1) What were the motivations to develop Jardiance for Type-2 diabetic patients? How is Jardiance different from previous diabetic treatments e.g. Trajenta, TrajentaDuo?
When developing a drug to treat Type-2 diabetes, it is important to develop one that addresses the cardiovascular (CV) safety of the drug beyond glycemia alone. Jardiance was developed with the expectation that it would meet this criteria. As shown by the results from the EMPA-REG outcome clinical trial, Jardiance was indeed found to have demonstrated CV superiority.
The trial showed that Jardiance significantly reduced CV death by 38%, hospitalization for heart failure by 35% and improved survival by significantly reducing all-cause mortality by 32% in high CV risk Type-2 Diabetes Mellitus patients.
Jardiance is also different because it belongs to a newer form of treatment called SGLT2 inhibitors, which is available to adults with type 2 diabetes. SGLT2 inhibitors function by blocking the reabsorption of glucose in the kidneys by helping the body remove the excess glucose through urination. Trajenta and TrajentaDuo, however, belong to a class of inhibitors called DPP-4 inhibitors.
Jardiance also stands apart from the other treatments because it is the first and only drug which has shown cardiovascular risk reduction in a dedicated outcome trial.
2) What should we know about the relative risk of Type-2 diabetes CVD onset?
Type-2 diabetes patients are up to four times more likely to have a heart attack or stroke as people who do not have diabetes. Cardiovascular disease (CVD) is also responsible for around 50 percent of deaths in people with Type-2 diabetes, making it the leading cause of death in diabetes patients.
Other complications such as stroke, all manifestations of coronary heart disease, myocardial infarction, sudden death, and angina pectoris are at least twice more common in patients with Type-2 diabetes compared to non-diabetic patients.
3) Why is Jardiance not recommended for Type-I diabetic patients?
In Type-1 diabetes, the cause of hyperglycemia is the absolute lack of beta cells - these are the endocrine cells producing insulin. Thus, the treatment for Type-1 diabetes is insulin replacement. At the moment, no oral glucose lowering therapies are indicated for patients with Type-1 diabetes.
Type-1 results when all the beta cells of the body are destroyed by auto immune cells; thereby rendering patients with an absolute lack of insulin. This is not hereditary.
Type-2 results from decreased insulin secretion or impaired insulin action or both. This is the most common type of diabetes worldwide. This is hereditary. Environmental factors like sedentary lifestyle and increased caloric intake are known to precipitate the onset of Type-2 Diabetes Mellitus.
In the body, we have SGLT2 which allows for the body to reabsorb sugar from the urine back to the blood. In patients with Type-2 diabetes, it has been shown that SGLT2 are more active than usual leading to further increase in blood glucose levels.
SGLT2 inhibitors such as Jardiance functions by blocking the reabsorption of glucose in the kidneys by helping the body remove the excess glucose through urination. This helps reduce blood glucose, body weight and blood pressure.
4) Tell us more about EMPA-REG OutcomeTM, and if the data collected during the clinical trials may be granted to address other research hypothesis?
The EMPA-REG OUTCOME trial, was a long-term clinical trial which investigated CV outcomes for Jardiance in >7,000 adults with T2D at high risk for CV events. EMPA-REG OUTCOME was a multi-centre, randomised, double-blind, placebo-controlled trial. The study was designed to assess the effect of Jardiance compared with placebo added to standard of care on CV events in adults with Type-2 Diabetes at high risk of CV events. The study was designed to first test for non-inferiority and then for superiority.
Standard of care comprised glucose lowering agents and CV drugs, which includes antihypertensive, lipid lowering agents and anti-platelets. The primary endpoint was the time to first occurrence of CV death, heart attack or non-fatal stroke. The key secondary endpoints were the time to first occurrence of CV death, heart attack, non-fatal stroke or hospitalisation for unstable angina pectoris.
The study only addressed the CV effects of Jardiance. Given the results, it is likely that there will be more questions like ‘how did Jardiance do this?’. The mechanistic reason that has not been addressed in the study. As such, we expect that a lot of studies in the future will be done to address this question.
Pros and Cons of EMPA-REG OUTCOME clinical trial
In a large-scale study such as the EMPA-REG OUTCOME, there will be a lot of challenges, particularly because it is carried out in 42 countries and in 590 sites. A lot of investigators will be involved. Training for all scientists involved in the trial and the recruitment of patients are crucial to the study. Another vital point is the retention of patients in the study – for the study to be very valid, you need to ensure that majority of patients will stay on the trial. For the EMPA-REG-OUTCOME, more than 97% of the patients completed the study and the vital status of more than 99% of the patients was known at the end of the study.
For more detailed information on the results of the study, one can log on to www.empa-reg-outcome.com.
5) Will Jardiance be made as the first line of treatment for Type-2 diabetic patients?
SGLT2 inhibitors as a class is included in the ADA-EASD guidelines on the treatment of hyperglycemia in Type-2 Diabetes Mellitus as one of the possible add-ons to patients not achieving good control on metformin. How the result of the trial will impact the guidelines – we really don’t know at present; although there are already some discussions that the guidelines will change based on the results of the trial.
About the Interviewee
Dr Editha Arceo is the Head of Medical Affairs at Boehringer Ingelheim ROPU SEASK. She was previously the Medical Director of Boehringer Ingelheim Philippines.
Dr Edith graduated from the UERM College of Medicine where she also took up residency in Internal Medicine. She attended the University of Hong Kong for a fellowship in Endocrinology.
Prior to joining Boehringer Ingelheim, Dr Edith was an active consultant in Internal Medicine and Endocrinology at the UERM Medical Center and St Luke’s Medical Center. She was also previously an Associate Professor of Medicine at the UERM College of Medicine and the President of Diabetes Philippines.