Elsevier

The Lancet

Volume 398, Issue 10296, 17–23 July 2021, Pages 262-276
The Lancet

Review
SGLT2 inhibitors and GLP-1 receptor agonists: established and emerging indications

https://doi.org/10.1016/S0140-6736(21)00536-5Get rights and content

Summary

SGLT2 inhibitors and GLP-1 receptor agonists are used in patients with type 2 diabetes as glucose lowering therapies, with additional benefits of weight loss and blood pressure reduction. Data from cardiovascular outcome trials have highlighted that these drugs confer protection against major cardiovascular disease in those with established atherosclerotic cardiovascular disease, reduce the risk of admission to hospital for heart failure, and reduce cardiovascular and all-cause mortality. Ongoing research using hard renal endpoints such as end stage kidney disease rather than surrogate markers might clarify the renoprotective benefits of both agents. When used for glucose lowering, SGLT2 inhibitors are most effective if the estimated glomerular filtration rate is more than 60 ml per min per 1·73m2 at initiation and should be avoided where there is a risk of diabetic ketoacidosis. GLP-1 receptor agonists are contraindicated in those with a history of medullary thyroid cancer and used with caution in patients with a history of pancreatitis of a known cause. These drugs are now second-line, or even arguably first-line, glucose lowering therapies in patients with cardiorenal disease, irrespective of glycaemic control. If an SGLT2 inhibitor or GLP-1 receptor agonist is considered suitable in patients with type 2 diabetes, treatment should be prioritised according to existing evidence: GLP-1 receptor agonists should be considered in patients at a high risk of, or with established, cardiovascular disease and SGLT2 inhibitors considered for patients with heart failure (with reduced ejection fraction) or chronic kidney disease (with or without established cardiovascular disease). There is now compelling data on the benefits of these drugs for a range of other clinical indications even without type 2 diabetes, including for GLP-1 receptor agonists in patients with obesity and overweight with weight-related comorbidities.

Introduction

Type 2 diabetes has a major disease burden, including cardiovascular disease (CVD) and renal or chronic kidney disease (CKD). Although intensive glucose control reduces microvascular complications in type 1 and type 2 diabetes, trials of glucose lowering therapies have shown variable effects on CVD (possible harm with some drugs and other drugs showing no benefit). The regulatory requirements for cardiovascular outcome trials (CVOTs) for newer glucose lowering therapies has yielded important and unexpected outcomes for SGLT2 inhibitors and GLP-1 receptor agonists. Aside from metabolic efficacy and cardiovascular safety, these drugs confer cardiorenal protection and, particularly for SGLT2 inhibitors, can prevent and treat heart failure. Considering their dual effect on bodyweight and glycaemic control, combining these two classes is attractive in type 2 diabetes, but there is emerging evidence of multiple benefits for a range of clinical indications in patients without type 2 diabetes. This Review will describe and compare the evidence around the SGLT2 inhibitors and GLP-1 receptor agonists individually and in combination.

Section snippets

Mechanism of action

SGLT2 inhibitors are inhibitors of renal glucose reabsorption resulting in substantial glycosuria. Most compounds are highly selective for SGLT2, which is located in the renal proximal tubules, 200–2500 times more selective than for SGLT1, which is located in the kidneys and gut.1, 2, 3 At therapeutic doses, approximately 60–100 g of glucose is excreted in the urine, thus directly removing glucose from the systemic circulation and lowering blood glucose. This simple method of action increases

Effect of SGLT2 inhibitors on cardiorenal outcomes in type 2 diabetes

Four randomised controlled CVOTs and a renal outcomes trial with SGLT2 inhibitors in people with type 2 diabetes are summarised in table 1.8, 9, 10, 15

Use of SGLT2 inhibitors as treatment adjunct in type 1 diabetes

For people with type 1 diabetes in Europe, but not the USA, dapagliflozin and sotagliflozin have been approved for patients with a suboptimal control of insulin and a body mass index (BMI) of more than 27 kg/m2 based on safety and efficacy data from the phase 3 DEPICT (dapagliflozin) and TANDEM (sotagliflozin) clinical programmes. Pooled analysis from these clinical programmes supported the European Medicines Agency decision to limit their use to those with a BMI of more than 27 kg/m2 because

Cardiovascular and renal benefits in patients without diabetes

There have been no completed dedicated CVOTs or renal endpoint trials that have exclusively included patients without type 2 diabetes. Following on from the CREDENCE study, the effect of SGLT2 inhibitors in non-diabetic kidney disease is of interest given the common pathophysiological pathways in CKD.8 DAPA-CKD examined the effects of dapagliflozin on CKD in patients with and without type 2 diabetes.12 One other large clinical trial with renal specific endpoints, EMPA-KIDNEY (NCT03594110), has

