SGLT 2 use in Type 1 diabetes benefits and risks

We are coming up on 100 years of insulin management of Type 1 Diabetes.

In that hundred years we have seen the development of long acting insulins, and faster acting insulins, and even inhaled insulin. But the general view of treatment of diabetes has been split into two paradigms: Insulin management and Non-insulin management. This fueled the idea that there are 2 kinds of diabetes, Type 1 an Type 2. However we are finding that the reality of diabetes management is no so black and white. There are many mechanisms in the body that regulate our blood sugar, and insulin works on just one of those mechanisms.  For years doctors and patients have been asking ‘why not use the other mechanisms AND insulin?” Doctors have been prescribing medications FDA approved for use in type 2 diabetes management for patients diagnosed with Type 1. It makes sense! The liver of a patient with type 2 and the liver of a patient with type 1 both react to metformin to reduce hepatic glucose output. This use of medication is referred to as “off label” use. And let’s face it, the type 1 diabetes community pretty much lives in a world of off label use. From sticking our CGMs wherever we please, to hacking our pumps to make our own hybrid closed loop systems, we don’t tend to wait for FDA approval for much. The FDA usually catches up to what we’ve been doing for years and finally gives doctors the nod to start prescribing these treatments to the wider world.

This is the case this year as multiple pharmaceuticals companies have submitted study data to the FDA for approval of an indication for SGLT2 inhibitor(SGLT2i) medications to be indicated for use in persons with Type 1 diabetes alongside insulin.

Current SGLT2i medications include:

• canagliflozin (Invokana)
• dapagliflozin (Farxiga)
• empagliflozin (Jardiance)
• empagliflozin/linagliptin (Glyxambi)
• empagliflozin/metformin (Synjardy)
• dapagliflozin/metformin (Xigduo XR)

So what do these medications do? How can they benefit people with type 1 diabetes? What are the risks associated with these medications?

SGLT2 inhibitor medications act on a section of the kidney called the Glomerulus. The glomeruli are bundles of blood vessels in the kidneys that work to filter out waste products and balance the composition of our blood (there are nearly a million glomeruli in our kidneys) The glomerulus has lots of tiny channels that allow different chemicals through from the blood stream to a renal tubule for elimination through urination.  This would be pretty straight forward if it were a one way street, but in that renal tubules are these channels called SGLT2. Their job is to keep us from losing glucose on urine. (We worked hard to hunt and gather for those precious glucose molecules and we don’t want to waste life saving calories to urination! Unless we are a person with diabetes, or possibly not a hunter-gatherer fighting for survival in the wilds where every calorie we consume is critical to survival) In a person without diabetes this keeps blood sugars from dropping too low when lots of fluid is lost to urination.

(image borrowed from Medscape.org)

So these medications INHIBIT that SGLT2 action, reducing that reuptake of glucose.  So excess glucose is filtered out of the blood stream and less of it can be reabsorbed so it passes in our urine.

The first obvious benefit of this is less glucose in our blood. Lower blood sugars and lower A1C. An added side benefit for some patients is that since they are urinating out glucose, they are urinating out calories and this can lead to a modest weight decrease as well. Because blood sugars are reduced without additional insulin patients also report easier weight loss.

Using less insulin has also been attributed to other health benefits including reduction in PCOS symptoms in women.

With reduced high blood sugars reduced glycemic variability is also a health benefit of SGLT2i medication addition to insulin therapy.

  These medications have also been linked to reduced incidence of Cardiac disease, and stroke. When we urinate out more sugar we also urinate out more water and any plumber can tell you that when pipes carry less water volume the pressure on the system lowers. The reduction of blood pressure along with reduction in blood glucose reduce risks of heart attack and stroke.

So with benefits like that why are we all not already on these medications?!
Of course any medication that works on a part of our body as critical as the kidneys has potentially harmful side effects as well.

First and most common among these is genital yeast infections and UTI. Our urinary symptom is typically sterile. But there’s always that old joke about the design strategy of putting them so close to a waste treatment facility. Typically our urinary tracts are at little risk for infection when our blood sugars are well controlled. There is very little to no glucose in urine for bacteria to consume, so they don’t grow in that area. But SGLT2i medications force glucose into the urine stream, even when blood sugars are very well controlled. This feeds bacteria in an area where they are already pretty close by! And once bacteria are in the urinary tract it is just a hop skip and jump to the bladder (Bladder infection) and kidneys (kidney infection).  So persons who have a history of recurrent UTI, bladder or kidney infections should not use SGLT2i medications. Our kidneys are already at enough risk as persons with diabetes. Any  loss of kidney function could be made worse by the SGLT2i medication itself. Anyone on these medications should take extra care to make sure they are practicing excellent bathroom hygiene. Incontinence materials and under clothes must be changed often and the area kept clean and dry to reduce bacterial transmission.

