer period. According to a new reimbursement policy, we are presently able to initiate GLP-1RA in patients with a BMI over 30 kg/m2 or 28 kg/m2 if they have proven CV disease after failure of dual oral therapy and SGLT-2i irrespective of patient's BMI, thus enabling us to establish the actual value of GLP-1RA and SGLT-2i combination treatment.