1. UNDERSTANDING THE CONNECTION BETWEEN CARDIOVASCULAR DISEASE (CVD) AND TYPE 2 DIABETES: CARDIORENAL SYNDROME

The relationship between type 2 diabetes and risk factors for patients with a history of atherosclerotic CVD or heart failure (HF) 

Part of understanding the cardiorenal system is to be aware that patients living with diabetes share common risk factors which can lead to cardiac and renal dysfunction. These factors include hypertension, dyslipidaemia, hyperglycaemia, obesity, tobacco use/smoking, and various other issues. These in turn have effects on the: 

• Cardiovascular system e.g., cardiac muscle dysfunction, atherosclerosis, HF, diastolic irregularly, left ventricular hypertrophy (LVH), and for 
• The kidney (renal) system e.g., chronic kidney disease (CKD), acute kidney disease, and various levels of kidney disfunction, albuminuria and reduced glomerular filtration rate (GFR). 

This combination ultimately influences outcomes such as: HF, major adverse cardiac events (MACE) and serious renal effects. Which in turn results in organ damage and disfunction. 

With all these risk factors being considered, there remains a high chance of cardio-metabolic risk and renal disease, which becomes apparent at the point of presentation, namely: an increase in CVD and kidney disease or a combination of both. 

How to reduce cardiovascular risk in people living with type 2 diabetes 

An understanding of cardiovascular risk should also form part of the management of diabetes. It’s important to assess and treat patients in a patient-centred manner. This can be done by: 

• Correct history taking 
• Good clinical examination 
• Good bio-profiling with appropriate blood and urine testing and 
• Consultations with nephrologists, cardiologists, and endocrinologists.^1,2 

The use of evidence-based science to structure the management approach, which reduces risks must include: 

• Lifestyle management at all levels 
• Improving healthy eating habits 
• Exercising regularly 
• Improving adherence to medication 
• Stress control 
• Reducing excessive alcohol use 
• Stop smoking (a major cardiovascular and renal risk factor).^1,2 

Managing type 2 diabetes and CVD 

This interplay play between CVDs and type 2 diabetes has played an important role in the movement of precision medicine in a more detailed way, e.g., determining blood pressure, e-GFR, potassium levels, kidney injury molecules and microalbuminuria.  

Traditional targets used focussed on treating of: 

• HPA1c to < 7% (this results in the improvement of microvascular disease and long-term benefits such as macrovascular risks – although this remains a residual risk) 
• LDLc to < 1.8 mmol/l and  
• Blood pressure to < 140 mmHg.^1,2

But should also have new targets for the cardiovascular and renal targets which are aimed at: 

• Measuring microalbuminuria and  
• GFR.^1,2

Long term goals are aimed at preventing complications, e.g., for the: 

• Cardiovascular system e.g., decreased hospital admission for HF and MACE (e.g., ischemic heart disease, percutaneous interventions, and stroke), and for the 
• Renal system e.g., decreased renal replacement therapy and dialysis.^1,2

The main aim towards targeting treatment in type 2 diabetes is: 

• To prevent complications e.g., hospitalisation for HF 
• To prevent major adverse cardiovascular outcomes 
• To determine the need for renal replacement therapy/dialysis.^1,2

Dapagliflozin, empagliflozin, and canagliflozin (not yet available in SA) are SGLT2 inhibitors that decrease renal glucose reabsorption and increase urinary glucose and sodium excretion.³ This implies that SGLT2 inhibitors exert a diuretic effect which has been suggested as a possible mechanism of the cardiorenal benefit in the EMPA-REG Outcome and CANVAS3 (see point 4). 

Through the expanding of new knowledge about molecules available on the market studies have shown that SGLT-2 inhibitors have various effects on the cardiovascular and renal systems including a decrease in renal disease and MACE. Applying this in a patient centric manner can ensure the best outcomes are reached.

2. THE SCIENCE BEHIND SGLT-2 INHIBITORS AND GLP-1 RECEPTOR AGONISTS

The combination of SGLT2-inhibitors and GLP-1 receptor agonists results in greater outcomes for people living with type 2 diabetes.^4,5,6,7 When treatment is initiated early enough, and HbA1c goals are achieved, this results in lowering of diabetic related morbidity and mortality in early-stage type 2 diabetes. 

