#243 Diabetes Triple Distilled

November 23, 2020 | By Molly Heublein

SGLT2 inhibitors, GLP1 Agonists, A1C goals and more!

Listen in as we recap four of our favorite diabetes episodes to bring you the pearls you need to stay up to date on type 2 diabetes management in the clinic.  We cover pitfalls of A1c testing, guidelines for A1C targets, when and how to use the newer medications SGLT-2 inhibitors and GLP-1 agonists.  We wrap up with a discussion of managing DM2 in patients with kidney disease and in which patients to consider de-intensifying treatment.  Feel confident managing diabetes with the latest data in 2020!

Listeners can claim 4 HOURS of Free CE credit for this episode through VCU Health at http://curbsiders.vcuhealth.org/ (CME goes live at 0900 ET on the episode’s release date).

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Credits

• Written and Produced by: Molly Heublein, MD
• Infographic and Cover Art: Isabel Valdez, PA
• Show Notes: Isabel Valdez, PA; Molly Heublein, MD
• Hosts: Stuart Brigham MD; Matthew Watto MD, FACP; Paul Williams MD, FACP, Molly Heublein, MD
• Editors: Emi Okamoto MD (written materials); Clair Morgan of nodderly.com

Sponsor

ACP’s I Raise the Rates

Join with other clinicians in working to raise influenza and other adult vaccination rates. Visit acponline.org/ai to access free tools and learn new strategies to support your efforts. 

VCU Health CE

The Curbsiders are partnering with VCU Health Continuing Education to offer FREE continuing education credits for physicians and other healthcare professionals. Visit curbsiders.vcuhealth.org and search for this episode to claim credit. See info sheet for further directions. Note: A free VCU Health CloudCME account is required in order to seek credit.

How to Claim VCU CME Credit

Time Stamps

• Sponsor – ACP’s I Raise The Rates acponline.org/ai

• Sponsor – VCU Health CE curbsiders.vcuhealth.org 

• 0:00 Intro
• 2:45 Pitfalls of A1c testing
• 7:00 Diabetes goals/A1c guidelines; Macrovascular vs Microvascular benefits
• 16:20 Choosing between SGLT2 inhibitors vs GLP1 agonists
• 19:10 Stuart rants on insulin for symptomatic hyperglycemia
• Sponsor – ACP’s I Raise The Rates acponline.org/ai
• 22:32 Start your patient on an SGLT2i and counsel them about potential adverse events
• 30:30 GLP-1 agonists
• 36:50 Deintensification; Diabetes Treatment in CKD
• Sponsor – VCU Health CE curbsiders.vcuhealth.org 

Diabetes Triple Distilled Pearls

1. The hemoglobin A1c value can be artificially higher in patients who have conditions that cause prolonged red blood cell survival and artificially lower in patients with higher red blood cell turnover.
2. Tight A1c  control itself with pharmacotherapy has not reliably shown patient centered benefits- this may be changing with our new medications!
3. SGLT-2 inhibitors lower blood sugar without significant hypoglycemia, encourage weight loss, and lower blood pressure.  They reduce heart failure complications, slow progression of CKD, reduce CVD, and lower death rates.
4. GLP-1 agonists lower blood sugar without significant hypoglycemia and encourage weight loss.  They reduce cardiovascular disease outcomes and lower death rates.
5. Consider de-intensifying therapy in diabetic patients treated with pharmacotherapy with an A1c <6.5% if they do not have specific indications for SGLT-2 inhibitors or GLP-1 agonists.

Curbsiders Episodes Covered:

#51: Diabetes Treatment in 2017 Dr. Jonathan D. Laffert reviews AACE guidelines.  Air date: August 7, 2017

#96: Diabetes: A1C targets & ACP guidelines controversy Dr. Devan Kansagara discusses ACP guidance statements with a nice review of original type 2 diabetes trial data.  Air date: May 21, 2018

#168 Diabetes Update Dr. Jeff Colburn reviews DOD/VA guidelines and goes into medications in more detail.  Air date: August 26, 2019

#204 SGLT-2 Inhibitors NephMadness deep dive into SGLT-2s.  Air date: April 6, 2020

When the A1c is unreliable

Anything that increases RBC turnover (i.e. destruction by a mechanical valve) can artificially cause a low A1c.  In contrast, any condition that causes the RBCs to hang around longer, such as iron deficiency anemia, will allow more sugar to stick to them and can artificially increase the A1c (Radin, 2014).  Checking a fructosamine level or frequent home fingersticks can give you more information if you suspect an inaccuracy.  The A1c is an average- so if someone has high highs and low lows it could look falsely reassuring.    

Setting Goals for Diabetic Patients

2020 American Association of Clinical Endocrinologists (AACE) Type 2 Diabetes Algorithm- In Episode #51, Dr. Leffer discussed the American Association of Clinical Endocrinology A1c targets; AACE suggests A1c less than 6.5% is appropriate for most patients, though there should be consideration for burden, cost, side effects and risk of hypoglycemia.

American Diabetes Association (ADA) – An A1c goal for many nonpregnant adults of less than 7% is appropriate per the ADA 2020. Achievement of lower A1C levels (such as <6.5%) may be acceptable if this can be achieved safely without significant hypoglycemia or other adverse effects of treatment.  Less stringent A1c goals (such as <8%) may be appropriate for patients with complicated comorbidities.

American College of Physicians (ACP) Guidance Statement–  In Episode #96, Dr. Kasagara discussed A1c goals between 7% and 8% in most patients with type 2 diabetes.  Higher targets may be appropriate in patients with comorbidities.

