Apart from CVD, patients living with diabetes are also at increased risk of kidney disease. According to the American Centers for Disease Control and Prevention, one in three patients living with diabetes has kidney disease. Kidney damage caused by diabetes usually occurs over a long period and is exacerbated by hypertension and hyperglycaemia.³ 

Lifestyle management and cardioprotective therapeutics vital tools in preventing CVD 

According to a 2022 scientific statement by the American Heart Association, lifestyle management (eg diabetes self-management education and support, medical nutrition therapy to encourage weight reduction if needed, physical activity, smoking cessation, psychosocial care), and cardioprotective therapeutics as vital tools in the primary and secondary prevention of CVD in patients living with T2DM.¹  

Several pharmacotherapeutics are available for the effective management of patients living with T2DM. These include for example insulin, metformin, sulfonylureas, and glitazones.⁴  

However, one of the drawbacks of these agents is that they have limited efficacy in improving CV outcomes in patients living with T2DM. According to Rieg and Vallon, some of these agents may even increase the risk of CV mortality.⁴  

Numerous studies have shown that sodium-glucose cotransporter 2 inhibitors (SGLT2i), first approved in 2013, are not only effective in reducing the risk of hypoglycaemia, but also offer cardio- and renal-protection.⁴ 

Cardio-protective effects 

The Dapagliflozin Effect on Cardiovascular Events (DECLARE-TIMI 58) study examined the efficacy and safety of dapagliflozin 10mg, compared with placebo, in addition to standard of care. The trial enrolled >17 000 people with T2DM who either had existing CVD, or no established CVD but with multiple risk factors. The latter group accounted for >10 000 of the participants.^5,6  

DECLARE-TIMI 58 had two primary efficacy endpoints: Major adverse cardiovascular events (MACE), defined as CV death, myocardial infarction (MI), or ischaemic stroke – together referred to as 3P-MACE.⁵  

Treatment with dapagliflozin resulted in a lower rate of CV death or hospitalisation due to heart failure (HF) versus placebo (4.9% versus 5.8%). This reduction in composite rate reflected a lower rate of hospitalisation due to HF alone.⁵  

In patients with prior MI, dapagliflozin was associated with a 16% relative reduced risk in 3P-MACE and a 2.6% absolute risk reduction versus placebo (15.2% versus 17.8%).⁷ 

Reno-protective effects 

SGLT2is reduce intraglomerular pressure, thereby preventing kidney disease and slowing its progression. The renal-protective effects associated with SGLT‐2 inhibitors are generally observed over a wide range of estimated glomerular filtration rate (eGFR) ranges and albuminuria categories.⁸ 

Beernink et al recently (2023) showed that dapagliflozin reduces CV and kidney events in patients with T2DM and chronic kidney disease (CKD) across baseline background glucose-lowering therapy.⁹  

Beernik et al’s study included >4000 adult patients with a baseline eGFR 25ml/min/1.732 to 75mL/min/1.73 m² and a urinary albumin-to-creatinine ratio of 200mg/g-5000mg/g. Patients were randomised to dapagliflozin 10mg or placebo once daily. The primary endpoint was a composite of ≥50% eGFR decline, end-stage KD, and kidney or CV cause of death.⁹  

Secondary endpoints included a kidney composite endpoint (primary composite endpoint without CV death), a CV composite endpoint (hospitalisation due to HF or CV death), and all-cause mortality.⁹  

The team showed that the effects of dapagliflozin on the primary composite outcome were consistent across glucose-lowering classes. Similarly, they found consistent benefit of dapagliflozin compared with placebo on the secondary endpoints regardless of background glucose-lowering class or number of glucose-lowering therapies.⁹  

The same applied to the rate of decline in the eGFR rate and safety endpoints. Dapagliflozin reduced the initiation of insulin therapy during follow-up.⁹ 

Despite efficacy, why are SGLT2i inhibitors underutilised? 

A number of international medical societies including the American Diabetes Association (ADA), American College of Cardiology (ACC), Kidney Disease: Improving Global Outcomes (KGIDO), the European Society of Cardiology (ESC) in collaboration with the European Association for the Study of Diabetes (EASD) and the National Institute for Health and Care Excellence (NICE), recommend the use of SGLT‐2 inhibitors in T2DM management (see table 1). However, prescription rates in patients with T2DM remain low in day‐to‐day clinical practice.^8,12,13 

Table 1: International guideline recommendations for the use of SGLT2is ^8,12,13 

Despite the evidence of the CV and renal benefits of SGLT2is, as well as other newer options such as glucagon-like peptide-1 receptor agonists (GLP-1RA), sulphonylureas (46%) remain the most popular second-line anti-diabetic drug class followed by dipeptidyl peptidase 4 (20%).¹⁰ 

A review by Elliott-Knapp showed that between 2018 and 2020, only 11%-14% of American adults with T2DM receive treatment with a SGLT2i or a GLP-1RA despite clear indications for their use.¹¹   

