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Metformin has been the drug of choice for the treatment of diabetes since the 1950s, but new changes suggest the consideration of SGLT-2 inhibitors or GLT-1 agonists.

In the United States, an estimated 28.7 million people are currently diagnosed with diabetes.1.2 Type 2 diabetes mellitus (T2DM) accounts for approximately 90% among the diagnosed population.

The prevalence of T2DM has increased dramatically over the years and is largely associated with other comorbid conditions including, but not limited to obesity, chronic kidney disease (CKD), atherosclerotic cardiovascular disease (ASCVD), as well as rising micro- and macrovascular complications.

The American Diabetes Association (ADA) publishes a comprehensive guideline on the treatment of diabetes annually as the disease continues to develop. There has been a notable change in the 2022 Standards of Medical Care in Diabetes regarding first-line pharmacological therapy for T2DM.

The ADA now recommends a patient-centered approach following T2DM diagnosis. Metformin has been the drug of choice for the treatment of diabetes since the 1950s, but due to the pathophysiology of diabetes and its associated comorbidities, it is now preferred to use newer and more patient specific forms of therapy.

The new guideline states that other drugs, specifically glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose co-transporter 2 (SGLT2) inhibitors, can be initiated independently of A1C and metformin therapy, particularly for the individuals at high risk for heart failure, CKD, and/or ASCVD. Both classes offer cardiovascular benefits and lower all-cause mortality while promoting the benefits metformin provides, such as glycemic control and weight loss.1.3

Patients with T2DM are 2 to 4 times more likely to develop cardiovascular (CV) diseases due to increased risk factors, such as hypertension, obesity, and hyperlipidemia.4 Current guidelines emphasize reducing blood pressure in T2DM patients to avoid CV events that propelled interest GLP-1 receptor agonists, which can treat hyperglycemia and its complications.

A meta-analysis of the LEAD trials, which tested the efficacy of liraglutide compared to standard treatment, found that the usage of liraglutide reduced systolic blood pressure (between -2.7 and -6.6 mmHg), LDL-C (-7.73 mg/dL) , total triglycerides (5.03 mg/dL), and reduction of HbA1c levels (-1.2%).5 According to the ADVANCE study, a 4 year-long analysis on the usage of hypertensive agents on macrovascular and microvascular outcomes in T2DM, a reduction in 5.6 mmHG systolic pressure and 2.2 diastolic pressure reduced the risk of CV deaths by 18%.

GLP-1’s cardioprotective benefits and glycemic control make it an ideal agent for the treatment of type 2 diabetes with comorbidities.6 In fact, in a retrospective database analysis, 39,275 patients who initiated exenatide therapy had lower rates of CVD-related hospitalization (P=0.02), CV-events (P<0.01), and all-cause hospitalization (P=0.01) compared to the non-exenatide-treated patients.7

SGLT2 inhibitors have recently been tested in several clinical trials for cardiovascular safety and diabetes mellitus efficacy. The EMPA-REG study (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) was a randomized, double-blind, parallel-group, placebo-controlled, phase 3 trial that investigated empagliflozin at high and low doses in comparison to placebos, with a total of 7064 participants.

The primary endpoint was the time to first occurrence of major adverse CV events (MACE), such as CV death, non-fatal myocardial infarction, and non-fatal stroke. The study included patients on non-pharmacological therapy (diet and exercise) who were drug naive or pre-treated with unchanged anti-diabetic therapy in the prior 12 weeks, and HbA1c range of >7% and ≤9% or >7% and ≤10%, respectively. The final outcome of the trial reported that empagliflozin (10.5%) is superior to placebo (12.1%) in improving glycemic control and reducing CV events in T2DM patients.

Another clinical trial involving SGLT2 that specifically investigated the cardiovascular benefit against established heart failure was DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure). DAPA-HF was a randomized, double-blind, placebo-controlled, phase 3 trial, which tested the efficacy and safety of dapagliflozin in individuals with heart failure, regardless of the presence of diabetes.

The study enrolled 4744 participants and the primary endpoint was a composite of CV death, hospitalization due to heart failure, or urgent visit due to heart failure. The composite outcome occurred in 16.3% of the dapagliflozin group (386/2373) and in 21.2% of the placebo group (502/2371).8th

Each of the individual outcomes of the composite were less common in the dapagliflozin group and this study further supported that there is a substantial, clinically significant cardiovascular benefit to the SGLT2 inhibitors, especially in individuals with a history significant for heart failure.

For individuals currently diagnosed with T2DM, these new guidelines have little effect on their pharmacotherapeutic regimen and would still involve metformin, either as monotherapy or combination therapy. However, for the estimated 96 million people with pre-diabetes and the growing number of patients with gradual diabetes onset, the new guidelines present health care professionals with options to better manage the progressive nature of T2DM and prevent unwanted outcomes from, or resulting in, comorbid conditions.

Although metformin is safe, effective, and relatively inexpensive, it does not provide patients with a more targeted therapy, nor can it be initiated regardless of A1C.

About the Authors

Kevin Nguyen PharmD, PGY-1 Pharmacy Resident at Einstein Medical Center Philadelphia.

Anita Hu, PharmD Candidate 2024 at Temple University School of Pharmacy.

Jessica Cho, PharmD Candidate 2024 at Temple University School of Pharmacy.

Monida Tum, PharmD Candidate 2024 at Temple University School of Pharmacy.

References

1. American Diabetes Association. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2021. diabetes care. 2021; 44 (Supplement 1): S111-S124. https://doi.org/10.2337/dc21-S009

2. National diabetes statistical report. Centers for Disease Control and Prevention. 2022. https://www.cdc.gov/diabetes/data/statistics-report/index.html

3. American Diabetes Association Professional Practice Committee. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2022. diabetes care. 2022; 45 (Supplement_1): S125-S143. https://doi.org/10.2337/dc22-S009

4. Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA. 1979; 241(19):2035-2038.

5. Plutzky J, Garber A, Toft AD, Poulter NR. Meta-analysis demonstrates that liraglutide, a once daily human GLP-1 analogue significantly reduces lipids and other markers of cardiovascular risk in T2DM. diabetologicals. 2009; 52:S299.

6. Patel A; ADVANCE Collaborative Group, MacMahon S, Chalmers J, Neal B, Woodward M, Billot L, Harrap S, Poulter N, Marre M, Cooper M, Glasziou P, Grobbee DE, Hamet P, Heller S, Liu LS, Mancia G, Mogensen CE, Pan CY, Rodgers A, Williams B. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomized controlled trial. lancet. 2007; 370(9590):829-40. doi: 10.1016/S0140-6736(07)61303-8. PMID: 17765963.

7. Best JH, Hoogwerf BJ, Herman WH, Pelletier EM, Smith DB, Wenten M, Hussein MA. Risk of cardiovascular disease events in patients with type 2 diabetes prescribed the glucagon-like peptide-1 (GLP-1) receptor agonist exenatide twice daily or other glucose-lowering therapies. diabetes care. 2011; 34(90). http://dx.doi.org/10.2337/dc10-1393

8. McMurray, JJV, Solomon, SD, Inzucchi, SE, Køber, L., Kosiborod, MN, Martinez, FA, Ponikowski, P., Sabatine, MS, Anand, IS, Bělohlávek, J., Böhm, M., Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukát A, Ge J, … Langkilde A-M. (2019). Dapagliflozin in patients with heart failure and reduced ejection fraction. New England Journal of Medicine, 381(21), 1995-2008. https://doi.org/10.1056/nejmoa1911303

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