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ACC guidance for prescribing SGLT2i, GLP-1RAs to lower risk of CV outcomes

M3 India Newsdesk Dec 17, 2018

The American College of Cardiology (ACC) has released a new consensus decision pathway in November 2018 to guide cardiologists for using the two new classes of diabetes drugs- sodium-glucose cotransporter type 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1RAs).

In patients with type 2 diabetes (T2D), over the past twenty years, the main cause of higher morbidity and mortality continues to be cardiovascular disease. Recently, the chances of preventing CV disease in T2D patients have increased since some drugs have shown significant reductions in the risk of major adverse cardiovascular events (MACE). These drugs include some sodium-glucose cotransporter 2 (SGLT) inhibitors and some glucagon-like peptide 1 receptor agonists (GLP-1RAs).

SGLT2 Inhibitors

The EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial) and the CANVAS (Canagliflozin Cardiovascular Assessment Study) Program (comprising the CANVAS and CANVAS-R trials) were two large randomised, controlled trials in T2D patients, that proved the CV reduction benefits of SGLT2 inhibitors.

  1. EMPA-REG OUTCOME Trial: The patients were randomised on 1:1:1, 10 mg and 20 mg Empagliflozin, or a matching placebo. Of the total 7,028 patients enrolled, 47% had a multivessel disease, 47% had a history of Myocardial infarction (MI), and 25% had undergone coronary artery bypass grafting (CABG). The dosage of SGLT2 inhibitors did not have a significant impact on the reduction of CV outcomes, but the trial proved that Empagliflozin was superior to placebo in lowering CV outcomes.
  2. CANVAS Trial: Unlike the EMPA-REG OUTCOME trial where all enrolled patients had prior CV events, in the CANVAS trial 33% of the patients enrolled had no prior CV events. Canagliflozin showed a 14% 3P-MACE reduction in CV events, similar to Empagliflozin in the EMPA-REG study.

Both trials showed that empagliflozin and canagliflozin can lower MACE (Major Adverse Cardiac Event) and HF (heart failure). However, empagliflozin showed higher (38%) reduction in CV death as compared to 13% by canagliflozin. 

Points to consider before prescribing:

  • SGLT2 inhibitors result in an increased risk of genital mycotic infections such as candida vaginitis in women and balanitis in men, but occur rarely and usually easily resolve with a course of antifungal agents without causing any serious infection
  • Some case reports have shown that there are more chances of diabetic ketoacidosis occurring without significant hyperglycemia, also known as euglycemic diabetic ketoacidosis due to SGLT2 inhibitors


T2D patients show benefits in CV risk reduction from the use of GLP-1RA.  Only liraglutide has positively shown to reduce CV events in comparison with the 6 other FDA approved GLP-1RAs (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide semaglutide). The trials testing the cardiovascular benefits of GLP-1RAs used a 3P-MACE outcome of CV death, non-fatal MI or non-fatal stroke.

9,340 patients in the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial of which 81% had ASCVD or older patients with ASCVD risk (19% of the total) were given either with liraglutide or placebo. On comparing liraglutide with placebo, the reduction in the 3-point MACE composite was 13% (HR: 0.87; 95% CI: 0.78 to 0.97; p = 0.01 for superiority) and the all-cause mortality was reduced by 15% (HR: 0.85; 95% CI: 0.74 to 0.97; p = 0.02)

Points to consider before prescribing:

  • Heart rate of patients can also be increased due to GLP-1RAs
  • Nausea and vomiting are the most common side effects seen with GLP-1RAs
  • Acute cholecystitis can also occur along with an increased risk of gallbladder disease
  • Precautions should be taken for patients with a prior history of gastric surgery
  • In cases of severe renal impairment or end-stage renal disease, liraglutide and semaglutide should be given with caution 
  • Semaglutide has been shown to increase diabetic retinopathy complications, therefore if the patient has not undergone any eye examination in last 12 months, then they should be advised to undergo a guideline-recommended eye examination before starting of the therapy

SGLT2 or GLP-1RAs: Which to prescribe?

  1. Both classes of drugs have demonstrated equal benefits in reducing cardiovascular events. Therefore, the question for cardiologists boils down to a good understanding of what will work for the patient as well as a couple of other factors like: 
  2. Route of administration
  3. SGLT2 inhibitors can be taken orally, whereas GLP-1RAs are administered the subcutaneous route. However, GLP-1RAs can be administered with a small device, so patient acceptance may be higher.
  4. Cost should also be discussed with patients.
  5. Patients who may be at a higher risk or those with heart failure may be benefitted more from SGLT2 inhibitors.
  6. Patients suffering from osteoporosis, or those who have had amputations, severe peripheral artery disease (PAD), or peripheral neuropathy previously, or soft tissue ulcers or infections may have more benefits over risks if they are prescribed GLP-1RAs.

Other key points to consider

  1. Clinicians will face many situations in which they would like to start their patients with either SGLT2 or GLP-1RAs.
  2. The CV outcomes in T2D patients and in those already having ASCVD risk can be improved by some SGLT2 inhibitor and GLP-1RAs.
  3. When new antihyperglycemic therapies are added for cardiovascular benefits, patients taking insulin or insulin secretagogue such as sulfonylurea or glinide should be advised about the risk of hypoglycemic events.
  4. SGLT2 inhibitors or GLP-1 RAs which have CV benefits are recommended for the treatment in T2D patients with clinical ASCVD risk even if they are being treated with metformin.
  5. In those patients in which metformin is contraindicated or if they are not able to tolerate metformin, SGLT2 inhibitors or GLP-1 RAs should be given.
  6. When SGLT2 inhibitors or GLP-1RA are used on their own, or with metformin and other glucose-lowering medication, (except for insulin secretagogues) they offer a lower risk of hypoglycemia.
  7. Non-glycemic benefits in systolic blood pressure and weight are also seen with SGLT2 inhibitors or GLP-1RA usage.
  8. SGLT2 inhibitors have shown CV benefits and they appear to improve both MACE and HF risk even though there is a risk of genital mycotic infection.
  9. Before starting SGLT2 inhibitors, the patient should be educated about the greater risk of genital mycotic infections, and these may be reduced by paying particular attention to personal hygiene. Initial treatment with topical antifungal agents can be given.
  10. SGLT2 inhibitors are administered orally whereas GLP-1RA is administered subcutaneously, and this difference can influence the decision making of the patient and the physician.
  11. After starting SGLT2 inhibitors, the slightly higher risk of euglycemic diabetic ketoacidosis should be informed to the patients. If they see some symptoms associated with diabetic ketoacidosis such as nausea, vomiting, abdominal pain, generalised weakness, they should seek immediate care.
  12. After starting SGLT2 inhibitors, drastic reductions in insulin dosages of more than 20% should be avoided.
  13. GLP-1RA are best started at the lowest dose, with gradual increases of the dose once every few weeks. By doing this and the patient eating smaller portions of meals, nausea and vomiting can be reduced.
  14. In patients treated with longer-acting GLP-1RAs, nausea and vomiting are usually self-limited and it does not signify any gastrointestinal pathology.
  15. Before giving semaglutide, a recent eye examination of the patient should be done.
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