Diabetes MellitusLecture 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

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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

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Pramlintide Postprandial Effects

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Pramlintide Efficacy

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•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‡

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

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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

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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

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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

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Dapagliflozin

• 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

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Dapagliflozin: Bone Issues

• Bone demineralization, fractures: noted in patients also with kidney disease

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Empagliflozin

• 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

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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)• All eGFR 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

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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

• Βeta-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)

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SGLT2i: Place in Therapy (AACE, PSW)

PSW Diabetes Toolkit19

AACE

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

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Considerations:Insulin for Type 2 Diabetes• +/- discontinue oral agents• Long-standing Type 2 diabetes• NPH or detemir or glargine or degludec• Abrupt vs 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

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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

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Insulin Dosing: Type 2(See JPSW insulin dosing article-Canvas for specifics)

Bedtime/basal regimens

• Treat-to-Target Trial

• Hirsch real-world approach

• IDC protocols

Basal/bolus regimens

• Moordian method

• IDC protocols

• Premix initiation

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Type 2 insulin dosing: typical start 0.1-0.2 units/kg single daily dose

0.2-0.5 units/kg more intense insulin

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

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U-500 vs U-100 PK & PD inObese, Healthy Volunteers

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Diabetes Care. epub ahead of print 10.12.11

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

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U-300 Insulin glargine: Toujeo® SoloStar® pen• Approved 2.25.15; launched

April 2015 • 300 units per mL• Injected once daily at same time• Effects last beyond 24 hours

• Advantages• Dose contained in one-third

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

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U-200 insulin degludec: Tresiba 200 units/mL FlexTouch®

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• 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

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

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Diabetes Care. 2008;31:1-6.

Relationship of A1c to blood glucose

eAG calculator

https://professional.diabetes.org/diapro/glucose_calc

False Low or False High A1c

False Low• Kidney disease (CKD)• Anemia/elevated reticulocyte

count• IV iron/ESAs

False High

• Kidney disease (CKD)• Hypothyroidism/thyroid

hormone replacement• Deficiencies

• Iron• B12• folate

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Glycemia Monitoring: Fructosamine

• Fructosamine• Not routine• Usually done

• Hemoglobinopathies• When A1c and SMBG do not correlate

• Frequency of testing (2 weeks to monthly)

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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

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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

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For what medications would 2 hour postprandial glucose monitoring be helpful to assess efficacy?

Postprandial glucose & A1c

35Monnier. Diabetes Care. 2003;26(3):884.

Self Monitoring of Blood Glucose (SMBG)

• SMBG (ADA recommendations):• unstable Type 1• pregnancy• hypo/hyperglycemia• hypoglycemic unawareness• intensive insulin therapy• insulin treated patients

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SMBG Supplies

• $$$• Glucose meter monitoring

• Meter• Strips• Lancet device• Lancets• +/- Alcohol swabs

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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

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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

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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

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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

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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)

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