The second most common side effect of SGLT2i medications is hypotension or low blood pressure. Anyone who has experienced a sleepless night of high blood sugars because they had to run to the bathroom every couple of hours can tell you that when our body is flushing out sugar, we are flushing the loo! A LOT! Having a medication that is keeping more glucose in our urine means that we are also going to pass more urine. This can lead to a reduction of the fluid in our bodies referred to as hypovolemia. And any plumber can tell you that a system with less volume operates at lower pressure. This reduced pressure can cause blood to no longer effectively travel to our brains, particularly with changes from laying to sitting, or sitting to standing referred to as orthostatic hypotension. This results in increased fall risk or risks of fainting. Particularly for patients on blood pressure medications, or other medications that can reduce fluid volume (such as furosemide (Lasix), HCTZ etc) or some anti-anxiety or pain medications, this risk if multiplied. This loss of fluid can also cause electrolyte imbalances in the blood that can be life threatening. Both the loss of fluid and the imbalance of electrolytes can cause kidney function loss. SGLT2i medications should not be used by patients with renal impairment. Labs should be done following start of the medications, and while they are used to monitor for electrolyte balance and renal function.

There is one side effect specific to people on insulin that poses the most serious and sudden risk, DKA. Diabetic Ketoacidosis is a potentially deadly complication of diabetes in which the body, without sufficient insulin, uses fats for energy. The biproduct of this process is ketone buildup in the blood stream which lowers the blood PH leading to vomiting, slurred speech, lethargy, coma, multi-organ failure and death. Typically someone on insulin gets a warning that DKA is coming, high blood sugar.

However, in studies of persons using SGLT2i medication while on insulin, patients were found to experience DKA, without elevations in blood sugar! This is called Euglycemic DKA. DKA risk is increased with use of SGLT2i medications as:

• The fluid volume loss due to increased urination concentrates ketones in the blood
• The fluid depletion and medication action reduce the elimination of ketones through urination
• SGLT2i action on pancreatic alpha cells may cause glucagon levels to rise promoting ketogenesis in the liver, increasing ketones in the blood.
• The reduction of blood sugar can also lead to reduction in insulin doses to a level that increases the body’s use of fats for energy which increases ketosis.

With these risks in place the addition of illness, a pump failure or missed insulin dose could be seriously hazardous. And because we do not get the marked insulin increase that would typically alert us to a problem treatment may be delayed until significant damage is done.

An additional concern for people on insulin is that our kidneys reduce glucose from our blood stream when our blood sugar is above 160. Below that line, muscle action and insulin lower blood sugar, and we use that knowledge to adjust our insulin doses and activities to prevent hypoglycemia. However, SGLT2i medications cause the kidneys to continue lowering blood glucose levels even when they are well below 160. In fact, we could be hypoglycemic and still passing glucose in our urine. This means that patients on these medications would need to  adjust how they bolus for meals, corrections and adjust for activities.

To mitigate these side effect possibilities persons on insulin using an SGLT2i medication should:

• Regularly check for ketones even without extreme elevations.
• Establish a clear sick day plan for when to stop SGLT2i medications and how to dose insulin to prevent ketones
• Maintain hydration to reduce the impact of fluid volume depletion or dehydration
• Never skip insulin doses
• Have good communication with your prescriber’s office to review dosage change needs
• Review dietary changes with a skilled healthcare professional to ensure adequate carbohydrate intake to avoid additional ketosis.
• Whenever we start a new medication we should always ask our doctors: what class of medication we are starting, how it works on our bodies, what possible side effects might be and how to prevent them.

It is also recommended that patients on both insulin and an SGLT2i carry this wallet card on their person in case of medical emergency and update their Medic-alert or other emergency medical records to include this update. This will alert medical professionals as they might not seek DKA as a cause of medical problems in the absence of elevated blood sugars.  This card also outlines the STITCH protocol for reacting to the presence of ketones for someone on both insulin and an SGLT2i medication.

So now you’re thinking, you’ve told me how GREAT these medications are, and you’ve told me scary risks of using these medications, how do I decide what to do?

As with all medication choices this is an individual balance of risks and benefits that you should discuss with a prescriber who knows your history, and the medications being discussed, well.  If you are a person on insulin who is really struggling with post prandial peaks, has a high cardiac risk profile, and are willing and able to monitor for ketones more often, an SGLT2 medication addition might be right for you.

Whether you are struggling with diabetes management, or would like more information on medication options available, schedule an appointment with Integrated Diabetes Services. We help people manage their insulin more effectively so perhaps a secondary medication is not needed. We also help guide patients to secondary medication options that can help them overcome barriers and achieve their goals. Diabetes management is highly individual with many mechanisms of action. It is encouraging to see more options becoming available for management of this disease. It is also important to be educated on staying safe while we wade into this emerging area of treatment innovation.