Cardiovascular Benefit of New Diabetes Medications (Magnotti, 4/22/2020)

One of the reasons I love Grand Rounds is that each week I know-- whatever the topic, whomever the speaker-- I will walk away wiser. My curiosity will have been piqued. I will have learned something. I will have been challenged.  I will be a better family physician. And I will have often have new (more educated) questions.

And as expected, this week, Dr. Mike Magnotti (SMGR Endocrinology) did not disappoint. He gave an excellent presentation on the cardiovascular benefits of two classes of "new" diabetic medications: GLP-1 analogs and SGLT-2 inhibitors. Definite practice changer for me.

Here are a few questions to start you off:

• Do you manage your diabetic patients with cardiovascular disease  (CVD) differently than those without CVD?
• Are you aware of the evidence that both the GLP-1 and SGLT2-inhibitors reduce stroke, MI and possibly even CV death in diabetics with CVD?
• Are you using GLP-1 agonists for cardiovascular benefit?  What about SGLT-2 inhibitors?
• How do you (and your patients) assess whether or not they should be on one of these new meds?

I don't know about you, but I have a hard time keeping these medications in my head-- the names are complicated, the abbreviations don't make it simpler, the mechanisms of action are new, and nothing sticks. Plus, until recently they have been unavailable to most of my patients due to cost and/or insurance restrictions.

In case you are in the same boat as me, here's a brief summary of the two classes of meds Dr. Magnotti presented evidence for in CV risk reduction:

GLP-1 agonists: glucagon-like peptide 1 agonists (aka incretin mimetics) are almost all INJECTABLE medications (except for one new oral version of semaglutide). They act on the gut: improve glucose-dependent insulin release, suppress glucagon, suppress hepatic glucose output, decrease the rate of gastric emptying, and suppress appetite.  

• Benefits of GLP-1 agonists include HbA1c reduction of 1.2-1.7%, weight loss, no risk of hypoglycemia (unless combined with insulin or sulfonylurea), and CV risk reduction  (non fatal heart attack and stroke-- see below for details)
• Side effects: mostly GI (nausea, vomiting, constipation, diarrhea), headache, injection site reaction, possibly pancreatitis, and a black box warning MEN2 or medullary thyroid cancer
• Currently available forms: short and long acting exenatide, liraglutide, dulaglutide, semaglutide (oral and sq)

SGLT-2 inhibitors: sodium-glucose co-transporter-2 inhibitors (aka gliflozins) are ORAL medications that inhibit resorption of glucose into the kidneys, thereby lowering blood sugar

• Benefits of SGLT-2 inhibitors include: Hba1c reduction 0.8-1.2%, systolic BP reduction (~5mm Hg), weight loss (2-4% of body weight), heart failure risk reduction, slowed progression of CKD, CV risk reduction (non fatal heart attack and stroke-- see below for details), and even CVD death reduction (empagliflozin only)
• Side effects:  yeast infections (women>>men), UTI/pyelo, polyuria, transient decrease in GFR, orthostasis (esp in elderly), small increase in LDL, hypoglycemia (if combined with sulfonylurea, insulin), DKA with minimal glucose elevation, increase in fractures, possible increase in amputation, fournier's gangrene
• Currently available forms: canagliflozin, empagliflozin, dapagliflozin, ertugliflozin

Is HbA1c lowering the only outcome that matters?
Standard diabetes management has focused on reduction of HbA1c, which we know prevents progression of microvascular disease but has little effect on macrovascular outcomes. HbA1c goals are the metric by which we have considered a patient "controlled" or "uncontrolled". You all know, our  goal is HbA1c<7 in most adults, <8 in elderly and those with significant comorbidity.  Secondary goals have been to prevent/avoid hypoglycemia and prevent weight gain/promote weight loss.

It may be time to rework our paradigm; start thinking diabetes meds in CV Risk Reduction
Yes, we know lowering HbA1c is important to prevent retinopathy, diabetic nephropathy, peripheral neuropathy. However, we also know that cardiovascular disease (CVD) is an important cause of morbidity and mortality in diabetic patients. What if there were medications that reduce HbA1c and also reduce the risk of MI, stroke, and CV death?

Guess what? There are! Both the GLP-1 agonists and the SGLT-2 inhibitors seem to have a positive effect on CV outcomes (ie they reduce heart attack, stroke, and maybe even CV death). To be right up front, no one is exactly sure why.

