type 2 diabetes management goals - admin.abcsignup.com€¦ · 1/15/2018 2 fasting insulin glucagon...

1/15/2018

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Current Diabetes Medications

Claire Baker, M.D.

Diabetes & Endocrine Associates

January 24, 2018

Disclosures

• None

Objectives

• Identify categories of diabetes

medications

• Understand the pharmacology of

diabetes medications

NON-INSULIN AGENTS


Diabetes Med Classes• Biguanides (metformin)

• Sulfonylureas (SU)

• Meglitinides (GLN)

• Thiazolidinediones (TZD)

• GLP-1 Receptor Agonists (GLP1)

• DPP-IV Inhibitors (DPP4)

• SGLT2 Inhibitors (SGLT2)

• Alpha Glucosidase Inhibitors (AGi)

• Amylin Analog (pramlintide, PRAM)

• Dopamine Agonist (bromocriptine, BQR)

• Bile Acid Sequestrant (cholesevelam, COLSVL)

• Insulin

MealtimeInsulin

Glucagon

Liver

Fat Muscle

Gut

Pancreas

Brain

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FastingInsulinGlucagon

Glucose

Old Paradigm: Components of

Glycemic Defects in Diabetes

Insulin demand Insulin supply

Hyperglycemia

↑ Insulin Resistance ↓Beta Cell Function

New Paradigm: Ominous Octet

DeFronzo RA. Diabetes. 2009;58:773-795

MuscleDecreased glucose

uptake

LiverIncreased endogenous glucose production

Adipose (fat)Increased free fatty

acid production

Digestive tractDecreased incretin effect

KidneyIncreased glucose reabsorption

BrainNeurotransmitter

dysfunction

Hyperglycemia

Pancreatic Beta CellDecreased Insulin Secretion

Pancreatic Alpha CellIncreased Glucagon Secretion












• Insulin

Metformin

• Mechanism

– Inhibit hepatic gluconeogenesis (primary effect)

– Decreases intestinal absorption of glucose

– Improves insulin sensitivity by improving

peripheral glucose uptake

• Renally cleared

• XR tablets will occasionally be eliminated in

feces intact

• Metformin, Glucophage, Glumetza, Fortamet, Riomet (a liquid version)– May be XR or ER

• With SU– Metaglip (glipizide/metformin)

– Glucovance(glyburide/metformin)

• With TZD– ActoPlus Met

(pioglitazone/metformin)

– Avandamet(rosiglitazone/metformin)

• With GLN– Prandimet

(repaglinide/metformin)

• With SGLT2

– Synjardy(empagliflozin/metformin)

– Xigduo(dapagliflozin/metformin)

– Invokament(canagliflozin/metformin)

• With DPP4

– Janumet (sitagliptin/metformin)

– Jentadueto(linagliptin/metformin)

– Kombiglyze(saxagliptin/metformin)

– Kazano (alogliptin/metformin)

Metformin: Available Meds

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Pharmacologically Targeting the Ominous Octet



uptake



acid production




dysfunction

Metformin














• Insulin

Sulfonylureas (SU)

• Stimulate insulin release from beta cells

• Long duration of action: taken once or twice daily

• Hepatic metabolism with active metabolites that are renally cleared

• Glipizide (Glucotrol)– Metaglip (glipizide/metformin

• Glyburide (Diabeta, Micronase, Glynase)– Glucovance (glyburide/metformin

• Glimepiride (Amaryl)– Duetact (pioglitazone/glimepiride

– Avandaryl (rosiglitazone/glimepiride)




uptake



acid production




dysfunction

SU

Metformin












• Dopamine Agonist (bromocriptine, BCR)


• Insulin

Meglitinides (GLN)

• Stimulate insulin release from beta cells via different receptor than the SU

• Have rapid onset and short duration, so taken before each meal

• Hepatic metabolism with active metabolites that are renally cleared

• Repaglinide (Prandin)

– Prandimet (repaglinide/metformin)

• Nateglinide (Starlix)

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uptake



acid production




dysfunction

SU, GLN

Metformin














• Insulin

TZDs

• Improve insulin sensitivity by acting on adipose tissue, muscle, and the liver

• Hepatic metabolism

• Pioglitazone (Actos)– ActoPlus Met (pioglitazone/metformin)

