11/2/2016 Jeopardy: Update on Diabetes Pharmacotherapy cornell medication update handout for...
Transcript of 11/2/2016 Jeopardy: Update on Diabetes Pharmacotherapy cornell medication update handout for...
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Jeopardy: Update on Diabetes Pharmacotherapy
Susan Cornell, BS, PharmD, CDE, FAPhA, FAADE
Associate ProfessorMidwestern University ‐ Chicago College of Pharmacy
• Describe the mechanism of action and unique features of the 6 classes of medications that are recommended by the ADA as second‐line therapies for type 2 diabetes.
• Discuss contraindications and side effect considerations when recommending second‐line therapies for type 2 diabetes.
• Given a patient case where the patient has reached the maximal dosage of metformin, select among second line treatment options for individualize care.
Objectives
Why is Glucose Control Important?
• 60% of people with type 2 diabetes have at least 1 complication because of diabetes
– Complications are often present at time of diagnosis
AACE. State of diabetes complications in America. 2007. http://multivu.prnewswire.com/mnr/AACE/2007/docs/Diabetes_Complications_Report.pdf
(accessed 2016 Aug 20).
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β‐cell Decline in Prediabetes and T2DM
DeFronzo RA. Diabetes. 2009; 58:773‐95.
Chan
ge in
insulin
/ chan
ge glucose / IR
Normal glucose tolerance
Impaired glucose tolerance
Type 2 diabetes
IR = insulin resistance
The Ominous Octet: Circa 2008
musclee
Pancreas‐ ß‐cellPancreas – α‐cell
Liver
GI tract‐stomach/small
intestine
Peripheral tissue
Brain
Kidney
Cornell S et al. Postgrad Med. 2012; 124:84‐94.Defronzo RA. Diabetes. 2009; 58:773‐95.
Fat cells(adipose tissue)
Hyperglycemia
Treatment Approach to T2DM• Dietary changes
• Reduce consumption of calories• Reduce consumption of simple carbohydrates
• Increase physical activity
• Medications• Improve or replace insulin secretion• Reduce insulin resistance• Reduce glucagon secretion• Reduce hepatic glucose production• Increase urinary glucose excretion
DeFronzo RA et al. Diabetes Care. 2013; 36(suppl 2):S127‐38.
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Insulin (1) Bolus insulin
– Insulin lispro• U100
• U200
– Insulin aspart
– Insulin glulisine
– Insulin human inhaled
– Regular human insulin
Basal insulin– Insulin NPH
– Insulin detemir
– Insulin degludec• U100
• U200
– Insulin glargine• U100
• U300
Oral Medications (9)– -glucosidase inhibitors (AGI)
– Biguanides
– Bile acid sequestrants (BAS)
– Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins)
– Dopamine agonists
– Glinides
– Sulfonylureas (SU)
– Sodium Glucose Co-Transporter-2 inhibitors (SGLT-2i)
– Thiazolidinediones (TZDs or glitazones)
Non-insulin injectable agents (2)– Glucagon-like peptide-1 (GLP-1)
agonists
– Amylinomimetic
12 Pharmacotherapy Options
Cornell S et al. Postgrad Med. 2012;124:84-94. www.pdr.net (accessed 2016 June 30). .
ADA Standards of Medical Care in Diabetes (2015)
• Inzucchi SE et al. Diabetes Care. 2015; 38:140‐9.
Garber AJ. Endocr Pract. 2016; 22:84‐113.
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Oral Agents
• Affordable
• Possible weight loss benefit
• Low risk of hypoglycemia
• GI side effects can be managed
• Risk of lactic acidosis far less than feared
• Effectively lowers BG and A1c
– Though not sustainable as monotherapy
Metformin:Current Cornerstone of Therapy
Rational Choices for second‐line add‐on to Metformin
Drugs that target different metabolic defects
Combine medications that work at different tissue sites for synergy
Drugs that target fasting and postprandial glucose control
Select therapies that support patient goals Low hypo risk
Weight neutral, loss
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Sulfonylureas
• Glimepiride – Amaryl ®
• 1mg, 2mg, 4mg• Once daily
• Glipizide – Glucotrol ®
• 5mg, 10mg• Once to twice daily
– Glucotrol XL ®• 2.5mg, 5mg, 10mg• Once daily
• Glyburide – Micronase ®
• 1.25mg, 2.5mg, 5mg• Once to twice daily
– Diabeta ®• 1.25mg, 2.5mg, 5mg• Once to twice daily
– Glynase ®• 1.5mg, 3mg, 6mg• Once to twice daily
Sulfonylureas: 1st Generation
Titrate every 2-4 weeks based on FPG
Sulfonylureas• Stimulates insulin release from the pancreas
– Long acting stimulation (>6 hours)
– Requires endogenous insulin to be affective; therefore better used early in the disease; if necessary
– Short durability
• Lowers fasting and postprandial glucoseDecreases A1c by 1.5‐2% (~45‐60 mg/dl)
• Most common side effects• Hypoglycemia• Weight gain
• may inhibit ischemic pre‐conditioning
Cornell S, Lullo A. Diabetes Trends 2009.
