Among the dirty little secrets of the older diabetes medicines was that they usually made you gain weight, they could cause low blood sugar suddenly and unexpectedly, and they had no particular benefit to the most important consequence of type 2 diabetes (T2D) – heart disease.
All that changed with the release of two newer classes of diabetes medicines. The first are called GLP1-RA’s (to be explained, below) which include brand names Byetta, Victoza, Bydureon-BCise, Trulicity, and Ozempic. The second are SGLT2i’s (ignore that too, for now) named Invokana, Jardiance, Farxiga, and Steglatro. Whew – that’s a lot of names and choices. And there’s more to come! That’s what happens when you have a good thing going.
Here are some of the good things they do:
- They don’t cause low blood sugar by themselves.
- Although the details of research studies are always nuanced, and different drugs have different levels of study outcomes, in general the evidence is very strong that these medicines significantly decrease risk of death from all causes, heart attacks, sudden death, and stroke. SGLT2’s also prevent hospitalization for heart failure. Guidelines from diabetes and heart disease societies name these meds specifically as first choices to treat people with T2D who have established cardiovascular disease (CVD). Since there is no official definition of “established CVD”, it can be argued that all adults with T2D should be treated with SGLT2 inhibitors and/or GLP1-RA’s.
- These medicines also lower body weight by 3-7%, and the weight stays off for many years of follow-up. The weight lost is mainly from fat, not fluid or muscle, though there is always some of that too. The amount of weight loss varies widely, and while these are specifically not supposed to be weight drugs, this percentage of weight loss is significant for metabolic health.
- The medicines lower systolic blood pressure by about 5 mmHg, which is about as much as most blood pressure agents. Systolic is the higher number on blood pressure. Lowering blood pressure is one of the most important ways to prevent CVD and especially stroke.
- While the definitive studies are soon to be released, it appears these drugs prevent the usual decline of kidney function with age, which everybody has but which people with T2D have twice as fast. Preventing chronic kidney disease (CKD) may be the most significant contribution since it greatly increases risk for CVD and is among the biggest drains on the U.S. healthcare budget.
While the old, inexpensive generic drug metformin is still typically used first for T2D, many argue the benefits of GLP1-RA’s and SGLT2 inhibitors are more than worth the money and that they ultimately save money. I still support metformin because of many other virtues that it has, but would argue against using sulfonylureas because of risk of hypoglycemia and weight gain, and maybe even worsening risk for CVD. Too bad today’s insurance goes for cheapest in the short term instead of the most value in the long term. Regardless, most people with T2D will eventually require combinations of these meds anyway.
So How Do They Work?
Well this is cool too, and they are very different.
GLP1-RA’s are “glucagon-like peptide receptor agonists” because native GLP1 physically resembles glucagon even though its actions are almost opposite. GLP1 is co-secreted with insulin in normal physiology and in many ways has actions that are complementary to insulin. It enhances the actual secretion of insulin in proportion to glucose, inhibits levels of the actual hormone glucagon (which would raise glucose), slows the otherwise faster stomach emptying of T2D, and, remarkably, signals the brain when you’ve had enough food, so most people eat less and lose weight. GLP1-RA’s act like GLP1.
GLP1-RA’s have to be injected, like insulin, but they still are really easy to live with because they can be taken anytime daily (Victoza) or weekly (Bydureon-BCise, Trulicity, and Ozempic), come in easy dose pens, and have needles so small you can hardly feel them if you don’t use alcohol to prep the skin. Byetta has to be used twice daily and timed before meals, so although it was the original GLP1-RA from San Diego-based Amylin Pharmaceuticals, it is used less often today. An oral GLP1-RA has been developed and is in the later stages of review by the FDA.
SGLT2 inhibitors are once-daily tablets that cause the kidneys to release glucose into the urine, generally 65 to 100 grams daily (100 grams is roughly 400 calories, if you wondered). The kidneys have a system to absorb glucose from the urine called the “sodium-glucose-luminal-contransporters 1 and 2”, and SGLT21’s inhibit that absorption. You would think that losing 400 calories per day would reduce a person to dust in no time, but the body has many compensatory mechanisms so the weight eventually plateaus and some people, somehow, don’t lose much weight while others lose 10-15 lbs.
What Are the Side Effects?
As you might guess from the way they work, people taking SGLT2i’s pee more urine at first, and so should increase water intake by about a quart daily for the first week or so. After that it tends to return to a normal steady state. And because the urine is full of sugar, you have to be careful with good hygiene around urination, especially for women, to avoid yeast infections. If yeast infections do happen, it’s rarely more than once and is easily treatable with over-the-counter remedies for three days (not one, because of diabetes itself).
The GLP1-RA’s have to be started at low dose and built up slowly over a few weeks to minimize gastrointestinal side effects like nausea or diarrhea. Once stable, those side effects don’t occur.
Every person is unique, however, so one always needs to be cautious with any new medication.
Good News for Those with Type 1 Diabetes?
Although not approved for use in people with type 1, there is very promising research that has been done showing benefits of both classes of agents, especially the SGLT2i’s, to smooth out glucose variability, especially around meals, and to somewhat decrease insulin requirements. We are still working out the safety issues and the best strategies for introducing these agents to avoid diabetic ketoacidosis, but I anticipate their use in type 1 soon.
Good News for People Who Don’t Have Diabetes?
Perhaps. SGLT2i’s are being tested for those at risk for congestive heart failure, in particular, and both classes for heart and kidney preservation as well. We should know more in a few years, but stay tuned. There is an enormous amount of research interest in these meds and in the lessons they are teaching about human physiology.
If these agents are so good, why isn’t everyone on them and why do we still have so much poor diabetes control and diabetes complications? It’s beyond the scope of this piece to tackle that, but we need to do it as a community and as a nation. Dr. Edelman and Dr. Polonsky have contributed important work in this area, and the ADA has held consensus conferences to address this gap between possibility and reality. But knowledge is power, and now you have more knowledge about these exciting medications. And always remember that good nutrition, keeping fit, sleeping well, maintaining purpose, reveling in humor, and embracing friends and loved ones remain the mainstays of any plan to be healthy.