Start with a free account for 3 free CME credits. Already a subscriber? Sign in.

SGLT2 Inhibitors and GLP1 Agonists

Neda Frayha, MD and Elizabeth Lamos, MD
00:00
26:56

No me gusta!

The flash player was unable to start. If you have a flash blocker then try unblocking the flash content - it should be visible below.

The world of diabetes management has changed dramatically in the past several years. Given the new ADA guidelines and all the new literature on SGLT2 inhibitors and GLP1 receptor antagonists, endocrinologist Dr. Beth Lamos is back to help us understand how to use these drugs in practice. 

Pearls:

  • SGLT-2 inhibitors and GLP-1 agonists are gaining more traction as second-line agents after metformin given the increase in data suggesting their beneficial effects on not just weight loss and A1c reduction, but also renal and CV protection.
  • GLP-1 agonists may be beneficial for patients who want to have a once weekly injection.
  • SGLT-2 inhibitors (-flozins):
    • Mechanism:
      • Blocks the  SGLT-2 receptor in the kidney allowing glucose to be lost in the urine
    • Benefits:
      • A1c reduction 0.5-1%
      • May lead to weight loss
      • May reduce blood pressure
      • Renal protection
      • Some have been shown to reduce MACE outcomes
    • Risk/downside:
      • Renal insufficiency, particularly in those with some baseline renal dysfunction
        • Contraindicated if GFR < 30
      • Diabetic ketoacidosis that can happen at normal glucose levels with the following risk factors:
        • Illness
        • Surgical stress
        • Alcohol use
        • Reduction in insulin with food intake
      • Orthostatic hypotension
      • Potential increase in fungal infections
      • Rare but serious genital infections including gangrene
      • Increased risk of amputation with canagliflozin for people with peripheral vascular disease or severe peripheral neuropathy
    • Studies:
      • EMPA-REG (empagliflozin)
        • Showed reduction in MACE outcomes
      • CANVAS (canagliflozin)
        • Showed reduction in hospitalization and heart failure
      • DECLARE (dapagliflozin)
        • Mixed but did not show increase in CV risk
  • GLP-1 agonists (-tide):
    • Mechanism:
      • Stimulate incretin to make us feel fuller faster, tel the brain we are not hungry and regulate insulin/glucagon from the pancreas
    • Benefits:
      • Weight loss
      • A1c reduction
      • May be once a week injection (semaglutide and dulaglutide)
      • Reduction of CV disease (semaglutide and dulaglutide)
      • Likely improvement in renal function
    • Risk/downsides:
      • Injectable
      • GI side effect in 30-40% of people: nausea and diarrhea that generally subsides with time
        • Should not be used for someone with history of gastroparesis
      • Semaglutide (signal for retinopathy risk)
      • Contraindicated in those with medullary thyroid cancer or family history of MEN2A or 2B
      • Small increase in pancreatitis risk
    • Studies:
      • LEADER (liraglutide)
      • SUSTAIN (semaglutide)

 

REFERENCES:

  1. American Diabetes Association. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2018. Diabetes Care. 2018 Jan;41(Suppl 1):S73-S85. doi: 10.2337/dc18-S008. Review. PubMed PMID: 29222379.
  2. Gerstein HC, Colhoun HM, Dagenais GR, et al for the REWIND Investigators. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019 Jul 13;394(10193):121-130. doi:10.1016/S0140-6736(19)31149-3. Epub 2019 Jun 9. PubMed PMID: 31189511.
  3. Marso SP, Daniels GH, Brown-Frandsen K, et al for the LEADER Trial Investigators. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016 Jul 28;375(4):311-22. doi: 10.1056/NEJMoa1603827. Epub 2016 Jun 13. PubMed PMID: 27295427; PubMed Central PMCID: PMC4985288.
  4. Neal B, Perkovic V, Mahaffey KW, et al for the CANVAS Program Collaborative Group. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017 Aug 17;377(7):644-657. doi: 10.1056/NEJMoa1611925. Epub 2017 Jun 12. PubMed PMID: 28605608.
  5. Perkovic V, Jardine MJ, Neal B, et al for the CREDENCE Trial Investigators. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019 Jun 13;380(24):2295-2306. doi: 10.1056/NEJMoa1811744. Epub 2019 Apr 14. PubMed PMID: 30990260.
  6. Wanner C, Inzucchi SE, Lachin JM, et al for the EMPA-REG OUTCOME Investigators. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med. 2016 Jul 28;375(4):323-34. doi: 10.1056/NEJMoa1515920. Epub 2016 Jun 14. PubMed PMID: 27299675.

Katina C. -

Hello, excellent segment, thank you! I am wondering what your thoughts are/if you all use oral semaglutide (rybelsus)? Seems like potentially a great option, but I don't see a lot of data in terms of comparison to other GLP-1's, C/V benefit, etc yet. Thanks!

Neda F., MD -

Hi Katina! Thanks for your excellent question! I've asked Dr. Lamos to weigh in and will keep you posted as soon as we hear back. :) -- Neda

Neda F., MD -

Hi Katina. Here is Dr. Lamos' response:

"The use of oral semaglutide or not is probably clinical inertia. It's effective and associated with weight loss when compared to placebo (and later to SGLT-2 inhibitor and DPP-4 inhibitor). It's particularly better at the higher doses.

Interestingly, when oral was put against liraglutide, oral semaglutide glucose control was similar but semaglutide had greater weight loss. There was a series of trials that showed that oral semaglutide was efficacious in individuals already on metformin, SU, SGLT-2 inh and/or insulin.

Seems safe up to moderate renal dysfunction.

Against placebo there was a trend towards beneficial cardiovascular effects in high risk patients but the study was actually designed as a non-inferiority trial.

These were the Pioneer Trials if someone wanted to do a deep dive.

So clinically, I am just more inclined to go with the once weekly GLP-1 RA injections. It reduces the pill burden and is very well tolerated, but there is no reason that someone couldn't pursue oral GLP-1RA for a really injection averse patient. Especially now that Trulicity (dulaglutide) is available at the 3 mg and 4.5 mg dose we have more room for titration.

Hope this helps!"

To join the conversation, you need to subscribe.

Sign up today for full access to all episodes and to join the conversation.

To download files, you need to subscribe.

Sign up today for full access to all episodes.
Hippo Primary Care RAP September 2020 Summary 658 KB - PDF

To earn CME for this chapter, you need to subscribe.

Sign up today for full access to all episodes and earn CME.

0.25 Free AMA PRA Category 1 Credits™ certified by Hippo Education or 0.25 Free prescribed credits by the American Academy of Family Physicians certified by AAFP (2020)

  1. Complete Quiz
  2. Complete Evaluation
  3. Print Certificate

3.25 AMA PRA Category 1 Credits™ certified by Hippo Education or 3.25 prescribed credits by the American Academy of Family Physicians certified by AAFP (2020)

  1. Complete Quiz
  2. Complete Evaluation
  3. Print Certificate