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Meglitinides
• Repaglinide– Prandin ®
• 0.5mg, 1mg, 2mg• Up to three times daily before meals
• Nateglinide– Starlix ®
• 60mg, 120mg• Up to three times daily before meals
Glinides
• Stimulates insulin release from the pancreatic beta cells
– Short acting stimulation (30 minutes to 4 hours)– Requires endogenous insulin to be affective; therefore better used early in the disease; if necessary
– Short durability
• Lowers postprandial glucose• Decreases A1c by 0.5‐1% (~15‐30 mg/dl; more postprandial)
• Most common side effects• Hypoglycemia• Weight gain
Cornell S, Lullo A. Diabetes Trends 2009.
TZD’s (Glitazones)
• Pioglitazone– Actos ®– 15mg, 30mg, 45mg– Once daily
• Rosiglitazone– Avandia ®– 2mg, 4mg, 8mg– Once to twice daily
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TZD’s (Glitazones)
• Stimulates PPRA γ to increase GLUT‐4 transporter production; thereby moving glucose from the blood into the peripheral tissue.
• Also reduces adipose fat– Can be used thru duration provided insulin is present
– Good durability
• Lowers fasting and postprandial glucose
• Decreases A1c by 1.0‐1.5% (~30‐45 mg/dl)
• Most common side effects
• Edema (swelling) usually in the legs
• Weight gain
• Possible ↑ risk of fractures.
• Takes 4‐6 weeks (or more) to take affect and requires insulin (endogenous or exogenous) Cornell S, Lullo A. Diabetes Trends 2009.
DPP4 Inhibitors (gliptins)• Sitagliptin (Januvia ®)
– 25 mg, 50 mg, & 100 mg
– Once‐daily dosing
– Dose adjustment in renal impairment
• Saxagliptin (Onglyza ® )– 2.5 mg & 5 mg
– Once‐daily dosing
– Dose adjustment in renal impairment
• Linagliptin (Tradjenta ®)– 5 mg
– Once‐daily dosing
• Alogliptin (Nesina ®)– 6.25 mg, 12.5 mg, & 25 mg
– Once‐daily dosing
– Dose adjustment in renal impairment
DPP4 Inhibitors (gliptins)
• Inhibits DPP‐4 enzyme in the GI tract that breaks down GLP‐1 resul ng in ↑ endogenous GLP‐1. – glucagon suppression (from pancreatic alpha cell) results in ↓ liver glucose production
– Enhances appropriate insulin and amylin secretion from the pancreatic beta cells
– Can be used thru duration provided insulin is present• Promising durability
• Lowers postprandial glucose– Decrease A1c by 0.5 to 0.7% ( ~15‐20 mg/dl; most postprandial)
• Most common side effects• Stuffy, runny nose• Headache• Upper respiratory tract infection
Cornell S. Dorsey VJ. Postgraduate Medicine. 2012;124(4):84-94.
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Sodium Glucose Co‐Transporter‐2 Inhibitors (SGLT‐2i)
• Canagliflozin– Invokana ®
• 100mg & 300mg• taken once daily before first meal of the day.
• Dapagliflozin– Farxiga ®
• 5mg & 10mg• taken once daily (ideally, before first meal of the day).
• Empagliflozin– Jardiance ®
• 10mg & 25mg• taken once daily (ideally, before first meal of the day).
Sodium Glucose Co‐Transporter‐2 Inhibitors (SGLT‐2i)
• ↓ renal glucose reabsorption in the early proximal tubule of the kidney
– Possibly reduces adipose fat ‐ likely due to ↑ water and fat urina on (elimination)
• Lowers fasting glucose– Decreases A1c by 0.7‐1% (~20‐30 mg/dl)
• Most common side effects‐ Weight loss‐ Vaginal and male genital infections ‐ Rash‐ UTI‐ Frequent urination‐ Increased thirst ‐ GI problems (when combined with metformin)
List JF, et al. Diabetes Care. 2009;32(4):650-657.
Wilding JP, et al. Diabetes Care. 2009;32(9):1656-1662.
