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SGLT2 Inhibitors and GLP-1 Receptor Agonists for T2D
TAKE-HOME MESSAGE
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Despite conflicting evidence, sodium–glucose transporter 2 (SGLT2) inhibitors and glucagon–like peptide-1 (GLP-1) receptor agonists are thought to decrease cardiovascular and renal complications when added to other glucose–lowering drugs in adults with type 2 diabetes. However, the relative and absolute benefits and harms of these drugs across all important outcomes and at varying levels of cardiovascular and kidney disease risk are not clear.
- SGLT2 inhibitors and GLP-1 receptor agonists are associated with reductions in all-cause and cardiovascular mortality, myocardial infarction, kidney failure, and serious hyperglycemia. These drugs seem to be associated with reduction in body weight without leading to severe hypoglycemia. While relative effects on cardiovascular mortality, myocardial infarction, kidney failure, health–related quality of life, and serious hyperglycemia were similar between the two drugs, there were substantial differences in absolute benefits with respect to cardiovascular and renal disease risk.
abstract
This abstract is available on the publisher's site.
Access this abstract nowOBJECTIVE
To evaluate sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists in patients with type 2 diabetes at varying cardiovascular and renal risk.
DESIGN
Network meta-analysis.
DATA SOURCES
Medline, Embase, and Cochrane CENTRAL up to 11 August 2020.
ELIGIBILITY CRITERIA FOR SELECTING STUDIES
Randomised controlled trials comparing SGLT-2 inhibitors or GLP-1 receptor agonists with placebo, standard care, or other glucose lowering treatment in adults with type 2 diabetes with follow up of 24 weeks or longer. Studies were screened independently by two reviewers for eligibility, extracted data, and assessed risk of bias.
MAIN OUTCOME MEASURES
Frequentist random effects network meta-analysis was carried out and GRADE (grading of recommendations assessment, development, and evaluation) used to assess evidence certainty. Results included estimated absolute effects of treatment per 1000 patients treated for five years for patients at very low risk (no cardiovascular risk factors), low risk (three or more cardiovascular risk factors), moderate risk (cardiovascular disease), high risk (chronic kidney disease), and very high risk (cardiovascular disease and kidney disease). A guideline panel provided oversight of the systematic review.
RESULTS
764 trials including 421 346 patients proved eligible. All results refer to the addition of SGLT-2 inhibitors and GLP-1 receptor agonists to existing diabetes treatment. Both classes of drugs lowered all cause mortality, cardiovascular mortality, non-fatal myocardial infarction, and kidney failure (high certainty evidence). Notable differences were found between the two agents: SGLT-2 inhibitors reduced mortality and admission to hospital for heart failure more than GLP-1 receptor agonists, and GLP-1 receptor agonists reduced non-fatal stroke more than SGLT-2 inhibitors (which appeared to have no effect). SGLT-2 inhibitors caused genital infection (high certainty), whereas GLP-1 receptor agonists might cause severe gastrointestinal events (low certainty). Low certainty evidence suggested that SGLT-2 inhibitors and GLP-1 receptor agonists might lower body weight. Little or no evidence was found for the effect of SGLT-2 inhibitors or GLP-1 receptor agonists on limb amputation, blindness, eye disease, neuropathic pain, or health related quality of life. The absolute benefits of these drugs vary substantially across patients from low to very high risk of cardiovascular and renal outcomes (eg, SGLT-2 inhibitors resulted in 5 to 48 fewer deaths in 1000 patients over five years; see interactive decision support tool (https://magicevidence.org/match-it/200820dist/#!/) for all outcomes.
CONCLUSIONS
In patients with type 2 diabetes, SGLT-2 inhibitors and GLP-1 receptor agonists reduced cardiovascular and renal outcomes, with notable differences in benefits and harms. Absolute benefits are determined by individual risk profiles of patients, with clear implications for clinical practice, as reflected in the BMJ Rapid Recommendations directly informed by this systematic review.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO CRD42019153180.
Additional Info
Disclosure statements are available on the authors' profiles:
Sodium-Glucose Cotransporter Protein-2 (SGLT-2) Inhibitors and Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists for Type 2 Diabetes: Systematic Review and Network Meta-Analysis of Randomised Controlled Trials
BMJ 2021 Jan 13;372(xx)m4573, SC Palmer, B Tendal, RA Mustafa, PO Vandvik, S Li, Q Hao, D Tunnicliffe, M Ruospo, P Natale, V Saglimbene, A Nicolucci, DW Johnson, M Tonelli, MC Rossi, SV Badve, Y Cho, AC Nadeau-Fredette, M Burke, LI Faruque, A Lloyd, N Ahmad, Y Liu, S Tiv, T Millard, L Gagliardi, N Kolanu, RD Barmanray, R McMorrow, AK Raygoza Cortez, H White, X Chen, X Zhou, J Liu, AF Rodríguez, AD González-Colmenero, Y Wang, L Li, S Sutanto, RC Solis, F Díaz González-Colmenero, R Rodriguez-Gutierrez, M Walsh, G Guyatt, GFM StrippoliFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Primary Care
SGLT2 Inhibitors and GLP1-RAs: Do They Have Benefits Across the Spectrum of Risk?
There have been many studies with SGLT2 inhibitors and GLP1-RAs, and often the patient populations are different. This is a good thing because we can see the effects of these medications on different types of patients, but it is hard to know if these agents are beneficial for patients across different risk categories.
To this end, this article took 764 trials that included 421,346 patients. These patients covered the whole spectrum of risk ranging from the very low–risk to the very high–risk category. The researchers also used the data to see how these agents worked compared with placebo and also how well they worked compared with each other.
When the authors evaluated the data based on the patient’s risk category, as expected, the higher-risk patients had greater benefit with more events prevented. The lower-risk patients did have benefit but to a smaller degree. For example, for SGLT2 inhibitors, in the very high–risk patient, there were 48 fewer deaths per 1000 patients over a 5-year period. On the other hand, at the other extreme, the very low–risk individuals had only 5 fewer deaths. So, what this large meta-analysis is telling us is that we can treat across the spectrum of patients with SGLT2 inhibitors or GLP1-RAs. The magnitude of the benefits may be different, but there are benefits throughout the spectrum of patients. However, for specific endpoints like all-cause mortality, SGLT2 inhibitors lowered it more than GLP1-RAs. For non-fatal MI, both were equal; but, for non-fatal strokes, the GLP1-RAs did better than SGLT2 inhibitors. For renal failure, both were similar in benefit; whereas, for heart failure hospitalization, SGLT2 inhibitors had the advantage.
Perhaps the combination of the two classes will be the way of the future as it would give our patients the best protection that each class can offer.