Dr Aidin Rawshani

When metformin and lifestyle changes are not enough


New drugs for type 2 diabetes: which is best?

Approximately 400,000 Swedes are diagnosed with type 2 diabetes and most likely this is an underestimate because many people have the disease without knowing it (diabetes does not have to cause any symptoms). Over the past 20 years, healthcare has made great success in terms of morbidity and mortality among people with diabetes. This actually applies to both type 2 and type 1 diabetes. Research from Sweden shows that there has been a dramatic decrease in mortality, coronary heart disease and other cardiovascular diseases (see below).

Denna graf visar hur den totala dödligheten, samt död till följd av hjärt-kärlsjukdom, minskat sedan 1998 bland personer med typ 2 diabetes. De blå linjerna representerar trender för personer med typ 2 diabetes och de röda linjerna representerar den övriga befolkningen.
This graph shows how overall mortality, as well as death from cardiovascular diseases, decreased since 1998among people with type 2 diabetes. The blue lines represent trends for people with type 2 diabetes and the red lines represent the rest of the population. These data are from the National Diabetes Register (NDR). Source: Rawshani et al (The New England Journal of Medicine, 2016).

Despite this, people with type 2 diabetes still have high mortality and risk of cardiovascular disease. Drug development has developed over the last decade several drugs that improve blood sugar and which hopefully will improve the survival and quality of life of people with type 2 diabetes. The most successful, of the new, medicines are the following groups:

  • DPP4 inhibitors – This group includes Januvia, Galvus, Onglyza, Trajenta
  • GLP-1 agonists – This group includes Bydureon, Byetta, Saxenda, Victoza, Luxumia, Trulicity
  • SGLT2 inhibitors – This group includes Forxiga, Invokana, Jardiance.

Today, it is considered that these drugs should be used if satisfactory sugar control with metformin and lifestyle changes is not achieved. There is evidence that SGLT-2 inhibitors have very good efficacy and dramatically reduce the risk of cardiovascular disease and death. Unfortunately, these three drugs have never been directly compared against each other, which means that we can not say for sure which one is the best (i.e., has the least side effects and the best effect on the risk of cardiovascular disease). Fortunately, a study has now been published, comparing these three drug classes via statistical methods.

The study was published in the prestigious journal JAMA and has attracted great interest. Note that in this study, only the effect of these drugs on cardiovascular disease and death was compared. Therefore, adverse reactions have not been compared. The study, which weighed the results of a wide range of studies, included 176310 patients.

Results of the study

  • SGLT-2 inhibitors resulted in a 20% reduction in relative risk of death. SGLT-2 inhibitors also reduced the risk of cardiovascular disease and heart failure.
  • GLP-1 inhibitors resulted in a 12% reduction in the relative risk of death. GLP-1 inhibitors also reduced the risk of cardiovascular disease. GLP-1 inhibitors brought a higher risk of side effects that allowed treatment to be discontinued (compared with SGLT-2 inhibitors).
  • DPP4 inhibitors did not reduce the risk of death.
  • SGLT-2 inhibitors and GLP-1 inhibitors were more effective than DPP4 inhibitors.

Conclusion: SGLT-2 inhibitors and GLP-1 inhibitors reduce the risk of death and cardiovascular disease. The effect seems to be better for SGLT-2 inhibitors. DPP4 inhibitors do not reduce the risk of death.

What does this mean for those who have type 2 diabetes?

The message is that if lifestyle changes and metformin are inadequate, then several drugs remain to try. Controlling your blood sugar is extremely important if you have type 2 diabetes. Needless to say, rearrangement of the diet, increased exercise and metformin are still the basic bolts in treatment. Thus, the above drugs are used when the foundation bolts are insufficient. There is quite strong scientific support that these newer drugs are effective and that they can even reduce the risk of cardiovascular disease and death. The best effect is likely to have SGLT-2 inhibitors. However, it should be emphasised that several studies have reported a slight increased risk of amputation of toes when using SGLT-2 inhibitors. So far, however, it has been considered that this risk is small compared to the benefits of the medicine (i.e. reduced risk of death, cardiovascular disease and heart failure).

What does this mean for those who have type 1 diabetes?

Type 1 diabetes has been treated with insulin alone for almost 100 years. It is only recently that doctors and scientists tried using tablets to lower blood sugar. However, this is an area that is still under development and at the moment no recommendations can be made. At the moment, several studies are underway in which SGLT-2 inhibitors are being tested in type 1 diabetes and it appears to work, but major studies are still needed to be able to express their opinion on safety and efficacy.

Read the article: Association Between Use of Sodium-Glucose Cotransporter 2 Inhivents, Glucagon-like Peptide 1 Agonists, and Dipeptidyl Peptidase 4 Inhigors With All-Cause Mortality in Patients With Type 2 Diabetes A Systematic Review and Meta-Analysis.


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