Diabetes Mellitus Lecture 4 Learning Objectives: Lec 4
• Compare & contrast the pharmacodynamic efficacy and adverse effect profiles of pramlintide and SGLT-2 inhibitors • Discuss use of insulin products (including concentrated insulins) for patients with type 1 & type 2 diabetes • Recommend appropriate treatment and monitoring parameters for patients taking the above medications • Create glucose monitoring plans for patients with type 1 and type 2 diabetes • Counsel a patient related to glucose monitoring
2 Pramlintide (Symlin®)
• Synthetic analog of human amylin • Amylin produced by β-cells • Slows gastric emptying • Decreases postprandial glucagon conc. • Centrally mediated effects on appetite • Reduce preprandial rapid- or short-acting insulin doses (even 70/30) by 50% • Duration of action: 3 hours • 0 to 0.5% drop in A1c
3 Pramlintide Postprandial Effects
4 Pramlintide Efficacy
•Smoother blood glucose levels throughout the day •An improvement in the number of blood glucose levels within the normal glycemic range of 70 to 180 mg/dL‡
5 Pramlintide
• Main side effect: nausea* (30-37%) • Dosing for Type 1 DM • Start 15 mcg prior to major meals • Titrate in 15 mcg increments when no nausea present x 3 days • Max: 60 mcg per dose • Dosing for Type 2 DM • Start 60 mcg prior to major meals • Increase to 120 mcg doses when no nausea present x 3-7 days • SMBG: pre & post meals + bedtime
6 Canagliflozin (Invokana®)
• FDA approval 3.29.13 • Dosing: • Start: 100 mg once daily prior to first meal (if eGFR is at least 45 mL/min/1.73m2) • Titrate: from 100 mg to 300 mg after 12 weeks (if needed) • Max dose • 300 mg once daily & eGFR is at least 60 • 100 mg once daily if eGFR 45-59 7 Canagliflozin • Efficacy • 100 mg: A1c -0.7 to -0.8% • 300 mg: A1c -0.8% to -1.0% • Adults >65 may have slightly less effect (& greater toxicity) • Toxicity • Increased urination • Mycotic genital infections • Women: 10-12% • Men: 4% • UTI:% 4-8 • Dizziness, orthostatic hypotension • Adults >65 likely to have greater decrease in body weight & greater decreases in SBP & DBP • Hyperkalemia: 1-2% (more likely if predisposed to hyperkalemia) • Pricing • ~$17.16 per day
8 Canagliflozin: bone fracture, decreased BMD • FDA strengthened label warnings: Sep 10, 2015 • Drug: canagliflozin • Fractures: • More frequent cana vs placebo • 12 wks after starting cana • Often minor trauma (fall from standing) • Decreased BMD: • Greater bone loss: hip, lower spine vs placebo
http://www.fda.gov/Drugs/DrugSafety/ucm461449.htm Canagliflozin: amputations
• CANVAS, CANVAS-R trials • Type 2 diabetes + CVD/risk for CVD • Amputations: 2-fold increased risk • Most frequent: toe, midfoot • Also: leg • Some: multiple amputations, both limbs • Not all people had risk factors for amputations • Consider risks for amputation • Prior amputation • PVD • Neuropathy • Foot ulcers • Patient monitoring: infection, new pain/discomfort, lower limb/foot ulcers • Canagliflozin boxed warning • Flip side: CREDENCE trial (April 2019 pub): No amputation increase
• Farxiga® approved 1.8.14 • Dosing: • Start 5 mg every morning (±food) • No adjustment if hepatic impairment • Avoid use if eGFR less than 45 mL/min (increased adverse reactions)-updated 3.1.19 • Can increase to 10 mg in about 4-8 weeks • Efficacy: A1c -0.6 to -0.9% monotherapy • Toxicity: 5% or greater genital mycotic infections, UTIs; orthostatic hypotension, dehydration possible, hyperkalemia possible • Pricing: $17.22 per day
11 Dapagliflozin: Bone Issues
• Bone demineralization, fractures: noted in patients also with kidney disease
• Jardiance® approved 8.1.14 • Dosing: • Start 10 mg once daily in AM (±food) • May titrate to 25 mg at 12 weeks • Efficacy: A1c -0.7 to -0.8% monotherapy • Toxicity: • UTIs • Female genital infections • Orthostatic sx & dehydration & hyperkalemia possible • Pricing: $17.22/day
13 ASCVD Benefits: SGLT-2i