Veterans Association/Department of Defense (VA/DoD) Clinical Practice Guideline–   Dr. Colburn discussed similar targets to those in the ACP in Episode #168 with lower targets for patients with minimal microvascular changes and long life expectancy (6-7%) and higher A1c targets for those with shorter life span or advanced microvascular complications (8-9%).

Macrovascular/Microvascular Benefits

Studies looking at older medications including sulfonylureas, metformin, insulin, and thiazolidinediones (TZDs) do not consistently show a benefit for macrovascular benefits, with a possible exception of metformin after many years of use.  Tighter A1c control reduces surrogate endpoints for microvascular disease such as albuminuria, photocoagulation for diabetic retinopathy and painful peripheral neuropathy  (Rodriguez-Gutierrez R 2016).  

Newer medications: SGLT-2 Inhibitors and GLP-1 Agonists

Benefits of these newer medications

The new classes of medications were studied as secondary prevention in patients with underlying CKD or cardiovascular disease and have shown significant benefits in reduction in cardiovascular, renal disease, and even death regardless of A1c targets (Tuttle 2020, Lee 2020) 

SGLT-2 Inhibitors

Sodium glucose cotransporter-2 inhibitors are oral medications cause glucosuria and natriuresis. SGLT-2 inhibitors lower blood sugar by causing loss of glucose in the urine- leading to a low risk of hypoglycemia while having the added benefits of lowering blood pressure and encouraging weight loss. These drugs have been shown to reduce death, cardiovascular disease outcomes, and lower heart failure complications and kidney disease progression (Tuttle 2020).  Clinicians should be aware that these drugs pose an increased rate of genital fungal infections (Johnnson 2013), while rates of urinary tract infections are not significantly increased (Sarafidis 2020).  Other rare adverse risks include euglycemic diabetic ketoacidosis (DKA) and Fournier’s gangrene.  The FDA removed the black box warning for increased risk of amputation, but still reports a small amputation risk with canagliflozin.  Watch for hypovolemia and/or hypotension when starting these in patients with tight blood pressure control or on thiazide diuretics (Tuttle 2020).

GLP-1 Agonists

Glucagon-like peptide 1 agonists are drugs that improve glucose dependent insulin release from the pancreas, decrease the secretion of glucagon and slow gastric emptying; as such, the most common side effects to discuss with patients include nausea, early satiety and weight loss. These agents have a low risk of hypoglycemia alone, though Dr. Colburn warns of potential hypoglycemia in combination with sulfonylureas or insulin (he suggests reducing 20-30% insulin dose reduction when adding GLP-1 agonists).  They are given as a once daily or once weekly injections, or more recently semaglutide is available as once daily oral.  Once weekly dosing can take up to 5 weeks to reach steady state drug levels, so blood sugar reduction builds slowly.  There is a concern for an increased risk of medullary thyroid cancer in animal studies; best practice is to avoid using these in patients with MEN syndrome or a history of medullary thyroid cancer.  The data regarding pancreatic cancer and pancreatitis is inconclusive, there may be an increased risk so probably best to avoid in patients with a history of pancreatitis. GLP-1 agonists have been shown to reduce death and cardiovascular outcomes (Lee 2020, Zheng et al 2018)

Deintensification 

ACP Guidance Statement 3: Clinicians should consider deintensifying pharmacologic therapy in patients with type 2 diabetes who achieve HbA1c levels less than 6.5%.

T2DM Treatment in CKD  

GLP-1 agonists are not nephrotoxic, but are renally cleared so at lower eGFRs there may be drug accumulation leading to more side effects (Sloan 2019).  

SGLT-2 inhibitors are less effective at lower eGFR, and are not recommended for use in patients with an eGFR less than 45 per prescribing information. The DAPA-CKD study showing renal benefit for SGLT-2s enrolled >10% of patients with an eGFR <30 (Wheeler 2020), so perhaps this indication will expand.

Recent studies have shown that metformin is safe to continue in established patients with CKD 3 (GFR 30-44 ml/min/1.73M^2) (Lazarus 2018).  However it is not recommend to initiate metformin if GFR < 45 (FDA)

Want even more diabetes material?!  The Curbsiders has extra episodes we didn’t have time to cover: 

#106 Hotcakes 

#25: Master hyperglycemia and DKA

#42 Diabetic Foot 

Cribsiders #7: Diagnosis and Management of T1DM

Goals

Listeners will be able to choose an A1c target for their patient with diabetes and consider the patients comorbidities when choosing therapy to reach that target.

Learning objectives

After listening to this episode listeners will…

1. Compare and contrast different diabetes guidelines and to choose an A1c target for a patient
2. Appreciate that diabetes is a high cardiovascular risk state, and most of our evidence supports blood pressure and lipid control over glycemic control in preventing serious outcomes in our patients
3. Explain the mechanism of action and possible side effects associated with GLP-1 agonists and SGLT-2 inhibitors 
4. Understand current data around cardio and renal protective effects seen in SGLT-2 inhibitors and GLP-1 agonists
5. Identify pitfalls in A1c testing
6. Review which patients should have their diabetic medications deintensified 

Disclosures

The Curbsiders report no relevant financial disclosures.

Citation

Heublein M, Valdez I, Brigham SK, Williams P, Watto M. “#243 Diabetes Triple Distilled. The Curbsiders Internal Medicine Podcast. http://thecurbsiders.com/episode-list November 23, 2020.