NEW THERAPIES 

Despite the therapeutic options available, the morbidity and mortality of people living with type 2 diabetes remain high. New therapy research solutions should regularly be investigated when dealing with people living with type 2 diabetes who also have heart failure (HF).^1a,2a

One group of medicines that form part of the four pillars of treating people living with type 2 diabetes is SGLT-2 inhibitors. Since type 2 diabetics are at high risk of developing or have, an established cardiovascular disease (CVD), SGLT2-2 inhibitors studies undertaken have proven to reduce cardiovascular (CV) events and mortality. SGLT-2 inhibitors are further recommended as part of the glucose-lowering regimen independent of HbA1c. 

SGLT-2 INHIBITORS 

The rationale behind the use of SGLT-2 inhibitors in the managements of people living with type 2 diabetes and HF can be explained by first looking at their mechanism of action. 

The mechanism of action^1a,2a 

SGLT-2 inhibitors block the absorption of glucose in the proximal tubules of the kidney – this leads to: 

• Increased excretion of glucose in the urine (glucosuria) – which also leads to loss of sodium (natriuresis) 
• The sodium and glucose that are excreted will draw water with them thus leading to a diuretic effect.^1a,2a

Since patients with HFrEF are driven by failure of the heart to pump and fluid overload, SGLT-2 inhibitors would thus be a good option of the four pillars of management. 

R&D of SGLT-2 inhibitors 

Extensive trials investigating the different types of SGLT2-inhibitors on CV outcomes have been undertaken. Some of these include EMPA-REG trial (empagliflozin), DECLARE-TIMI-58 trial (dapagliflozin), CANVAS trial (canagliflozin), EMPEROR-REDUCED trial (empagliflozin), and DAPA-Heart Failure trial (dapagliflozin).^1-5 

Benefits of SGLT-2 inhibitors^1a,2a 

In the management of type 2 diabetes and HF the desired effect would be to: 

• Decrease the fluid overload 
• Increase the pump action and after-load 
• Improve myocardial contractility. 

SGLT-2 inhibitors have been shown to benefit all three of the above areas. 

Additionally, SGLT-2 inhibitors also:^1a,2a 

• Modulate glucose metabolism in the myocardial cells, which improves the efficacy of localisation of glucose by these cells (hypoglycaemia effect), which in turn will also lead to decrease in HbA1c 
• Induces a drop in blood pressure (given the relationship between type 2 diabetes and hypertension) 
• Causes weight loss (which contributes towards improved management of the metabolic syndrome).^1a,2a

The early introduction of SGLT-2 inhibitors in the treatment cascade have shown to be beneficial. 

When should SGLT-2 inhibitors be introduced? 

The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) suggested the following: 

• If a patient has chronic kidney disease (CKD) or HF a SGLT2-inhibitor should be prescribed (irrespective of base line or target HbA1c)^1b,1c 
• If the patient has established atherosclerotic CVD, or is at high risk thereof, (e.g., patients > 50 years of age; +> 50% of narrowing of their carotid, coronary or lower extremity arteries, or with LVH [left ventricular hypertrophy]), then preference is first given to glucagon-like peptide-1 receptor agonists (GLP-1 RA) 

• Should the patient not tolerate a GLP-1 RA, an SGLT-2 inhibitor should be introduced.⁶

Considering the management of patients diagnosed with CVRM disorder, and their interplay, all people living with type 2 diabetes should be screened for CKD, HF, and atherosclerotic CVD. Management with appropriate medicines should be aimed to improve patients’ mortality and morbidity, reducing adverse outcomes as well as a reduction of hospitalisation.^{1b, 1c ,2a}

Precautions with SGLT-2 inhibitor therapy^1b,2b

Patients should be warned about the: 

• Potential effect of diabetic ketoacidosis (DKA) and when DKA signs are experienced, e.g., nausea, abdominal pain, dyspnoea, or general feeling unwell that therapy should be terminated (after consulting with their cardiologist) 
• Concomitant use of volume-depleting agents, e.g., diuretics, may put the patient at risk of hypotension – therefore the doses of diuretics and antihypertensive agents need to be reduced or stopped (after consulting with their cardiologist) 
• Fact that they should not be dehydrated, and that treatment with SGLT-2 inhibitors should be stopped (after consulting with their cardiologist) 
• Increased risk of genital and UTIs.^{1b, 2b}

THE MODERN APPROACH TO HEART FAILURE WITH REDUCED EJECTION FRACTION 

Management of patients with HFrEF, according to the 2020 South Africa Heart Failure Society guidelines, (which is based primarily on the European Society of Cardiology [ESC] guidelines) suggest the following:⁷

• Reduce the mortality rate 

• Reduce the extent of recurrent hospitalisations for HF 

• Improve functional capacity, clinical status and quality of life.⁷ 

Renin-angiotensin-aldosterone system inhibitors (RAAS), beta-blockers and mineralocorticoid receptor antagonists (MRAs) remain the cornerstone of therapy and should be initiated as soon as possible. This is particularly important when diuretic therapy is being contemplated to prevent the worsening of HF.  

All HF medicines should be initiated at low doses and up titrated every 2-3 weeks. Careful monitoring of the patient’s HF symptoms, the presence of side effects, heart rate and blood pressure, renal function, and potassium levels should be considered as main objectives. 