– Duetact (pioglitazone/glimepiride)

– Oseni (pioglitazone/alogliptin)

• Rosiglitazone (Avandia)– Avandamet (rosiglitazone/metformin)

– Avandaryl (rosiglitazone/glimepiride)




uptake



acid production




dysfunction

TZD

TZD

SU, GLN

Metformin, TZD














• Insulin

30 MM

α-Cells

–60 0 60 120 180 240

Time (min)

Carbohydrate meal

mg

/dL

Glucose120

100

80

μU

/mL Insulin

120

80

40

0

90

Glucagon

pg

/mL

120

110

100

Unger RH. N Engl J Med. 1971;285:443-449.

Response of Insulin and Glucagon After a Meal in

Persons Without Diabetes

β-Cells

Pancreatic islet

Islet boundary

Photomicrograph courtesy of Michael Sarras, PhD,

Rosalind Franklin University of Medicine and Science.

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Muller WA, et al. N Engl J Med. 1970;283:109-115.

80

100

120

140

160

–60 0 60 120 180 240

Time (min)

Glu

cagon (

pg/m

L)

0

50

100

150

–60 0 60 120 180 240

Insulin

(μ

U/m

L)

Non-DM

T2DM

Non-DM

T2DM

Inappropriate Insulin and Glucagon Responses to

Glucose in Patients With Type 2 Diabetes

Insulin Glucagon

Adapted from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-498.

Difference in Response to Oral vs Intravenous

Glucose Accounts for the Incretin Effect

0 60 120 180

Time (min)

C-P

eptide (

nm

ol/L)

Pla

sm

a G

lucose (

mg/d

L)

200

100

0

2.0

1.5

1.0

0.5

0.0

**

*

*

**

*

0 60 120 180

Time (min)

Oral glucose (50g)

or isoglycemic infusion

IV glucose

Oral glucose

MealtimeInsulin

Glucagon

Liver

FatMuscle

Gut

Pancreas

Brain

MealtimeInsulin

Glucagon

Liver

FatMuscle

Gut

Pancreas

Brain

Incretins

Increase glucose

dependent insulin

secretion

Decrease

hepatic glucose

production via

glucagon

suppression

Increase satiety

Slow gastric

emptying

*This effect is postulated to be mediated through the central nervous system

Adapted from Kolterman OG, et al. J Clin Endocrinol Metab. 2003;88:3082-3089; Adapted from Fehse F, et al.

J Clin Endocrinol Metab. 2005;90:5991-5997; Adapted from Nielsen LL, et al. Regul Pept. 2004;117:77-88

See accompanying Prescribing Information and safety information included in this presentation

Glucagon-Like Peptide1 Receptor

Agonists Incretins: Therapeutic Use

• GLP-1 is rapidly broken down by DPP-IV

limiting its usefulness as a medicine

• Current therapeutic options:

– GLP-1 analogs/mimetics/receptor agonists, which

resist degradation by DPP-IV

– DPP-IV inhibitors, which increase endogenous

levels of incretins

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GLP-1 Receptor AgonistsTanzeum (albiglutide) will be

discontinued by July 2018

Byetta (exenatide)Twice a Day

Two Doses (5 & 10 mcg)

Victoza (liraglutide)Once a Day

3 Doses (0.6, 1.2, 1.8 mg)

Bydureon (exenatide)Once a Week

One Dose (2 mg)

Trulicity (dulaglutide)Once a Week

Two Doses (0.75 and 1.5 mg)

Ozempic

(semiglutide)Once a week

2 Doses (0.5 and 1

mg)

GLP-1 and Insulin CombosOnce Daily Injections

Soliqua 100/33

• Glargine / Lixisenitide

• Delivers 15 – 60 units of

glargine along with 5 – 20

mg of lixisenatide

Xultophy 100/3.6

• Tresiba (degludec) and

Victoza (liraglutide)

• Delivers 10 – 50 units of

degludec and 0.36 – 1.8

mg of liraglutide




uptake



acid production




dysfunction

TZD

TZD

GLP1

GLP1

SU, GLN, GLP1

Metformin, TZD, GLP1

GLP1














• Insulin

DPP-4 Inhibitors

• Decrease metabolism of endogenous incretins, hence enhance typical incretin actions though to a lesser extent than the GLP1 drugs

