For decades, metformin has been the cornerstone of type 2 diabetes management, often the first medication prescribed to newly diagnosed patients. Though, a growing number of endocrinologists are advocating for a shift in approach, prioritizing newer classes of drugs like GLP-1 receptor agonists and SGLT2 inhibitors as first-line therapies. This change reflects a deeper understanding of the disease and a focus on protecting not just blood sugar levels, but also cardiovascular and kidney health.
The evolving treatment landscape is driven by mounting evidence demonstrating the benefits of GLP-1 RAs and SGLT2 inhibitors beyond glycemic control. These medications have shown promise in reducing the risk of major cardiovascular events, heart failure, and stroke, even independent of metformin leverage, according to a systematic review and meta-analysis published in the European Journal of Medical Research in January 2025 [1]. This is prompting clinicians to re-evaluate traditional treatment protocols and prioritize a more holistic approach to diabetes care.
The Rise of GLP-1 Receptor Agonists and SGLT2 Inhibitors
“While primary care physicians may still follow the traditional idea that metformin is ‘first line,’ I think most endocrinologists have been using GLP-1 receptor agonists and SGLT2 inhibitors as best-in-class therapy for nearly a decade,” says Michael Uzmann, MD, an endocrinologist and internist at A1Endocrinology in Las Vegas. This sentiment is echoed by Menachem Jacobs, MD, medical cofounder at Outlive Biology and a resident physician at Yale New Haven Hospital in Connecticut, who explains, “Recently… I shifted my strategy. I am now making it my top priority to safeguard the kidneys and heart right away. My go-to medications for patients with renal disease or heart failure are SGLT2 inhibitors or GLP-1 agonists. Organs are really saved by them.”
GLP-1 receptor agonists mimic a natural hormone that stimulates insulin release when you eat, while also slowing digestion and suppressing appetite, often leading to significant weight loss. These medications, including dulaglutide (Trulicity), exenatide (Byetta), liraglutide (Victoza), lixisenatide (Adlyxin), and semaglutide (Ozempic, Rybelsus), are primarily administered as injections, though semaglutide is also available in pill form. Possible side effects can include nausea, vomiting, and diarrhea, and rarely, pancreatitis.
SGLT2 inhibitors, operate by preventing the kidneys from reabsorbing sugar, allowing it to be excreted in urine. Medications in this class – bexagliflozin (Brenzavvy), canagliflozin (Invokana), dapagliflozin (Farxiga), empagliflozin (Jardiance), and ertugliflozin (Steglatro) – are particularly recommended for individuals with heart failure or chronic kidney disease [2]. While generally well-tolerated, potential side effects include increased urinary frequency, dizziness, and a small risk of serious complications like low blood pressure or diabetic ketoacidosis.
Other Medications in the Diabetes Arsenal
While GLP-1 RAs and SGLT2 inhibitors are gaining prominence, other medication classes remain vital tools in diabetes management. Metformin, a biguanide, remains a viable option, particularly for individuals without contraindications such as decreased kidney function, heart failure, or alcohol dependence. It lowers glucose production in the liver and improves insulin sensitivity. However, long-term use can potentially lead to vitamin B12 deficiency.
Other options include:
- DPP-4 Inhibitors: (alogliptin, linagliptin, saxagliptin, sitagliptin) – These support release more insulin by blocking an enzyme that breaks down incretin hormones.
- Sulfonylureas: (glimepiride, glipizide, glyburide) – Older medications that stimulate insulin release, but carry a higher risk of hypoglycemia and weight gain.
- Meglitinides: (repaglinide, nateglinide) – Similar to sulfonylureas, but faster-acting.
- Thiazolidinediones (TZDs): (pioglitazone, rosiglitazone) – Improve insulin sensitivity, but are less frequently prescribed due to potential risks.
- Bromocriptine: A supplemental medication that can help lower blood sugar.
In cases where oral medications and non-insulin injectables are insufficient, insulin therapy may be necessary. Kathleen Dungan, MD, an endocrinologist at the Ohio State University Wexner Medical Center, notes that most patients starting insulin therapy begin with a single daily injection of long-acting insulin.
The Future of Diabetes Treatment
Research continues to push the boundaries of diabetes treatment, with dual and triple agonists currently in clinical trials. These newer medications target multiple hormone receptors to further enhance blood sugar control and promote weight loss. The combination of GLP-1 receptor agonists and SGLT2 inhibitors is also being investigated, with early findings suggesting a synergistic effect in reducing cardiovascular and renal risks [5].
As our understanding of type 2 diabetes evolves, treatment strategies are becoming increasingly personalized and focused on protecting overall health, not just managing blood sugar. The shift away from a one-size-fits-all approach, with a greater emphasis on cardiovascular and kidney health, represents a significant step forward in improving outcomes for individuals living with this chronic condition.
This article provides informational purposes only and is not intended to be a substitute for professional medical advice. Always consult with a qualified healthcare provider for diagnosis and treatment of any medical condition.
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