Guidelines support replacing a RAAS inhibitor with an angiotensin receptor neprilysin inhibitor (ARN) inhibitor in patients who remain symptomatic despite the optimal treatment with a RAAS inhibitor, beta-blocker and MRA. 

New therapeutic recommendations of the 2020 released SA Heart Failure Guidelines focussed on the positioning of SGLT-2 inhibitors in the management cascade, and to further find evidence from the DAPA Heart Failure trial and the EMPEROR-REDUCED study.⁷ 

At the time after these guidelines were published, the only published study which indicated the beneficial effects of SGLT-2 inhibitors in patients with HFrEF (with or without diabetes) was the DAPA Heart Failure study (dapagliflozin). Therefore the emphasis on dapagliflozin’s use in the guidelines were due to the fact that there was no certainty whether this beneficial effect was a class effect or a specific medicine effect. 

After the publication of the 2020 South African Heart Failure Guidelines, trials such as EMPEROR-REDUCED trial, suggested dapagliflozin for the treatment of HFrEF patients. However, the 2021 ESC guidelines, which were published after the EMPEROR-REDUCED trial, recommended that both dapagliflozin and empagliflozin be used in the treatment of patients with HFrEF8. 

Currently no evidence exists on the order of when to initiate SGLT-2 inhibitors compared to beta-blockers and ARN inhibitors in a patient suffering from chronic HF. 

The understanding that the initiation of SGLT-2 inhibitors early in the treatment does not only protect the patient against HF, but also provides protection against renal dysfunction. This treatment strategy might make it easier to add other agents, e.g., MRA inhibitors (e.g., spironolactone) to the treatment regimen because the patient with further renal impairment may have high potassium levels, which may be exacerbated further by the addition of an MRA. 

Trokis (2022) reported that during the 2021 ESC congress a discussion took place about the time of titration in HF patients and that if it was prolonged, and a step through to the four pillars of therapy: RAAS inhibitors/ARN inhibitor, beta-blockers, MRAs and SGLT-2 inhibitors was done in the normal fashion, it might take 56 weeks for the patient to reach the four pillars of therapy and that during this delay, HF patients may suffer a CV event⁹. Later a better sequencing approach10 was published which concluded that clinicians should always aim at getting the patients on these four pillars of therapy as soon as possible. 

This paper suggested two sequencing therapies: 

• Conventional sequencing (which typically is ≥ 6 months):
  • Step 1: ACE inhibitor/ARB (angiotensin-rennin blocker)/ARN (angiotensin receptor neprilysin inhibitor)
  • Step 2: Beta-blocker
  • Step 3: MRA
  • Step 4: SGLT-2 inhibitor. 

• Proposed new sequencing (which should be done within 4 weeks, and thereafter up-titrate to the target)
  • Step 1: Beta-blocker
  • Step 2: ACE inhibitor/ARB/ARN inhibitor
  • Step 3: SGLT2-inhibitor. 

For this four-pillar approach, it will be advisable to introduce it as soon as possible, and where patient’s clinical responses allow up-titration of the dosages. 

RISK CLASSIFICATION FOR TYPE 2 DIABETES PATIENTS 

Risk classification is needed to assist in identifying patients who would benefit from taking the combination of an ARN inhibitor plus a beta-blocker plus a MRA and SGLT-2 inhibitor. 

To lower cost implications of this combination, it is important to identify patients who would benefit most from them. These include: 

• A person living with type 2 diabetes with atherosclerotic disease. Consideration should be placed on whether these patients are taking these medicines. If they are not taking these medications, they should be switched, or these medicines should be added to their treatment.^1a,2a 
• A patient with atherosclerotic disease who thereafter develops diabetes, should be managed by looking at treating their diabetes first and thereafter commencing with the above medicine combinations.^1a,2a 
• Patients who considered to be high risk includes people who have lived with diabetes for > 20 years. The age of the patient and their associated burden of risk in terms of CV risk factors, with or without atherosclerotic CD should also form part of this risk classification.^1a,2a 

As a pharmacist, you need to know the background of what HF is, what the different treatment options and combinations are, and that type 2 diabetic patients with HF needs strategised, rational medical treatment, compiling of the four pillars of agents, namely: RAAS inhibitors/ARN inhibitor, beta-blockers, MRAs and SGLT-2 inhibitors. 

REFERENCES 

This article was based on: 

1a. A MEDTalk presented by: Dr. Martin Mpe. MedTalk. Cardiorenal Series 3, Module 3. Type 2 diabetes and the heart. Martin Mpe. 2021. Available at: https://vimeo.com/560385809/a86135cd92 as well as www.denovomedica.com - accessed: 03 June 2023 

1b. Dr. Julian Trokis. MedTalk ZA. Diabetic Kidney Disease. Early detection and treatment. 2022. Available at: https://player.vimeo.com/video/711152088 as well as www.denovomedica.com - accessed: 05 June 2023 

1c. Dr. Julan Trokis. MedTalks ZA. Managing heart failure. Early detection and treatment. 2022. Available at: https://player.vimeo.com/video/716035589 as well as www.denovomedica.com – accessed: 05 June 2023 

2a. Aalbers, J. Early prevention and management of heart failure in type 2 diabetic patients. deNovo Medica, 2021, July, 1-6 

2b. Aalbers, J. Early intervention in type 2 diabetes to reduce kidney and cardiovascular complications. deNovo Medica, 2022, August, 1-12 

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