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!
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#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
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.
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%).
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).
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)
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).
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)
ACP Guidance Statement 3: Clinicians should consider deintensifying pharmacologic therapy in patients with type 2 diabetes who achieve HbA1c levels less than 6.5%.
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)
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.
After listening to this episode listeners will…
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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.
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