• Metabolism varies by drug

• Januvia (sitagliptin). Adjust dose based on GFR– Janumet (sitagliptin/metformin)

• Tradjenta (linagliptin). Dose stable regardless of GFR– Jentadueto (linagliptin/metformin)

– Glyxambi (linagliptin/empagliflozin)

• Onglyza (saxagliptin). Adjust dose based on GFR– Kombiglyze (saxagliptin/metformin)

• Nesina (alogliptin). Adjust dose based on GFR– Kazano (alogliptin/metformin)

– Oseni (alogliptin/pioglitazone)




uptake



acid production




dysfunction

TZD

TZD

GLP1

GLP1, DPP4

SU, GLN, GLP1, DPP4

Metformin, TZD, GLP1, DPP4

GLP1



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• Insulin

SGLT2 Inhibitors

• Increase glycosuria (and diuresis) via inhibition of SGLT2 in the proximal tubule

• Increase glucagon, which is unwanted and may be why these drugs increase risk of DKA

• Ineffective with CKD

• Invokana (canagliflozin)– Invokamet (canagliflozin/metformin)

• Jardiance (empagliflozin)– Synjardy (empagliflozin/metformin)

– Glyxambi (empagliflozin/linagliptin)

• Farxiga (dapagliflozin)– Xigduo (dapagliflozin/metformin)




uptake



acid production




dysfunction

TZD

TZD

GLP1

GLP1, DPP4

SGLT2

SU, GLN, GLP1, DPP4


GLP1














• Insulin

Alpha Glucosidase Inhibitors (AGi)

• Inhibit the GI tract alpha glucosidases that

convert complex polysaccharide

carbohydrates into monosaccharides

• This slows absorption of glucose from the gut

• Metabolism varies. Contraindicated with CKD

• Precose (acarbose)

• Glyset (miglitol)

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uptake



acid production




dysfunction

TZD

TZD

GLP1

GLP1, DPP4

SGLT2

SU, GLN, GLP1, DPP4


GLP1, AGi














• Insulin

MealtimeInsulin

Glucagon

Liver

FatMuscle

Gut

Pancreas

Brain

MealtimeInsulin

GlucagonAmylin

Liver

FatMuscle

Gut

Pancreas

Brain

Amylin

Secreted

with insulin

Amylin

Slows gastric

emptying

Increases

satiety

Suppresses

glucagon

secretion Secreted

with insulin

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Symlin (pramlintide)

• Amylin analogue (co-secreted with insulin)

• Effects similar to GLP1 except no increase in

insulin secretion

– Primarily reduces post-prandial glucose and

increases satiety

• For type 1 and type 2 diabetics on insulin

• Injection prior to each meal




uptake



acid production




dysfunction

TZD

TZD

GLP1, Pram

GLP1, DPP4, Pram

SGLT2

SU, GLN, GLP1, DPP4

Metformin, TZD, GLP1, DPP4, Pram

GLP1, AGi














• Insulin

Cycloset: Bromocriptine Quick Release

(BQR)

• Bromocriptine is a dopamine agonist, usually

used to treat hyperprolactinemia and

Parkinsons

• A quick release version can be taken in the

morning

• Reduces glucose, but exact mechanism

uncertain

• Cycloset (bromocriptine QR)




uptake



acid production




dysfunction

TZD

TZD

GLP1, Pram, BQR

GLP1, DPP4, Pram

SGLT2

SU, GLN, GLP1, DPP4


GLP1, AGi












• Dopamine Agonist (bromocriptine, BCR)


• Insulin

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Welchol (Colesevelam)

• Bile acid sequestrant usually used for

hypercholesterolemia

• Exact mechanism unknown

• Not hepatically or renally metabolized

• Welchol (colesevelam)




uptake



acid production




dysfunction

TZD

TZD

GLP1, Pram, BQR

GLP1, DPP4, Pram

SGLT2

SU, GLN, GLP1, DPP4


GLP1, AGi, COLSVL



Noninsulin Agents Available for T2DClass Primary Mechanism of Action Agent(s) Available as

-Glucosidase

inhibitors

Delay carbohydrate absorption from

intestine

Acarbose

Miglitol

Precose or generic

Glyset

Amylin analogue

Decrease glucagon secretion

Slow gastric emptying

Increase satiety

Pramlintide Symlin

Biguanide Decrease liver glucose production

Increase glucose uptake in muscleMetformin Glucophage or generic

Bile acid sequestrant Decrease liver glucose production?

