Type 2 Diabetes Management: What is new in 2021? (Magnotti, 8/18/2021)

SMGR Endocrinologist, Dr. Michael Magnotti, gave an information-packed review of the latest and greatest in DM2 management at Grand Rounds this week. It was fast and furious and full of really great info on updated management of DM2. A video recording of Dr. Magnotti's presentation is available HERE .

Here are my take home points up front:

1) Goals for DM management should include: achieving a specific a1c goal (based on age, risk factors, etc), avoiding hypoglycemia, avoiding weight gain (promoting weight loss if possible), minimizing side effects, and decreasing CV events. Insulin, unfortunately, doesn't accomplish many of these goals.

2) SO. . .first line, old school for DM management, is still metformin AND comprehensive lifestyle changes (including weight loss and physical activity)

3) Second line meds should be GLP-1 receptor agonist OR an SGLT-2 inhibitor for ALL diabetics. This is because these meds reduce a1c, do not cause hypoglycemia (unlike sulfonylureas), promote weight loss, and decrease CV events. This is even true if a1c is at goal (see ADA guidelines below)

4) SGLT-2 and GLP-1 have additional indications for which we might consider them regardless of DM; with established ASCVD, and heart failure (HFrEF and HFpEF), and chronic kidney disease with GFR>30 and/or proteinuria. There is rapidly evolving evidence that even in the absence of DM2 (or DM with good control), these medications can improve outcomes. More and more, the are be covered by insurance for these indications alone

5) GLP-1 agonists have the most potent a1c lowering and weight loss effects. They also clearly reduce CVD risk.

6) In addition to CVD risk reduction, SGLT-2 have evidence for improved outcomes in heart failure and CKD. This is a class effect. Don't get caught up on individual indications for which med. All SGLT-2 except ertugliflozin, the oldest and cheapest) impact all three conditions.

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Dr. Magnotti showed us this image of the Ominous Octet-- the eight pathways through which hyperglycemia occurs with DM2. You can see which mechanisms are in effect with the GLP-1 and SGLT2 medications. 

This, too, for your reference is the most updated graphic version of the 2020 ADA guidelines. Note the two LEFT columns, we are to consider the addition of meds for ASCVD, HF and CKD independently of a1c. The RIGHT two thirds of the page direct us to consider medications based on a1c not being at goal.

https://care.diabetesjournals.org/content/diacare/43/Supplement_1/S98/F1.large.jpg

For the life of me, I cannot EVER remember their names of these newish classes of meds and which is which. I think I am getting old. So for your reference and mine:

GLP-1 Analogs: semaglutide (Ozempic injectable, *newer oral form Rybelsus), liraglutide (Victoza), dulaglutide (Trulicity), and exenatide (Byetta)

SGLT-2 Inhibitors: canagliflozin (Invokana), dapagliflozin (Farxiga), empagliflozin (Jardiance), ertugliflozin (Steglaro)

Okay, so let's recap the key points on both these categories of meds. 

First GLP-1:

• GLP-1 agonists begin working as soon as food hits the mouth--> hormonal disruption leading to decreased glucagon production and increased insulin, early satiety, and slowed gastric emptying (which is why they help with weight loss)
• if patients complain of nausea with GLP-1 it's probably because they are eating too much, need to cut back on food intake and nausea may improve
• GLP-1 agonists have been shown:
• 1-1.8% reduction in a1c
• 4-13 pounds weight loss
• NO hypoglycemia
• CV risk reduction
• Side effects: nausea/vomiting/constipation/Headache/injection site reaction/hypoglycemia (only if combined with insulin or sulfonylurea), and unclear link with pancreatitis
• Absolute contraindication: black box for animal studies showing association with medullary thyroid cancer and MEN2
• Relative contraindications: CrCl<30 (except exenatide, which has no SCr cutoff and okay in HD). There is a warning of AKI, which is a result of volume depletion
• GLP-1 Agonists that are HUMAN GLP-1 based: semaglutide, liraglutide, and dulaglutide (all of them EXCEPT exenatide) have CV risk reduction
• Oral semaglutide has no CVD reduction data (trials ongoing)

What's new about GLP-1 medications in 2021?

• Higher doses of dulaglutide (Trulicity (3.0 and 4.5mg)) have new data showing even more improvements in Hba1c, increased weight loss, but also more nausea (makes sense). 
• Titration can happen weekly, starting with 0.75mg--> 1.5mg--> 3--> 4.5 as tolerated
• Newish oral semaglutide MUST be taken on a completely empty stomach (with no other meds and <4 oz of water) to be effective. Otherwise it doesn't work
• Injectable dulaglutide now how has primary prevention data for CVD 
• consider rx'ing for patients with high CV risk
• Injectable semaglutide at high doses (2.4 mg vs. normal 1.0mg dose) has shown promise for even more weight loss 10-16% of body weight, with over 50% of patients losing 15% of their body weight

Okay, onto SLGT-2: 

• SGLT-2 meds block reabsorption of some (not all) of glucose from the tubules, causing glucosuria and urination, essentially a diuretic effect. They also have a Na effect on urine
• You can consider their positive impacts as a class effect, except ertugliflozin. You can use most of these interchangeably for CV risk reduction
• SGLT-2 studies show:
• A1c reduction 0.8-1.2% (little less than GLP-1)
• BP reduction of about 5mm Hg
• Weight loss 2-4% of body weight
• Renal protection (DM or CKD without DM)
• CV mortality risk reduction
• HF reduction (diagnosis and exacerbation, HFrEF and HFpEF)
• 3 point MACE reduction
• Contraindications to SGLT2: renal insufficiency (GFR<30, though data evolving), caution in advanced age (risk of orthostasis, volume depletion)
• Side effects: yeast infection (women>>> men, okay to treat through the first yeast infection, but if recurs, should stop), polyuria, volume depletion and transient decrease in GFR, orthostasis, small bump in LDL, hypoglycemia when combined with insulin/sulfonylureas, DKA with minimally elevated blood sugar, fournier's gangrene

What is new in SGLT-2 in 2021?

• Renal protection data (in BOTH diabetic and non-diabetic CKD)
• Canagliflozin RCT in pts with DM2 w/CKD with proteinuria--> decreased doubling of SCr, ESRD, renal death
• Empagliflozin in pts with DM2 with or without CKD--> reduced rates of doubling creatinine, progression to proteinuria, initiation of RRT, and renal death
• Dapagliflozin in pts with CKD GFR 25-75 and proteinuria (+/- DM)--> decreased doubling SCr, end stage renal disease, renal death (almost 50% risk reduction)
• HF risk reduction data (also presence/absence of DM)
• studies found decreased exacerbation of HF as well as diagnosis of HF in patients on SGLT-2 medications
• 30% reduction in hospitalization 
• Full data on HFpEF coming out this month. Stay tuned
• CV risk reduction data
• empagliflozin study found 38% reduction in CV mortality after 3 years of treatment (this is the most dramatic result)
• canagliflozin showed 0.86 reduction in 3 point MACE, liraglutide 0.87 reduction, semaglutide 0.74 reduction