#51: Diabetes treatment in 2017: New meds, insulin, and cardiac risk reduction

August 7, 2017 | By Matthew Watto, MD

Get cozy with these new drugs for diabetes treatment. Don’t be scared, they won’t bite. On this episode,  we interview Endocrinologist and current president of AACE, Dr. Jonathan D. Leffert, MD, FACP, FACE, ECNU about how to utilize the myriad of new diabetes drugs on the marketplace including SGLT2 inhibitors, DPP4 inhibitors, GLP1 agonists, and new ultra long acting insulins. Plus, we’ll teach you how to choose between agents, common side effects, A1C goals, and the cardiovascular benefits of these newer agents. Help patients afford their meds with this resource from AACE http://prescriptionhelp.aace.com

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Case: Case from Kashlak Memorial Hospital: 49 yo M with HTN, BMI 29, hyperlipidemia, family history of premature CAD (dad age 45yo), and type 2 diabetes with A1C increase from 6.4% to 9% while on metformin monotherapy.

Clinical Pearls:

1. Latent autoimmune diabetes of aging (LADA): Autoimmune disease similar to type 1 diabetes (DM1). Suspect if older adult presents w/new insulin dependence. Check glutamic acid decarboxylase (GAD) antibodies, which are most sensitive and specific. Often positive in LADA/DM1. Can also check islet cell Ab or insulin autoantibodies.
2. A1C and anemia: Based on red cell (RBC) survival. Falsely high a1c if RBC turnover is low → Older RBCs that accumulate more glucose e.g. Iron, vitamin B12, or folate deficiency anemia. Falsely low a1c if rapid RBC turnover e.g. hemolysis, or on treatment for iron, B12, or folate deficiency, or erythropoietin injections (Source: UptoDate)
3. Fructosamine and A1C: Fructosamine is bound to albumin in blood. Turnover of albumin is about 28 days vs 120 days for hemoglobin. Thus, fructosamine provides estimate of mean glucose levels over about 2 weeks (vs 3 months w/a1c). Use if unreliable a1c values (see anemia above).
4. SGLT2 inhibitor (SGLT2i): Inhibit cotransporter for sodium and glucose in proximal tubule of kidney. Lower a1c Low risk for hypoglycemia. Avoid use if eGFR is below 45 ml/min. Possible side effects = hypotension, hypovolemia, urinary frequency, candidal infections of genitals. Possible increased bone fractures, euglycemic DKA, and lower extremity amputations. Check renal function 4-6 weeks after starting an agent. Consider holding diuretic if BP borderline low even before starting SGLT2i. Some agents include empagliflozin (Jardiance), canagliflozin (Invokana).
5. Euglycemic DKA: Occurs in patients with DM1 or DM2 with low levels of endogenous insulin. SGLTi keeps blood glucose below 250 mg/dL → less insulin use → insulin deficiency and possible failure to recognize ketoacidosis.
6. GLP-1 agonists: Enhance glucose-dependent insulin secretion, slow gastric emptying, regulate postprandial glucagon, and reduce food intake. Injectable agents like liraglutide, exenatide, etc. Lower a1c 1% (avg, range 0.5-1.5%). Low risk hypoglycemia. Promote weight loss. Side effects: nausea, tachycardia, headache. Possible increased risk hepatobiliary disease. Avoid if h/o MEN syndrome or thyroid C cell tumors (Source UptoDate).
7. GLP-1 vs SGLT2: GLP1 generally with superior glucose lowering and weight loss, but require daily, or weekly injections. Possible CV risk reduction with both classes if patient has existing CVD.
8. DPP4 inhibitors: Block DPP-4 enzymatic degradation of GLP-1. Lower a1c 0.5%. Low risk hypoglycemia. Pointless and expensive to utilize concomitantly w/GLP-1 agonists, because they’re already resistant to endogenous DPP4. Side effects: headache, nasopharyngitis, and upper respiratory tract infection. Link to acute pancreatitis uncertain. (Source UptoDate)
9. Degludec: Long acting insulin. Daily injection. No peak, thus lower risk hypoglycemia.
10. U200 insulin = 200 units/mL vs U100 insulin = 100 units/mL. Thus, a volume of 0.5 mL U200 provides 100 units of insulin versus a volume of 0.5 mL U100 provides 50 units of insulin. U200 is more concentrated thus patients with large doses can inject less volume!!! Get it?
11. EMPA-REG Trial (empagliflozin), CANVAS Trial (canagliflozin), and Leader Trial (liraglutide): Each of these randomized placebo controlled trials in patients with DM2 and known CVD (“high CV risk”) showed lower incidence of primary composite outcome of death from CV causes, nonfatal MI, or nonfatal stroke with empagliflozin, canagliflozin, and liraglutide. Of note, possible increased risk lower extremity amputations in canagliflozin group.

Goal: Listeners will identify patients who may benefit from newer agents for diabetes, and safely utilize these agents for treatment of diabetes and cardiovascular risk reduction

Learning objectives:
After listening to this episode and reviewing the show notes listeners will…

1. Determine an appropriate A1C goal for each patient
2. List the new classes of medications available for type 2 diabetes treatment
3. Recall the basic mechanism of action for diabetes medications
4. Identify patients who may benefit from newer agents for type 2 diabetes treatment
5. Monitor and adjust a patient’s medication regimen to reach A1C goals
6. Counsel patients on possible side effects of newer agents for type 2 diabetes
7. Utilize diabetes medications to lower cardiovascular risk
8. Identify patients who may benefit from ultra long acting insulin
9. Explain the difference between U100, and U200 insulin

Disclosures:
Dr. Leffert reports research grants from Novo Nordisk, Inc., Boehringer Ingelheim, Sanofi US, AbbVie, Inc., Mylan Gmbh, Astra Zeneca, Bristol-Myers Squibb Research & Development, KOWA Research Institute.

Time Stamps

00:00 Intro
04:33 Getting to know our guest
09:50 Clinical case of diabetes
12:40 Latent autoimmune diabetes
15:16 Life expectancy and A1C goal
16:47 Anemia’s effect on A1C
18:40 Back to our case, choice of diabetes treatment
20:57 Lifestyle changes effect on A1C
22:55 Starting an SGLT2 inhibitor, what to look for
26:45 SGLT2 inhibitor use in patient already on diuretic
27:53 Discussion of CV risk reduction and newer diabetes treatment
33:27 Euglycemic DKA
34:30 Choice of agent GLP1 vs SGLT2 for diabetes treatment
37:10 Use of DPP4 inhibitors
38:55 Back to the case
39:37 Degludec, long acting insulin for diabetes treatment
41:34 Clinical case conclusion
43:03 Take home points
45:15 Outro

Links from the show:

1. Start with why (book) by Simon Sinek
2. AACE Algorithm for DM2 on iTunes
3. Is Glucose Self-Monitoring Worthwhile in Non–Insulin-Treated Diabetes? NEJM Journal Watch Jul 2017
4. Glucose Self-monitoring in Non–Insulin-Treated Patients With Type 2 Diabetes in Primary Care Settings A Randomized Trial. JAMA June 2017
5. (EMPA-REG) Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes NEJM 2015
6. (CANVAS) Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes NEJM 2017
7. Glucose-lowering drugs or strategies and cardiovascular outcomes in patients with or at risk for type 2 diabetes: a meta-analysis of randomised controlled trials. Lancet Diabetes Endo 2015
8. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes NEJM 2016