GLP-1 receptor agonistsMechanism of action

GLP-1 is a gut-derived peptide secreted from intestinal epithelial L-cells, in response to nutrients, particularly glucose and fat. GLP-1 has physiological actions on multiple target organs. It is an incretin, augmenting glucose-stimulated insulin secretion by pancreatic β-cells, additionally stimulating β-cell neogenesis and inhibiting apoptosis, and reducing glucagon secretion from α-cells (shown in rodent models).29 Insulin secretion is only increased above approximately 3·5 mmol/L glucose,

Effect of GLP-1 receptor agonists on cardiorenal outcomes in type 2 diabetes

Despite the different structure and duration of action of the various GLP-1 receptor agonists, the results of various studies in heterogeneous patient populations have amassed substantial evidence to show the clear role of GLP-1 receptor agonists in cardiovascular, renal, and stroke protection, and their effect on mortality in patients with type 2 diabetes (table 3, appendix p 3).

Use of GLP-1 receptor agonists as treatment adjunct in type 1 diabetes

Few high-quality studies have assessed the safety and efficacy of GLP-1 receptor agonists as adjunctive therapy in patients with type 1 diabetes. The efficacy and safety of liraglutide as add-on to insulin treatment in patients with overweight and type 1 diabetes has been evaluated. Despite a modest effect on HbA1c (mean, 0·15–0·20% reduction), reductions in weight (–6·8 kg) and insulin requirements were seen with liraglutide.64 There might be a subgroup of patients with overweight and obesity

GLP-1 receptor agonists in obesity and prediabetes

Liraglutide (3·0 mg), has been approved for weight management in multiple countries, as an adjunct to a reduced calorie diet and increased physical activity. The Satiety and Clinical Adiposity Liraglutide Evidence (SCALE) phase 3 clinical development programme investigated the safety and efficacy of 3·0 mg liraglutide (once per day subcutaneous injection) in people with and without type 2 diabetes. Patients had a dose-dependent mean weight loss of 5·7–9·2% (6·0–8·8 kg) versus 0·2–3·1% (0·2–3·0

Non-alcoholic fatty liver disease (NAFLD)

There are currently no licensed therapies for NAFLD but even modest weight loss (approximately 8 kg) in patients with type 2 diabetes substantially reduces hepatic steatosis (by approximately 80%), concomitantly improving hepatic insulin resistance.73 Randomised controlled trials with SGLT2 inhibitors and GLP-1 receptor agonists have shown improved liver enzymes and reductions in liver fat in patients with type 2 diabetes, but only GLP-1 receptor agonists (liraglutide and semaglutide) have

Efficacy studies comparing SGLT2 inhibitors and GLP-1 receptor agonists

In DURATION 8, comparing dapagliflozin (10 mg once per day) with exenatide (2 mg once per week), there were similar reductions in HbA1c (1·4–1·6%) but greater reductions in bodyweight with dapagliflozin.78 In SUSTAIN 8, comparing subcutaneous semaglutide (1·0 mg once per week) with canagliflozin (300 mg once per day), semaglutide was superior to canagliflozin in lowering both HbA1c and bodyweight (–4·7 kg vs –3·8 kg) after 52 weeks.79 Finally, in PIONEER 2, comparing oral semaglutide (14 mg)

Combination therapy

Overall, the evidence supports combination therapy with a GLP-1 receptor agonist and SGLT2 inhibitor with the additive benefits of glycaemic improvement and weight loss reflecting distinct and complementary mechanisms of action (table 4).78, 86, 87 Further studies are necessary to elucidate their combined effects on metabolic and cardiorenal disease (table 5).

Future directions

Newer formulations of GLP-1 receptor agonists are becoming available. Implantable GLP1 receptor agonists have been evaluated,91, 92 but the most encouraging is use of oral semaglutide, with compelling clinical data. GLP1 might also be one of several key peptide hormone receptors that can be targeted with novel co-peptides targeting GLP-1, glucose-dependent insulinotropic polypeptide, and glucagon receptors simultaneously in phase 2 and phase 3 trials.93 Evidence regarding combination therapy

Search strategy and selection criteria

We obtained citations for this publication through searches of PubMed up to May 12, 2021, with no lower limit set for the date, using both MeSH and free-text terms to identify relevant articles. The terms “glucagon-like peptide-1 receptor agonist” and “sodium glucose cotransporter 2 inhibitor” (including “exenatide”, “lixisenatide”, “albiglutide”, “dulaglutide”, “liraglutide”, “semaglutide”, “canagliflozin”, “dapagliflozin”, “empagliflozin”, and “ertugliflozin”) were searched for. We reviewed

Declaration of interests

EB is currently supported by a grant funded to the University of Liverpool by AstraZeneca and has received support for attendance at educational meetings by AstraZeneca and Sanofi. HJLH reports grants from AstraZeneca and Janssen during the conduct of the study (fees paid to institution); grants from AbbVie and Boehringer Ingelheim outside of the submitted work (fees paid to institution); and has acted as a consultant for AbbVie, Bayer, Boehringer Ingelheim, Chinook, CSL Pharma, Gilead, Merck,

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