Healthier hearts in Type 2 diabetes

Dr Angela Murphy educates us about new drugs that treat Type 2 diabetes and decrease the risk of heart disease.

I asked several of my patients what concerns them most about having diabetes. The answers were fairly consistent: high sugar levels, losing vision, amputations, kidney failure and needing dialysis, and dying early.

However, cardiovascular disease (CVD) which consists of heart attacks, heart failure and stroke is the cause of complications and death in two-thirds of patients with Type 2 diabetes. It would make sense to have treatment for diabetes that not only decreased the blood sugar but also the risk of heart disease.

In 2008, the Federal Drug Administration (FDA) in the USA stipulated that all new diabetic agents would need to prove that they do not increase the risk of CVD. This was in the wake of a medication (Rosiglitazone – insulin sensitiser) that had to be withdrawn due to adverse cardiac effects. Only Pioglitazone remains available from that group.  


The first of the new medications to market – the gliptins or DPP1V inhibitors – showed they were safe but did not improve cardiac outcomes. However, two new agents have, remarkably, done just that: empagliflozin (Jardiance) and liraglutide (Victoza).


This is a sodium glucose transport receptor (SGLT)-2 inhibitor. It acts by stopping the reabsorption of glucose in the kidney. Excess glucose is excreted in the urine which results in the lowering of blood glucose levels. This is accompanied by an estimated loss of 280kcal/day which contributes to a decrease in weight. There is also fluid and sodium losses resulting in blood pressure lowering and improvement in heart function.

The excellent results from the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–Removing Excess Glucose (EMPA-REG OUTCOME) trial, allowed the FDA to add another indication for treatment with Empagliflozin.  Empagliflozin is now registered:

  1. as an adjunct to diet and exercise to improve glycaemic control in adults with Type 2 diabetes mellitus.
  2. to reduce the risk of cardiovascular death in adult patients with Type 2 diabetes mellitus and established CVD.

In this ground-breaking trial, over 7000 patients with Type 2 diabetes were shown to have had a 38% relative risk reduction (RRR) in cardiovascular death with empagliflozin compared with placebo. There was also a statistical reduction in hospitalisation for heart failure, as well as a drop in all causes of death.

CANVAS programme

There are two other drugs in the SGLT-2 inhibitor class, viz. dapagliflozin (Forxiga) and canagliflozin (Invokana). The recent CANagliflozin CardioVascular Assessment Study (CANVAS) programme also reported a significant reduction in cardiovascular disease and hospitalisations for heart failure.

Over 10 000 patients with Type 2 diabetes were enrolled in the study with a third of the patients not yet having documented heart disease but they had to have two or more risk factors (hypertension, hyperlipidaemia or obesity).

This is exciting to know that the protection is also for patients who have not developed heart disease.

A concern with the use of Invokana was the reported increase in amputations, mainly of the toes but some leg amputations too. Patients with diabetic foot problems should probably not receive Invokana.

CVD-REAL study

It is possible that the SGLT-2 inhibitors as a class will be cardioprotective. The Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors (CVD-REAL) study shows just that.

This is a study that looked at 154 528 patients who received a SGLT-2 inhibitor from their own doctor for the first time. The results were compared with other classes of glucose-lowering drugs. Again, there was a significant improvement in hospitalisation for heart failure and reduction in all cause of deaths.

Only 13% of the patients had established cardiovascular disease which implies a benefit for the broader Type 2 diabetes population. In the USA, canagliflozin was the drug most used whereas in Europe it was dapagliflozin. This supports the idea of a class effect.


This is the second diabetic drug to receive cardiovascular approval from the FDA. Liraglutide is a glucagon like peptide-1 (GLP-1) agonist.

GLP-1 is a hormone released in the gut in response to food. GLP-1 then stimulates the pancreas to produce insulin. In Type 2 diabetes, this system is sluggish so a great deal of research has focussed on restoring this important system.

Liraglutide is a synthetic version of GLP-1 and when given (via subcutaneous injection), it raises the GLP-1 levels to above normal. In addition to the glucose lowering effects from stimulating the pancreas, liraglutide slows down gastric emptying, dampens the appetite centre and protects the heart muscle from damage in the event of a heart attack.

LEADER trial

The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results—A Long Term Evaluation (LEADER) trial showed a 13% reduction in the combined endpoint of heart attack, stroke and cardiovascular death compared with placebo.

The official FDA approved package leaflet now reads that liraglutide is indicated:

  • as an adjunct to diet and exercise to improve glycaemic control in adults with Type 2 diabetes mellitus.
  • as an adjunct to standard treatment of cardiovascular risk factors to reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal heart attack, or non-fatal stroke) in adults with Type 2 diabetes mellitus and high cardiovascular risk.

Current label indications

It is important to note that at this time the FDA label indications for these two drugs, Jardiance and Victoza, is for those people with diabetes and current heart disease.

The results of the CANVAS trials, as well as other ongoing trials, will allow the FDA to consider indications in the future for these medications to help reduce heart complications in those people with diabetes who have risk factors for but no known cardiovascular disease.

Should a Type 2 diabetes patient change his/her medications?

It is always important to review a prescription, especially with patients with diabetes. If sugar control is poor, if more cardiovascular risk factors have been identified, or if a patient has had a heart attack, stroke or been hospitalised for heart failure, it would be very valuable to consider changing or adding these new classes of medications.


Liraglutide, empagliflozin and dapagliflozin are available in South Africa. However, they are not available in the public sector and medical aids may not always fund them. Hopefully, as evidence continues to build of the importance of the extra benefits of these glucose lowering medications, they will become more accessible for all patients with Type 2 diabetes.


Dr Angela Murphy is a specialist physician working in the field of Diabetes and Endocrinology in Boksburg. She is part of the Netcare Sunward Park Bariatric Centre of Excellence as well as a specialist with the Centre for Diabetes Excellence (CDE) network.