Since 2008-- due to concern about thiazolidinidiones (TZD) actually showing increased CV risk in diabetic patients-- the FDA has required that any new blood sugar lowering med be evaluated for cardiovascular safety ("a cardiovascular outcome trial" or CVOT). Most of these studies use a composite endpoint called a 3 point MACE (time to a Major Adverse Cardiac Event, including non-fatal MI, CVA or cardiovascular death). Initial studies found most novel diabetes meds to be neutral, but  more recently, they started to show some benefit.

Here are the studies Dr. Magnotti reviewed during Grand Rounds:

• EMPA-REG: (empagliflozin), NEJM 2015
• DM2, a1c range 7-10%, BMI<45, established CVD--> primary outcome 3P MACE 
• Relative risk reduction of 38%, 2.2% Absolute risk reduction
• NNT 46 patients for 3.1 years to prevent on CV death (for comparison sake, NNT is 31 patients for simvastatin x5.4 years, 49 patients with ramipril x 5 years)
• There were also significant reductions in all-cause mortality and heart failure hospitalizations
• FDA indication for empagliflozin: to reduce risk of CV death in diabetic patients with known CVD
• CANVAS/CANVAS R (canagliflozin), Circulation 2018
• Primary outcome: 3P MACE
• Relative risk reduction 14%, NNT=224
• LEADER: (liraglutide), NEJM 2016
• Primary outcome: 3P MACE
• Relative risk reduction, 13%, 3P MACE
• Reduction in all cause mortality 15%, CV death 22%
• SUSTAIN 6 (semaglutide injection), NEJM 2016
• 26% relative risk reduction 3P MACE

Dr. Magnotti's summary of the literature: 

• To date, 5 new diabetes agents have been shown to lead to a significant reduction in 3 point MACE. 
• This effect is INDEPENDENT of A1c and other risk factors. 
• These were all measured in addition to other standard of care therapies (such as ASA and statin)

In light of these studies, both the American Diabetes Association (in 2018, again in 2020) and the American COllege of Cardiologists (ACC, 2020) have updated their guidelines with regards to using SGLT-2 and GLP1 medications in diabetes. 

For patients with known ASCVD, these medications should now considered first line after metformin (see diagrams below from ADA and ACC).

ADA guidelines HERE in FULL text (snippet of image).

ACC guidelines HERE in FULL text (snippet of image). 

In Type 2 patients with Diabetes AND CVD (ie. known CAD, hx MI, hx CVA, PVD), regardless of A1c or current diabetes therapy, patient should be started on EITHER GLP-1 (liraglutide daily injection, dulaglutide weekly injection, semaglutide weekly injection) OR SGTL-2 (empagiflozin oral, canagliflozin oral)

Dr. Magnotti's Considerations when choosing an SGLT2 vs. GLP-1

• SGTlL-2 in patients with Heart Failure, CKD (GFR>30), those who might need improved BP control (or who you aren't worried to be on a diuretic), someone with history of pancreatitis, gastroparesis, significant nausea, or MEN2/MTC
• GLP-1 in patients who need MORE Hba1c reduction, CKD with GFR<30, recurrent yeast infections or UTI, concern for risk of DKA or other potential side effects from SGLT-2

Some practicalities:

You don't need to adjust a patient's other diabetes meds UNLESS they are on insulin or sulfonylurea (for risk of hypoglycemia)

• IF they are on a sulfonylurea:
• A1C<7 to 7.5, stop the sulfonylurea
• A1C 7.5-8.5, cut sulfonylurea dose in half
• A1c >8, no change
• IF on basal insulin
• a1c<7, cut insulin dose in half
• a1c7-8, reduce insulin dose by 20%
• IF on prandial insulin, consider getting endocrinology input OR cut prandial insulin at least in HALF. 
• IF patient on antihypertensive, for SGLT2, consider reducing dose, if diuretic cut dose or stop

What about insurance coverage?

Coverage has substantially improved for these medications with CV indications. (Even with Partnership Health Plan). There are NO other medications that can be used for "step therapy" for CV risk reduction, so be sure to prescribe these under CVD (rather than DM). 

What about patients who don't want to take an injection?

If the patient meets criteria for a GLP-1 but doesn't want an injection, remind them: 1) this isn't insulin 2) they will likely LOSE weight and improve their blood sugar control and 3) they will reduce their risk of heart attack and stroke. Then get them nursing and diabetic educator assistance with getting over the injection!

If you work in the hospital, you might at least consider discharging every diabetic patient with established CVD (MI, CVA, TIA, PVD) on a GLP-1 or SGLT-2 agent. 

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Another reason I love Grand Rounds is that I love sitting in the same room with engaged, big-brained, big hearted colleagues. (This is the part I miss during our shelter in place-- Zoom works-- but it sure isn't the same). Join us next week on Zoom. We will be back in that conference room eventually.