What are some of the barriers to the uptake of SGLT2is? Barriers include:^8,14  

• Inconsistencies within the current clinical guidelines for second‐line therapy in T2DM. 
• Lack of knowledge about SGLT2is – especially among cardiologists: Cardiologists are among the lowest prescribers of SGLT‐2is (< 1%‐< 5%) despite these agents’ proven cardio- and renoprotective benefits. 
• Uncertainty as to how to define specific indications: For example, the clinical definitions of CVDs such as congestive HF and HF with reduced ejection fraction, differ or may be challenging to diagnose in general practice. 
• Differences in the prescribing information across SGLT‐2is: May cause confusion among clinicians (eg the permitted prescribing eGFR range for glycaemic control in patients with T2DM can vary across SGLT‐2is). 
• Concerns over side effects - particularly in primary care: Rare side effects potentially related to empagliflozin, canagliflozin, and ertugliflozin use include urosepsis (0.4%) and pyelonephritis (0.3%). The safety profile of SGLT2is is nevertheless well established. 
• Therapeutic inertia among clinicians: May play a role in the lack of uptake of this class of drugs, with many clinicians continuing to focus on glycaemic control as the primary outcome in the treatment of T2DM. 
• Affordability and access to SGLT2is: Studies show that SGLT2is may be more cost‐effective than insulin and sulphonylureas and are associated with increased quality‐adjusted life years because of weight loss and decreased prevalence of CV morbidities. 

Conclusion 

Acharya and Deedwania stress clinicians need to embrace the evidence and switch from traditional anti-diabetic medications to newer proven CV benefits.¹⁵ 

With more affordable SGLT2is entering the South African market, there is a need to switch from traditional anti-diabetic agents to newer therapies with proven cardio-renal benefits.  

References 

1. Joseph JJ, Deedwania P, Acharya T, et al. Comprehensive Management of Cardiovascular Risk Factors for Adults With Type 2 Diabetes: A Scientific Statement From the American Heart Association. Circulation, 2022. 
2. Martín-Timón I, Sevillano-Collantes C, Segura-Galindo A, et al. Type 2 diabetes and cardiovascular disease: Have all risk factors the same strength? World J Diabetes, 2014 Aug 15;5(4):444-70. doi: 10.4239/wjd.v5.i4.444. PMID: 25126392; PMCID: PMC4127581. 
3. Centers for Disease Control and Prevention. Chronic Kidney Disease in the United States, 2019. Atlanta, GA: US Department of Health and Human Services. Centers for Disease Control and Prevention; 2019. 
4. Rieg T, Vallon V. Development of SGLT1 and SGLT2 inhibitors. Diabetologia, 2018 Oct;61(10):2079-2086. doi: 10.1007/s00125-018-4654-7. Epub 2018 Aug 22. PMID: 30132033; PMCID: PMC6124499. 
5. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med, 2019;380:347–357.  
6. Raz I, Mosenzon O, Bonaca MP, et al. DECLARE-TIMI 58: participants’ baseline characteristics. Diabetes Obes Metab, 2018;20:1102–1110. 
7. Furtado RHM, Bonaca MP, Raz I, et al. Dapagliflozin and cardiovascular outcomes in patients with type 2 diabetes and previous myocardial infarction: subanalysis from DECLARE TIMI-58 Trial. Circulation, 2019;139(22):2516–27. 
8. Khunti K, Jabbour S, Cos X, et al. Sodium-glucose co-transporter-2 inhibitors in patients with type 2 diabetes: Barriers and solutions for improving uptake in routine clinical practice. Diabetes Obes Metab, 2022 Jul;24(7):1187-1196. doi: 10.1111/dom.14684. Epub 2022 Mar 30. PMID: 35238129; PMCID: PMC9313799. 
9. Beernink JM, Persson F, Jongs N, et al. Efficacy of Dapagliflozin by Baseline Diabetes Medications: A Prespecified Analysis From the DAPA-CKD Study. Diabetes Care, 2023 Mar 1;46(3):602-607. doi: 10.2337/dc22-1514. PMID: 36662635; PMCID: PMC10020024. 
10. Montvida O, Shaw J, Atherton JJ, et al. Long-term Trends in Antidiabetes Drug Usage in the US: Real-world Evidence in Patients Newly Diagnosed With Type 2 Diabetes. Diabetes Care, 2018 Jan;41(1):69-78. doi: 10.2337/dc17-1414. Epub 2017 Nov 6. PMID: 29109299. 
11. Elliot Knapp D. US Underuse of GLP-1RA, SGLT-2i in Type 2 Diabetes Persists. [Internet]. 2022. Available from: https://www.medscape.com/viewarticle/968488 
12. El Sayed NA, Aleppo G, Aroda VR, et al.  Summary of Revisions: Standards of Care in Diabetes—2023. [Internet]. Available from: https://diabetesjournals.org/care/article/46/Supplement_1/S5/148048/Summary-of-Revisions-Standards-of-Care-in-Diabetes 
13. American Diabetes Association Professional Practice Committee. Addendum. 11. Chronic Kidney Disease and Risk Management: Standards of Medical Care in Diabetes—2022. Diabetes Care 2022;45(Suppl. 1): S175–S184. [Internet]. Available from: https://diabetesjournals.org/care/article/45/9/2182/147052/Addendum-11-Chronic-Kidney-Disease-and-Risk 
14. Nishi L, Ghossein C, Srivastava A. Increasing Sodium-Glucose Cotransporter 2 Inhibitor Use in CKD: Perspectives and Presentation of a Clinical Pathway. Kidney Med, 2022 Mar 12;4(5):100446. doi: 10.1016/j.xkme.2022.100446. PMID: 35498158; PMCID: PMC9052139. 
15. Acharya T and Deedwania PC. The Role of Newer Anti-Diabetic Drugs in Cardiovascular Disease. American College of Cardiology.[Internet]. 2018. Available from: https://www.acc.org/Latest-in-Cardiology/Articles/2018/05/22/16/59/The-Role-of-Newer-Anti-Diabetic-Drugs-in-CV-Disease