One study, in which newly diagnosed people living with type 2 diabetes and those presenting with early sustained glycaemic control, HbA1c equal to 6.5-7.0%, showed a reduction of cardiovascular events.⁶ It was also found that an HbA1c level of ≥ 6.5% in the year after diagnosis was made, had an increased risk of micro- and macrovascular complications, while a HbA1c ≥ 7.0% was associated with an increased risk of mortality.⁷

3. BIO-PROFILING AND PRECISION MEDICINE IN DIABETES THERAPY

The traditional treatment of hyperglycaemia and risk factors which contributes an increased cardiovascular and renal risks, sets the scene for the introduction of a new medicine approach in the management of CVD and renal dysfunction, the so-called ‘precision medicine’ together with a more detailed bio-profiling approach.^1,2

Traditional bio-profiling includes the following:  

• Blood pressure measuring 
• Checking of the glomerulation filtration rate (eGFR) 
• Measuring potassium levels 
• Looking into kidney injury medicines, and  
• Assessing micro-albuminuria.^1,2 

Determining the outcome of the above tests, one can then assess where in the cardiorenal spectrum these patients are and act according with the selection of new medicine therapies which will in turn act on different points of the cardiorenal continuum. 

4. EVIDENCE FOR SGLT-2 INHIBITORS IN THE TREATMENT OF CARDIORENAL SYNDROME

The use of SGLT-2 inhibitors in the treatment of cardiorenal syndrome has become more apparent with new information that has emerged. There are several different clinical trials that illustrate the importance of the different SGLT-2 inhibitors. These include: the EMPA-REG OUTCOME study (empagliflozin), CANVAS (canagliflozin) and the DECLARE-TIMI (dapagliflozin). Table 1, below, indicates the treatment outcomes for both the cardiovascular and renal systems. 

Table 1: Clinical trials used in the management of the cardiovascular and renal systems¹ 

The above results are known as a ‘class effect’ and the findings have significant benefits across the spectrum of people living with type 2 diabetes, and those without diabetes. 

Diabetes, the cardiovascular system, and renal diseases are all interlinked. Therapy should be individualised for each patient. Knowledge of this interplay is important for understanding the rational behind the use of different medicines. 

REFERENCES 

1. This report was based on the MEDTalk presented by Dr. Sundeep Ruder. The source for this video is: Ruder, S.   Type 2 diabetes – target the cardiorenal syndrome. Available at: https://vimeo.com/560386428/256a3b5858 – accessed: 31 May 2023
2. Aalbers, J. Type 2 diabetes – target the cardiorenal syndrome, deNovo Medica 2021 (July).:1-4
3. Zannad F, Rossignol P, Cardiorenal Syndrome Revisited. Circulation. 2018;138(9):929–944. DOI: 10.1161/CIRCULATIONAHA.117.028814 https://www.ahajournals.org/doi/abs/10.1161/CIRCULATIONAHA.117.028814
4. Eickhoff MK, Dekkers CCJ, Kramers BJ, Laverman GD, Frimodt-Møller M, Jørgensen NR, Faber J, Danser AHJ, Gansevoort RT, Rossing P, et al. Effects of Dapagliflozin on Volume Status When Added to Renin–Angiotensin System Inhibitors. Journal of Clinical Medicine. 2019; 8(6):779. https://doi.org/10.3390/jcm8060779
5. Anderson, JE. Combining Glucagon-Like Peptide 1 Receptor Agonists and Sodium–Glucose Cotransporter 2 Inhibitors to Target Multiple Organ Defects in Type 2 Diabetes. Circulation, 2020;33(2):165-174
6. Busch RS, Kane MP. Combination SGLT2 inhibitor and GLP-1 receptor agonist therapy: a complementary approach to the treatment of type 2 diabetes. Postgrad Med 2017; 129:686–697
7. Alatorre CI, Hoogwerf BJ, Deeg MA, et al. Factors associated with stroke, myocardial infarction, ischemic heart disease, unstable angina, or mortality in patients from real world clinical practice with newly-diagnosed type 2 diabetes and early glycemic control. Current Medical Research and Opinion 2018; 34:337–343
8. Laiteerapong N, Ham SA, Gao Y, et al. The legacy effect in type 2 diabetes: impact of early glycemic control on future complications (the Diabetes & Aging Study). Diabetes Care 2019; 42:416–426

ADDITIONAL MATERIAL: 

Sattar N, McLaren J, Kristensen SL, Preiss D, McMurray JJ. SGLT2 Inhibition and cardiovascular events: why did EMPA-REG Outcomes surprise and what were the likely mechanisms? Diabetologia. 2016;59:1333–1339