Semaglutide and liraglutide in type 2 diabetes: effective and safe with and without SGLT-2-i

Based on empirical evidence, professional societies recommend early combination of metformin with an SGLT-2 inhibitor or a GLP-1 receptor agonist in type 2 diabetics. Increasingly, a combined application of the latter two classes of active ingredients is also being used. In a recently presented post hoc analysis of the SUSTAIN-10 trial, new efficacy and safety evidence was provided for this treatment strategy.

According to international guideline recommendations, optimal therapy for type 2 diabetes should be oriented toward cardiovascular and renal risk factors [1,2]. Both SGLT-2 inhibitors (SGLT-2-i) and GLP-1 receptor agonists (GLP-1-RA) show substantial metabolic and cardiorenal benefits, although these result from different mechanisms of action [3]. The current treatment guidelines of the Swiss Society of Endocrinology and Diabetology (SGED) recommend using one of these drug classes in combination with metformin at an early stage and combining it with the other class if a reduction in HbA1c to the desired level cannot be achieved to a sufficient extent [4]. This is congruent with the ADA/EASD consensus as well as the new ESC guidelines on cardiovascular risk reduction in diabetic patients, especially since most type 2 diabetics are in the high-risk category [5–7].

Regarding the combined use of GLP-1-RA and SGLT-2-i in clinical practice, data on the safety and efficacy of these two drug classes provide valuable guidance for therapeutic decision making. In the SUSTAIN-9 trial, adults with type 2 diabetes who had an HbA1c of 7.0-10.0% despite at least 90 days of therapy with an SGLT-2 inhibitor were randomized to once-weekly semaglutide (s.c.) 1.0 mg or placebo as an add-on* [8]. 216 of the patients (71.5%) were also on treatment with metformin and 39 (12.9%) received sulfonylureas. At 30 weeks after baseline, patients treated with semaglutide as an add-on had significantly greater reductions in HbA1c levels compared with the placebo group (estimated treatment difference -1.42% [95% KI –1,61 bis –1,24]**. The same pattern was seen with respect to body weight (-3.81 kg [-4.70 to -2.93]) (p<0.0001 in each case).

* following a dose escalation schedule of 0.25 mg semaglutide or placebo over 4 weeks and 0.50 mg semaglutide or placebo over 4 weeks
** -15.55 mmol/mol [-17.54 to -13.56]

New data on the combined use of GLP-1-RA and SGLT-2-i.

The SUSTAIN-10 trial evaluated the efficacy and safety of the GLP-1 RAs semaglutide (s.c.)and liraglutide (s.c.) in patients with type 2 diabetes [9]. Matthew Capehorn, MD, Rotherham (UK), presented at this year’s EASD Annual Meeting the results of a post-hoc analysis evaluating clinical outcomes depending on whether GLP-1-RA was used as monotherapy or combined with an SGLT-2 inhibitor [10,11]. The results of this post-hoc analysis indicate that the combination of GLP-1-RA and SGLT-2-i are associated with further reductions in HbA1c levels, body weight, and systolic blood pressure, without the appearance of additional safety signals.

Treatment effects of subcutaneously administered semaglutide 1.0 mg (1×/week) or liraglutide 1.2 mg (1×/d) on HbA1c and body weight in patients without SGLT-2 inhibitor (n=435) vs. with SGLT-2 inhibitor (n=142) at baseline were assessed. The proportion of those receiving metformin at baseline was similar in both treatment arms (97.2% and 94.0% with SGLT-2-i and 93.2% and 91.3% without SGLT-2-i, respectively). This was also true for sulfonylureas; the respective proportions were 50.7% and 51.4% without SGLT-2i and 35.6% and 31.9% with SGLT-2-i.

Regardless of the use of SGLT-2-i at baseline, at week 30, semaglutide 1.0 mg and liraglutide 1.2 mg results in a reduction of the HbA_{1c values}(without SGLT-2-i: 1.8% points and 1.1% points, respectively; with SGLT-2i: 1.6% points and 0.7% points, respectively). (Fig. 1). There was also an improvement in both groups with regard to body weight (weight reduction without SGLT-2-i: 5.9 and 2.2 kg respectively with SGLT-2-i 5.3 kg and 1.1 kg) and systolic blood pressure (without SGLT-2 inhibitor: 5.2 and 3.6 mmHg, with SGLT-2-i 2.4 mmHg and 3.2 mmHg).

No unexpected safety signals were registered in patients receiving both GLP-1-RA and SGLT-2-i. (Tab. 1). The rate of early treatment discontinuation due to adverse events proved to be relatively low in both those treated with semaglutide 1.0 mg, as well as in those treated with liraglutide 1.2 mg treated subgroups regardless of whether or not an SGLT-2 inibitor was used (without SGLT-2i: 13.4% and 6.4%, respectively; with SGLT-2-i 5.5% and 7.2%, respectively).

Congress: EASD Annual Meeting 2021

Literature:

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