Where Do GLP-1 Drugs and SGLT2 Inhibitors Fit in the Diabetes Treatment Playbook? | Research

The takeaway

SGLT2 inhibitors and incretin-based therapies offer weight loss, low hypoglycemia risk, and cardiovascular benefits over older diabetes drugs, but their higher cost and unique side effects require careful positioning in treatment algorithms.

Cardiovascular event reduction with empagliflozin
At the time of this review, empagliflozin was the first diabetes drug shown to reduce cardiovascular events in high-risk patients — a breakthrough that reshaped how these newer drug classes are positioned in treatment algorithms.

What the researchers found

SGLT2 inhibitors and incretin-based therapies (DPP-4 inhibitors and GLP-1 receptor agonists) offer clinically important advantages over older diabetes drugs: weight loss, low hypoglycemia risk, blood pressure reduction, and — for empagliflozin specifically — reduced cardiovascular events in high-risk patients. These drugs may also correct core type 2 diabetes defects by improving β-cell function and insulin sensitivity. However, GLP-1 RAs carry nausea risk, SGLT2i are associated with genital infections, volume depletion, and rare diabetic ketoacidosis, and pancreatitis risk with incretins remains unclear.

Why it matters

Positioning newer diabetes drug classes in treatment algorithms is one of the most consequential clinical decisions in endocrinology. With older drugs like metformin and sulfonylureas as the baseline, the added benefits of SGLT2 inhibitors and incretin-based therapies — particularly cardiovascular protection and weight reduction — must be weighed against their higher cost and unique side effect profiles to determine where they fit best in stepped treatment approaches.

How the study worked

Narrative review article synthesizing clinical trial data, pharmacological rationale, and current treatment guidelines for SGLT2 inhibitors, DPP-4 inhibitors, and GLP-1 receptor agonists in type 2 diabetes. Discusses positioning of these drug classes relative to established therapies and anticipates how ongoing cardiovascular outcome trials may shift recommendations.

Who was studied

Patients with type 2 diabetes at various stages of treatment escalation, including those at high cardiovascular risk

What this study cannot tell us

Published in 2016, the review predates major cardiovascular outcome trials for GLP-1 RAs (LEADER, SUSTAIN-6, REWIND) and additional SGLT2i trials (DECLARE, DAPA-HF). At the time, empagliflozin was the only agent with cardiovascular outcome data. The review does not quantify the cost-effectiveness of newer therapies. The pancreatitis question with incretin therapies was unresolved at the time of publication.

How to read the evidence

This is a narrative review published in Diabetes Care synthesizing clinical trial data and current guidelines. While it draws on randomized controlled trial evidence, the review format and the still-emerging cardiovascular outcome trial landscape at the time limit the strength of some conclusions.

When this study was published

Published in 2016, this review was written before several landmark cardiovascular outcome trials (LEADER, SUSTAIN-6, REWIND, DECLARE) were completed. The treatment algorithm positioning has since shifted significantly in favor of earlier use of both drug classes. The core pharmacological rationale remains accurate.

The bigger picture

This review captures a pivotal moment in diabetes treatment — when SGLT2 inhibitors and incretin therapies were transitioning from 'newer alternatives' to guideline-recommended first-line options. The cardiovascular benefits first demonstrated with empagliflozin (and later confirmed with other agents) fundamentally changed how diabetes treatment algorithms were structured, shifting the focus from pure glucose control to comprehensive cardiometabolic risk reduction.

Questions still open

Will ongoing cardiovascular outcome trials confirm cardioprotective benefits for additional GLP-1 receptor agonists and SGLT2 inhibitors?
At what point in the treatment algorithm should these newer agents be started — early alongside metformin, or only after metformin failure?
Is the additional cost of SGLT2 inhibitors and incretin therapies justified by their cardiovascular and weight benefits compared to generic older agents?

Common questions

What's the difference between SGLT2 inhibitors and GLP-1 drugs for diabetes?

SGLT2 inhibitors (like empagliflozin and dapagliflozin) work by blocking sugar reabsorption in the kidneys, so excess glucose leaves through urine. GLP-1 receptor agonists (like semaglutide and liraglutide) mimic a gut hormone that stimulates insulin release and suppresses appetite. Both cause weight loss and have cardiovascular benefits, but through completely different mechanisms — and they can be used together.

Why aren't these newer drugs given to everyone with type 2 diabetes right away?

Cost is the main barrier — these drugs are significantly more expensive than older generic medications like metformin. Guidelines traditionally recommend starting with cheaper, proven drugs and escalating to newer agents when needed. However, as more evidence of cardiovascular benefits has accumulated, guidelines have increasingly recommended earlier use of these drugs, especially for patients with heart disease or high cardiovascular risk.

Read the original research

Positioning SGLT2 Inhibitors/Incretin-Based Therapies in the Treatment Algorithm.

Diabetes care, 39 Suppl 2, S154-64

View on PubMed ↗Publisher’s paper ↗

Citation

Wilding, John P H; Rajeev, Surya Panicker; DeFronzo, Ralph A. (2016). Positioning SGLT2 Inhibitors/Incretin-Based Therapies in the Treatment Algorithm.. Diabetes care, 39 Suppl 2, S154-64. https://doi.org/10.2337/dcS15-3005