• FDA-approved cardiovascular indications • Canagliflozin: reduced risk major adverse CV events (MACE) in pts with CVD • Empagliflozin: reduced risk of CV death in pts with CVD • Meta-analysis (Lancet 1.5.19) • Hospitalization for composite of HF/CV death: • HR 0.77 (95% CI 0.71-0.84) in subjects with ASCVD but NO effect if only risk factors • HR 0.71 (95% CI 0.61-0.84) in subjects with history HF • HR 0.79 (95% CI 0.71-0.88) in subjects without HF • Composite MI/CVA/CV death • HR 0.86 (95% CI 0.80-0.93) in subjects with ASCVD but NO effect if only risk factors Kidney Benefits: SGLT2i
• Systematic review & meta-analysis (September 2019) • 3 meds: empagliflozin, canagliflozin, dapagliflozin • 38,723 subjects from 4 large studies (1 empa, 2 cana, 1 dapa) • Outcomes • Risk of dialysis, transplant, kidney-related death: RR 0.67 (95% CI 0.52-0.86) • End-stage kidney disease: RR 0.65 (95% CI 0.53-0.81) • Acute kidney injury: RR 0.75 (95% CI 0.66-0.85) • AllGFR e subgroups benefitted, including eGFR 30-45 • No difference in outcomes according to baseline albuminuria status or use of ACEi/ARB
Lancet Diabetes Endocrinol. 2019;7(11):845-854 Ertugliflozin
• Steglatro® approved 12.22.17 • Dosing: • 5 mg & 15 mg tablets available • Start 5 mg every morning (±food); can titrate in 4-8 weeks • LIVER: No adjustment if liver impairment but avoid if severe liver disease • KIDNEY: • eGFR 30 to < 60 mL/min (persistent): do not start, consider stopping if already taking • eGFR less than 30 mL/min (increased adverse reactions)-AVOID • Efficacy: A1c -0.6 to -0.9% monotherapy • Toxicity: 5% or greater genital mycotic infections, UTIs; orthostatic hypotension, dehydration possible, hyperkalemia possible • Pricing: average price $9.91 per day
16 Safety Concerns: euglycemic ketoacidosis & Fournier gangrene • euDKA: • Often LADA or T1DM or +GAD65 antibodies • Normal or mildly elevated BG (<250 mg/dL) + n/v/SOB/malaise • Associated factors • Β eta-cell insufficiency/longer disease • Reduced insulin doses • Prolonged starvation/intercurrent illness/surgery • FDA warning for all SGLT-2 inh: May 15, 2015 • Fournier Gangrene • FG=necrotizing fasciitis of the perineum (rare but serious, life-threatening) • Pt consultation: seek immediate medical attention if redness/ swelling/ tenderness of genital areas + fever SGLT2i: Place in Therapy (ADA)
18 SGLT2i: Place in Therapy (AACE, PSW)
AACE
PSW Diabetes Toolkit 19 Role of Insulin: Type 2 Diabetes • Who? • Stress to body • Hypersensitivity/intolerance to oral agents • Primary or secondary failure with oral agents • Initial tx for patients with ketosis, severe glycosuria or weight loss • Lean Type 2
20 Considerations: Insulin for Type 2 Diabetes • +/- discontinue oral agents • Long -standing Type 2 diabetes • NPH or detemir or glargine or degludec • sAbrupt v taper of oral agents • Consider in elderly: vision, dexterity, cognition, finances, caregiver • Increase in use of single daily dose insulin due to: • OHA failures • More patients with longer duration DM
21 Combination: Insulin & Oral Agents-WHY? • Resistance • True resistance vs. worsening disease • Barriers to multiple daily injections in older adults • Synergism • Insulin mechanism • Potential A1c but depends on how aggressively insulin titrated
22 Insulin Dosing: Type 2 (See JPSW insulin dosing article-Canvas for specifics)
Bedtime/basal regimens Basal/bolus regimens • Treat-to-Target Trial • Moordian method
• Hirsch real-world approach • IDC protocols
• IDC protocols • Premix initiation
Type 2 insulin dosing: typical start 0.1-0.2 units/kg single daily dose 0.2-0.5 units/kg more intense insulin
23 U-500 Regular Insulin • Candidates • Administration-MANY safety issues! • Vials: syringe issues (separate, 30 g needles avail if using TB syringes) • Dose by units AND by volume [e.g. 0.21 mL (105 units)] • Pens: preferred!!!!!!!!!!!!!!!!!!! • NO self-adjusting! • ± with meals • 2- 4 injections per day; occ need lowest dose at night
24 U-500 vs U-100 PK & PD in Obese, Healthy Volunteers
Diabetes Care. epub ahead of print 10.12.11
25 U-200 Insulin lispro: Humalog 200 units/mL KwikPen® • Bioequivalent: similar efficacy • 600 units in the pen • 200 units per mL x 3 mL in pen = 600 units per pen • Pen: same size, design, utility as U100 Humalog Kwikpen • Advantages • Similar efficacy as noted above • Fewer pens needed per month • Same dose in half the volume • Disadvantages • Possible dispensing confusion • Possible patient confusion given similar Kwikpen colors • Safety issues