Increase incretin levels?Colesevelam WelChol

DPP4 inhibitors

Increase glucose-dependent insulin

secretion


Alogliptin

Linagliptin

Saxagliptin

Sitagliptin

Nesina

Tradjenta

Onglyza

Januvia

Dopamine-2 agonist Activates dopaminergic receptors Bromocriptine Cycloset

Meglitinides Increase insulin secretionNateglinide

Repaglinide

Starlix or generic

Prandin

DPP4, dipeptidyl peptidase; HGP, hepatic glucose production.

Garber AJ, et al. Endocr Pract. 2017;23:207-238.

ADA. Diabetes Care. 2017;40:S64-S74.

Noninsulin Agents Available for T2D

Class Primary Mechanism of Action Agent(s) Available as

GLP1 receptor

agonists

Increase glucose-dependent insulin

secretion


Slow gastric emptying

Increase satiety

Albiglutide

Dulaglutide

Exenatide

Exenatide XR

Liraglutide

Semaglutide

Tanzeum

Trulicity

Byetta

Bydureon

Victoza

Ozempic

SGLT2 inhibitors Increase urinary excretion of

glucose

Canagliflozin

Dapagliflozin

Empagliflozin

Invokana

Farxiga

Jardiance

Sulfonylureas Increase insulin secretion

Glimepiride

Glipizide

Glyburide

Amaryl or generic

Glucotrol or generic

Diaeta, Glynase,

Micronase, or generic

Thiazolidinediones

Increase glucose uptake in muscle

and fat

Decrease HGP

Pioglitazone

Rosiglitazone

Actos

Avandia

GLP1, glucagon-like peptide; HGP, hepatic glucose production; SGLT2, sodium glucose cotransporter 2.

Garber AJ, et al. Endocr Pract. 2017;23:207-238.

ADA. Diabetes Care. 2017;40:S64-S74.

Fixed-Dose Oral Combination Agents

for Type 2 DiabetesClass Added Agent Available as

DPP4 inhibitor + SGLT-2 inhibitorLinagliptin + empagliflozin Glyxambi

Saxagliptin + dapagliflozin Qtern

Metformin + DPP4 inhibitor

Alogliptin Kazano

Linagliptin Jentadueto

Sitagliptin Janumet

Metformin + glinide Repaglinide Prandimet

Metformin + SGLT2 inhibitorCanagliflozin Invokamet

Dapagliflozin Xigduo XR

Metformin + sulfonylureaGlipizide Metaglip and generic

Glyburide Glucovance and generic

Metformin + thiazolidinedionePioglitazone ACTOplus Met

Rosiglitazone* Avandamet

Thiazolidinedione + DPP4 inhibitor Pioglitazone + alogliptin Oseni

Thiazolidinedione + sulfonylureaPioglitazone Duetact

Rosiglitazone Avandaryl

INSULIN


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Current Insulin Options

Type Basal Insulins Prandial Insulins Premixed Insulins

Human

Humulin

Novolin

Relion

U-100 NPH U-100 regular human insulin

U-500 regular human insulin

Afrezza: inhaled insulin

U-100 70/30

Analog U-100 Lantus (glargine)

U-100 Basaglar (glargine)

U-100 Levemir (detemir)

U-100 Tresiba (degludec)

U-200 Tresiba (degludec)

U-300 Toujeo (glargine)

U-100 Humalog (lispro)

U-100 Novolog (aspart)

U-100 Apidra (glulisine)

U-200 Humalog (lispro)

U-100 Fiasp (aspart + Vit B3)

