SGLT2 Inhibitors and Neurocognitive Decline Risk Reduction
Sodium Glucose Cotransporter-2 inhibitors (SGLT2-i). What a mouthful!
Developed for Type 2 Diabetes (T2DM) … so why should you have interest in these if you don’t have T2DM.
The medications most commonly used in this category are:
Canagliflozin (Invokana)
Dapagliflozin (Farxiga)
Empagliflozin (Jardiance)
These medications are approved for decreasing risk of cardiovascular death and hospitalization for heart failure patients, chronic kidney disease, and Type 2 Diabetes for glycemic control.
The SGLT2 Inhibitors are at the top of this list, which is focused on evidence for health-span and lifespan.
It is my current approach to neurocognitive decline, that medications that diminish risk of Alzheimer’s Disease (AD), also seem to decrease the risk of Parkinson’s Disease (PD). Once there is a diagnosis of one or the other, the treatment of these diseases changes, but presently there is no disease modifying treatment available, and medications focus on symptom relief, unfortunately with little effect to modify the natural history of the disease.
The articles I’ll present relate to possibly modifying the risk of ever getting the disease. This however is not based upon randomized control studies. It instead is based upon a range of data, such as noting that individuals who take SGLT2-I medications have a markedly lower rate of PD and AD. So once you have AD or PD, does it modify progression? We don’t know. There are also animal models and other reviews of effects that would be expected to benefit risk of AD or PD that consistently seem to provide support for these medications being a sensible option to prevent, and even potentially modify the natural course of disease.
As with much of what we do, it is a risk/benefit assessment. Worst case scenario, you get a rare adverse event with the drug - which would be very rare, especially in a non-diabetic. Perhaps it doesn’t modify your risk of AD or PD, but it seems like it will almost certainly decrease vascular disease, and should decrease cognitive decline. The problem is that the clock is ticking, and the high level trial to demonstrate this effect will not likely be with us any time soon.
This class of medications gets high levels in your brain, and because it inhibits your kidney’s reabsorption of glucose, you’ll urinate out 150-300 calories of glucose daily, with most patients increasing their calorie intake to compensate. You’ll increase your insulin sensitivity in your brain and in your periphery. There is evidence of vascular disease regression in patients who take these agents.
So the cost is an issue. Many of my patients choose to get these medications off-shore, where cost is more in the $20-50/month range, not the $500-700 they cost in the United States. Due to this articleclick on this to seeI presently do not recommend canagliflozin, and recommend dapagliflozin or empagliflozin in most situations.
Article Review
click on this link to seeRisk of Parkinson’s disease in these diabetic patients was only 28% that of those not on this medication. AD was only 10% the rate, and all dementia only 25% the risk of those not on an SGLT2-i. Incidentally, 16% lower rate of death, 36% less cardiac events, and 64% less cerebrovascular events. Looking pretty good!
In this articleclick on this link to seewhich is a review of use of SGLT2-i in patients with Type 2 Diabetes (T2DM), the focus is on decreasing risk of AD and the likely mechanisms of this. This article is rich with references supporting this position. It is important to note that patients with T2DM are a good group to study, because they have significantly elevated rates of cognitive decline and AD.
AD occurs more frequently in patients with cerebrovascular disease, and even in a brief 3 month treatment with empagliflozin, there was significant regression of intima media thickness (looking at the vascular disease in the brain and the arteries feeding it). Neuroinflammation is also associated with cognitive decline, and this class of drugs seems to decrease oxidative stress and neuroinflammation.
It is also interesting that the SGLT2-i’s may also act as a Acetylcholinesterase inhibitor (AChE) in the brain, and modify the composition of the cerebrospinal fluid. Given that patients with AD have reduced acetylcholine, this could even be therapeutically helpful in someone with established disease. It appears that Canagliflozin (Dapagliflozin also has significant AChE activity) has the most AChE activity, according to this review.
Furthermore, these agents in mice increased cerebral Brain-derived neurotrophic factor which in turn improved cognitive functioning. There are further details in regard to improving Oxidative stress, mitochondrial function, and mTOR signaling.
Insulin resistance in the brain is an important feature, present in 8 out of 10 patients with AD. This class of medications appears to improve insulin resistance in the brain.
Other articles to read in regard to PD and SGLT2-i’s include:
This articlediscusses the dual use for PD and AZ of this class of medication.
Here are details on a studyupcoming, which is likely too short, but will use an SGLT2-i in patients who already have AD and monitor outcomes.
General Cognitive Improvement with SGLT2-i’s?
This studyclick on this linkis interesting in showing that patients with T2DM who have been on an SGLT2-i for more than 3 years had “improved cognitive scores globally and in language domain and executive function.”
Combinations including an SGLT2-i and GLP-1?
In an upcoming blog, we will be detailing why we see GLP-1 drugs, like Trulicity (Dulaglutide), Ozempic (Semaglutide), and Mounjaro (Tirzepatide) as potential beneficial drugs in this space. An underlying theme, is improving insulin sensitivity in the brain is a possible mechanism for slowing neurocognitive decline.
This studyclick on this link to seelooks at whether adding an SGLT2-i to a GLP-1 was beneficial? The result was a 30% lower rate of adverse cardiovascular events, and a 57% lower risk of serious renal events. The next question was whether adding a GLP-1 to an SGLT2-i was beneficial? This resulted in a 29% decrease in major cardiovascular events, but didn’t decrease renal events.
Additions post publication:
This study demonstrates decreased atherosclerosis with use of SGLT2-i. This is yet another benefit of these medications.
This study In Nature discusses elimination of senescent cells and pathologic aging. Really interesting information on a drug initially for diabetics - but now a top anti-aging drug.
Conclusion:
This class of medications, initially approved for Type 2 Diabetes, appear to be excellent candidates for longevity, and also specifically for risk of neurocognitive decline.
It is important to note that most studies were performed on patients with Type 2 Diabetes, kidney disease, or heart failure, which are the common uses for these medications. We don’t have data with use in healthy individuals. Mechanistically, it shouldn’t make a difference, but we don’t have that data in hand. These groups are also at higher risk for having adverse outcomes, including neurocognitive decline than the general population.
There are risks, benefits and alternatives to be discussed with any intervention. Some patients will have reasons not to take this class of medications. There are rare side effects with any medication. It should also be noted that patients with significant chronic kidney disease (Stage IV) may see little benefit.
For many individuals, this will be part of a strategy to improve longevity, and decrease risk of neurocognitive decline.
Disclaimer:
This blog provides general education only and should not be used to diagnose or replace the advice of a qualified medical professional.
This content is not intended to be a substitute for consultation with a qualified and licensed physician or another medical provider.
Readers should consult a medical professional for advice, diagnosis and treatment relating to their individual case.
You should discuss any supplement/medication being considered with your medical professional before starting it.
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