26 U-300 Insulin glargine: Toujeo® SoloStar® pen • Approved 2.25.15; launched April 2015 • 300 units per mL • Advantages • Injected once daily at same time • Dose contained in one-third • Effects last beyond 24 hours volume compared to Lantus® • Smaller depot area may mean better insulin absorption • Disadvantages • Pen has green “button” as does a different insulin pen on market • Safety issues
27 U-200 insulin degludec: Tresiba 200 units/mL FlexTouch® • 600 units in the pen • 200 units per mL x 3 mL in pen = 600 units per pen • Pen: same size, design, utility as U100 degludec • Advantages • Up to 160 units in single injection • 2-unit dose increments • Same dose in half the volume compared to Tresiba 100 units/mL • In-use pen (regardless of storage) or unopened at room temp: 56 day expiration • Disadvantages • Possible dispensing confusion • Possible patient confusion given similar pen colors • Safety issues
28 Glycemia Monitoring: A1c
• Glycosylated hemoglobin (HbA1c or A1c) • average control over 3 months • nonfasting test • normal range: ~ 4-6% • frequency of testing (every 3 months) • ADAG study & conversion to average blood glucose • 28.7 X A1C – 46.7 = eAG
Diabetes Care. 2008;31:1-6.
29 Relationship of A1c to blood glucose eAG calculator
https://professional.diabetes.org/diapro/glucose_calc False Low or False High A1c
False Low False High • Kidney disease (CKD) • Kidney disease (CKD) • Anemia/elevated reticulocyte • Hypothyroidism/thyroid count hormone replacement • IV iron/ESAs • Deficiencies • Iron • B12 • folate
31 Glycemia Monitoring: Fructosamine
• Fructosamine • Not routine • Usually done • Hemoglobinopathies • When A1c and SMBG do not correlate • Frequency of testing (2 weeks to monthly)
32 Glycemia Monitoring: Fasting Plasma Glucose • Reproducible • Fasting 8 hours • Reflection: hepatic glucose production • Normal (non-DM) range 70-100 mg/dl (nonpregnant) • Goal for DM range 80 to 120 mg/dL or 90-130 mg/dl or 70-130 mg/dL (nonpregnant) • Clinical or home monitoring
33 Glycemia Monitoring: 1 to 2-hour Postprandial • Utility • Efficiency of peripheral glucose uptake • Goals: • see lecture 1 (<180 mg/dL) • 30-50 mg/dL above preprandial value • Clinic or home monitoring
For what medications would 2 hour postprandial glucose monitoring be helpful to assess efficacy?
34 Postprandial glucose & A1c
Monnier. Diabetes Care. 2003;26(3):884. 35 Self Monitoring of Blood Glucose (SMBG)
• SMBG (ADA recommendations): • unstable Type 1 • pregnancy • hypo/hyperglycemia • hypoglycemic unawareness • intensive insulin therapy • insulin treated patients
36 SMBG Supplies
• $$$ • Glucose meter monitoring • Meter • Strips • Lancet device • Lancets • +/- Alcohol swabs
37 SMBG-Type 1 Diabetes
• Overall: more intensive monitoring required • QID for intensive insulin therapy: otherwise, control falls to baseline • Unknown optimal frequency for other patients (3 or more times daily recommended) • More frequent with insulin dose changes
38 SMBG-Type 2 Diabetes
• Overall, less intensive monitoring required • Frequency of monitoring is patient-specific • Type 2 insulin patients: more frequent monitoring than if on oral agents only • More frequent with dose changes (insulin or oral agents) • Stable oral regimen: 2-3 times per week & just once daily on those days • Best time to check is FBG (prior to breakfast) with once daily monitoring
39 40 SMBG Pearls
• BID monitoring • Too frequent? Too infrequent? • QID monitoring can be painful • Option (if ok with rest of health care team): • Day 1: prior to breakfast, evening meal • Day 2: at noon, at bedtime • Repeat pattern • Option (if ok with rest of health care team): • 4x/day every other day
41 SMBG Pearls
• Postprandial glucose monitoring • For patients on • rapid -acting analog insulin (think onset,duration) • acarbose/miglitol (remember MOA) • DPP-4 inhibitor or GLP-1 agonist • Alternative site testing • When to avoid alt. site testing • Lancing device cap color
42 Key Points-glucose monitoring
• SMBG • Who to monitor? • When to monitor? • How to monitor? • Frequency • Fingertip vs alternate site • Think: E x 2 (educate & empower)
43