U-100 50/50 Humalog

U-100 70/30 Novolog

U-100 75/25 Humalog

Analogue insulins are associated with less hypoglycemia than human

insulins, although these differences are not always statistically significant

Pharmacokinetics of Available Insulins

Agent Onset (h) Peak (h) Duration (h) Considerations

Ba

sa

l

NPH 2-4 4-10 10-16Greater risk of nocturnal hypoglycemia compared to

insulin analogs

Glargine

Detemir

Degludec

~1-4

No

pronounced

peak*

Up to 24† Less nocturnal hypoglycemia compared to NPH

Ba

sa

l-

Pra

nd

ial

Regular U-500 ≤0.5 ~2-3 12-24

Inject 30 min before a meal

Indicated for highly insulin resistant individuals

Use caution when measuring dosage to avoid

inadvertent overdose

Pra

nd

ial

Regular ~0.5-1 ~2-3 Up to 8

Must be injected 30-45 min before a meal

Injection with or after a meal could increase risk

for hypoglycemia

Aspart

Glulisine

Lispro

Inhaled insulin

<0.5 ~0.5-2.5 ~3-5

Can be administered 0-15 min before a meal

Less risk of postprandial hypoglycemia compared

to regular insulin

* Exhibits a peak at higher dosages.

† Dose-dependent.

NPH, Neutral Protamine Hagedorn.

Moghissi E et al. Endocr Pract. 2013;19:526-535. Humulin R U-500 (concentrated) insulin prescribing information. Indianapolis: Lilly USA, LLC.

Insulin PharmacologyLong Acting Insulin Action Profiles

Short Acting Insulin Action Profiles What’s New With Insulin

• Ultra-rapid insulin

• Biosimilars

• More concentrations

• Inhaled insulins

• Patch delivery device

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Fiasp (aspart)

• Ultra rapid acting insulin

• Aspart (Novolog) with niacinamide (vitamin

B3) added

• Approved by FDA and will enter market soon

Fiasp (aspart + B3) vs Novolog (aspart)

Novorapid is the European and

Canadian tradename for Novolog

(aspart)

What’s New With Insulin


• Biosimilars




Generic vs Biosimilar

Generic

• Copies of brand name drugs with the same chemical structure and active ingredient. Are the same in regards to dosage form, safety, strength, route of administration, performance characteristics, and intended use

• Generic and brand are bioequivalent and can be substituted for one another without intervention of HCP

Biosimilar

• Biologic products made from living organisms, highly similar to reference product. Undergoesthorough structural and functional characterization of the product

• Intended to produce the same effects

• Not identical copies of biologic products and cannot be substituted without authorization of HCP

Biosimilar Glargine

• Original product: Lantus

– Available in vials and pens

• Biosimilar product: Basaglar

– Available in pens only

• Other biosimilars will be coming



• Biosimilars




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Insulin Concentrations

Concentration TypesUnits per

mL

Units per

Vial

Units per

Pen

U-100 Many 1001000 (10 mL

vial)

300 (3 mL

pen)

U-200

Humalog

(lispro)200 No Vials

600 (3 mL

pen)

Tresiba

(degludec)200 No Vials

600 (3 mL

pen)

U-300Toujeo

(glargine)300 No Vials

450 (1.5 mL

pen)

U-500Humulin

Regular500

10,000 (20

mL vial)

1500 (1.5 mL

pen)

Most insulins have been U-100. The U-100 indicates

there are 100 units of insulin per every 1 mL. Nearly

all insulin syringes are made for U-100 insulin.

• Regular insulin at 5 X the typical concentration

• Action profile is a mix of Regular and NPH

• For patients with significant insulin resistance

• High risk of dosing error which is minimized with the U-500 pen and the dedicated U-500 syringe

– Only use a U-100 syringe or tuberculin syringe with the vial when everyone is aware of the dose and concentration

Humulin U-500What’s New With Insulin


• Biosimilars




Afrezza: Technosphere Formulation of

Human Insulin

• Inhaled human

insulin which is very

rapidly absorbed

• For mealtimes only

• 4, 8, and 12 unit

cartridges



• Biosimilars




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V-Go

• Mechanical pump that patients fill with rapid acting insulin

• Changed daily

• Delivers 20, 30, or 40 units of background insulin over 24 hours

• 36 units are available for boluses, 2 units per click

Questions?

type 2 diabetes management goals - admin.abcsignup.com€¦ · 1/15/2018 2 fasting insulin glucagon...

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