SGLT-2 Inhibitors: Should They Be The First Line Therapy For Type-2 Diabetes? A Review Of Their Anti-diabetic Effects?
diabetes.co.uk
A review on SGLT-2 inhibitors. This review focuses if SGLT-2 inhibitors are effective to
be called a first-line therapy for type-2 diabetes?
Type 2 diabetes mellitus is a chronic metabolic disease characterized by high blood glucose level (hyperglycaemia) and associated with high cardiovascular risk. SGLT-2 inhibitors are sodium-glucose transporter-2 inhibitors.
SGLT1 and SGLT2 (and GLUT2) are the main players in renal glucose transport and if the inhibition of either SGLT2 or SGLT1 will show how it promotes the inhibition of absorption of glucose from the proximal tubule of the kidney and hence cause glycosuria.
However, SGLT-2 inhibitors not only affect glucose metabolism, but also renal
function, blood pressure and certain levels of adiposity in type 2 diabetes.
This is where their role in the cardiovascular system comes into discussion.
Commercially available SGLT-2i currently in different countries
are canagliflozin, dapagliflozin,
empagliflozin, and ertugliflozin. SGLT2i have also shown to lower the
HbA1C (glycated haemoglobin) 6-8 mmol/mol. But you should also know that the
prominent fact is that they promote this action without the risk of
hypoglycaemia (decreased blood sugar level than the minimum limit).
Cardiovascular trials showed an induced effect on lipid profile, blood pressure
and no weight gain.
Other Anti-Diabetic Medications.
Metformin, as we all know is around here for
decades and it is considered the first-line therapy for type-2 diabetes. But
some reports show that one third to a quarter of the people on metformin
actually experience gastrointestinal side effects. And this leads to
intolerance to metformin and titration of dose.
A glance into other anti-diabetic medications, every class has its own drawbacks. Well, I am not saying SGLT-2i are better than any of the other class available, But it’s clear that it has a slight upper hand when it comes to immediate action, measuring of response in hours and almost no titration of dose. It works for everyone and also no weight gain recorded.
On the other hand, if we were to look at thiazolidinediones, the response has to be measured in months only. Sulphonylureas and GLP-1 receptor agonist have their own issues. As we go further, you should also know that there are significant side effects to SGLT-2i unique to them like genital tract infections, lower leg amputations, electrolyte disturbances and bone fractures. But as a matter of fact, these side effects can be mitigated.
Physiological Role
Kidneys are a pair of bean-shaped organs on either
side of your spine, below your ribs and behind your belly, and have millions of
nephrons in them; which are the functional units of kidneys.
Now, the glucose filtered by the glomerulus of the kidney is reabsorbed by the proximal tubule of the kidney and surprisingly a healthy kidney can reabsorb about 180g of glucose.
There are cells within the lining of our intestines, and if you study them, we can see two types of glucose transporters
- Glucose transporters (GLUTs) - passive transporters
- Sodium-glucose cotransporters (SGLTs) - secondary-active transporters.
Location
SGLT2s are primarily located in the pancreatic alpha-cells and, also found in the cerebellum, Well then SGLT1s are primarily and widely located to the kidneys, heart, lungs, intestines and some found in our skeletal muscles.
Mechanism Of Action Of SGLT-2 Inhibitors.
Phlorizin a glycoside molecule obtained from bark and leaves of apple trees was the first natural inhibitor of SGLT1 and SGLT2. This was found almost 50 years ago but unfortunately, this was not water-soluble at that point. Only now when we have got them into bioavailable form, we can use them as an anti-diabetic drug.
Unlike other anti-diabetic medications which acts
by increasing the insulin levels or increasing insulin sensitivity in blood;
SGLT-2 inhibitors are insulin-independent.
So as we have seen above, SGLT-2 inhibitors work a bit differently, they actually make the kidneys excrete urine high in
glucose (glycosuria).
If we study closely into the proximal tubule of the kidney, we find the sodium-glucose transporter lined to them on the luminal side. Now, this transporter actually gives out sodium and glucose into the interstitial fluid which then goes into the bloodstream.
That is why this
sodium-glucose transporter 2 specifically is the site of inhibition for drugs
like Dapagliflozin, Canagliflozin and other SGLT-2 inhibitors.
So as a result of inhibition of the transporter,
the glucose cannot enter into the bloodstream and then gets unabsorbed and
excreted out through the urine.
CANVAS TRIAL
Population: Adult patients having T2DM [HbA1c greater than or equal to 7 to 10.5% at the screening], at high risk of CV events.
Intervention: Canagliflozin 100mg vs Canagliflozin 300mg
Control done: Placebo
Outcomes showed:
-Composite of CV mortality, nonfatal MI or nonfatal stroke.
-Now others are secondary, CV mortality
-Progression of albuminuria
-40% reduction in eGFR, renal replacement therapy or renal death.
-Hospitalization for heart failure
Based on this trial, it is clear that SGLT-2 inhibitors have some beneficial effects on the CV system, especially in HF patients, but still more studies are being done to establish these drugs beneficial to CVS.
Adverse Side Effects Which Counteracts The Claim Of SGLT-2 inhibitors As First-Line Agents.
The counteracting perspective of supporting sodium-glucose
transporter-2 inhibitors (SGLT-2i), comes to the questioning of its side effects.
The FDA has put a warning for the use overexploited use of SGLT-2 because of its response in increasing the vulvovaginal candidiasis in women about two times more, Increased risk of amputations, Diabetic ketoacidosis and acute renal failure, owing to its glycosuric actions.
But
these side effects are not actually predominant in a trial conducted.
Cost-wise Dilemma On SGLT-2i Vs Metformin
Seemingly metformin has a lower cost and is economical compared to SGLT-2i, But, Yes SGLT-2 inhibitors are very costly compared to metformin. This poses a major drawback to the use of gliflozins in rural areas.
But if we look into the statements by the American Association of Clinical Endocrinology and Dr George Grunberger, they say that it is long term complications, dialysis, hospitalizations and long term treatments that we should look into.
So once the generic becomes prominent the cost will reduce.
Therefore these long term dilemma can be avoided SGLT-2i are given from the beginning. Another thing to keep in mind is, a newer SGLT-2 inhibitor has come into the market: Remogliflozin which is about half or one-third of the price of the older gliflozins.
Conclusion
Even though no data is showing that beginning metformin as first-line therapy is harmful. Because most of the patients on metformin actually have no complaints or any frightening side effects.
But
looking at a long term perspective, some doctors believe that SGLT-2 inhibitors
have shown to be a way forward against T2DM.
But still, with a bitter scepticism, we have very limited
trials and studies that can actually say SGLT-2 inhibitors are predominantly
better than metformin, even WHO assumes it as a health equity issues and placed
sulphonylureas as second-line agents.
Maybe in future, with a more wide range of trials and evidence, SGLT2 inhibitors like Dapagliflozin which are effective in providing and maintaining a better and well-tolerated glycaemic control than with other anti-diabetic medications can emerge as a primary drug.
Now, because of its better CV effects, reduction in body weight, and reduced blood pressure, SGLT-2 inhibitors have shown improvement in cardiovascular function as well and is beneficial to patients suffering from cardiovascular disease.
But apart from this, a more detailed and evidence-based trial and conclusive reports have to be brought out before declaring these drugs as the first-line therapy for type-2 diabetes.
Excellent work man .
ReplyDelete