SGLT2 Inhibitors: Comparisons
Canagliflozin Dapagliflozin Empagliflozin
Efficacy (A1c lowering)
Monotherapy ↓ 0.77 ‐ 1.03% ↓ 0.8 – 0.9% ↓ 0.7 – 0.8%
Combination ↓ 0.79 ‐ 0.94% ↓ 0.7 – 0.8% ↓ 0.7 – 0.8%
Dose and Frequency
100‐300 mg once daily
5‐10 mg once daily
10‐25 mg once daily
Renal dose adjustment
CrCl <60 mL/min 100 mg once dailyUse not
recommended*No dosage adjustment
CrCl <45 mL/min Use not recommended
Invokana (canagliflozin) [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2013.Farxiga (dapagliflozin) [package insert]. Princeton, NJ: Bristol‐Myers Squibb Company; August 2014.
Jardiance (empagliflozin) [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2014.
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Injectable Agents
GLP‐1 Agonists
short‐acting GLP‐1 agonists
• Exenatide (Byetta ®)
– 5 mcg & 10 mcg
– Twice‐daily dosing
• Lixisenatide (Adlyxin ®)
– 10 mcg & 20 mcg
– once‐daily dosing
long‐acting GLP‐1 agonists
• Liraglutide (Victoza ®)
– 0.6 mg, 1.2 mg, & 1.8 mg
– Once‐daily dosing
•Exenatide (Bydureon ®)
– 2 mg
– Once‐weekly dosing
• Albiglutide (Tanzeum ®)
– 30mg & 50mg
– Once‐weekly dosing
• Dulaglutide (Trulicity ®)
– 0.75 mg & 1.5 mg
– Once‐weekly dosing
GLP‐1 Agonists
• GLP‐1 agonists “fix” 5 dysfunctional organs in T2DM– glucagon suppression from the pancreatic alpha cell
• Results in ↓ liver glucose production– Enhances appropriate insulin and amylin secretion from the pancreatic beta cell
• Results in brain satiety– Regulates the GI tract to slow gastric emptying time
– Can be used thru duration provided insulin is present• Promising durability
• Short acting agonists lowers postprandial glucose– Decreases A1c by 0.8‐1.5% (~20‐45 mg/dl; most postprandial)
• Long acting agonists lowers fasting and postprandial glucose– Decreases A1c by 0.8‐1.8% (~20‐50 mg/dl)
• Most common side effects– Weight loss– Stomach upset– Caution in patients at risk for pancreatitis
Cornell S. Dorsey VJ. Postgraduate Medicine. 2012;124(4):84-94.
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Differences in GLP‐1 agonists Exenatide BID
Lixisenatide Liraglutide Exenatide QW
Albiglutide Dulaglutide
Dose 5 & 10 mcg BID(within 30‐60 min of am/pm meal)
10 & 20 mcg (within 60 min of same meal once daily)
0.6 mg initial, then ↑ to 1.2 & 1.8 mgOnce daily, anytime
2 mg weekly 30mg & 50mg weekly
0.75 mg & 1.5 mgweekly
Max dose 10 mcg BID 20 mcg daily 1.8 mg daily 2mg weekly 50 mg weekly 1.5 mg weekly
Half‐ life 2‐4 hours 2‐4 hours 13 hours 5 days 5 days 5 days
Homology to GLP‐1
53% 50% 97% 53% 97% 90%
Antibodies 44% 69.8% 8.6% 44% 2.5% 2%
FPG or PPG effects
PPG PPG Both, FPG & PPG Both, FPG & PPG
Both, FPG & PPG
Both, FPG & PPG
FPG = fasting plasma glucose; PPG = postprandial plasma glucose
High‐Concentration or Low Volume Glargine (U300)
• Available only in a pen
– U‐300: 450 units/pen, max 80 units/inj
– Can be used for patients on small and large volumes of insulin
• Offers a smaller depot surface area, leading to a reduced rate of absorption
• Provides flatter and prolonged pharmacokinetic and pharmacodynamic profiles and more consistency
– Half‐life is ~23 hours
– Steady state in 4 days
– Duration of action ≤36 hours1. Garber AJ. Diabetes Obesity Metab; published online 31 Oct 2013].
2. Owens DR, et al. Diabetes Metab Res Rev. 2014;30(2):104‐19. 3. Steinstraesser A, et al. Diabetes Obes Metab. 2014 Feb 26. .
PK and PD of U300 Insulin Glargine vs U100 Insulin Glargine1
U300 glargine displays a more even and prolonged PK/PD profile compared with U100 glargine, offering blood glucose control beyond 24 hours
LLOQ
0
GIR
[mg/kg‐
1/m
in‐1] 3
1
Time (h)
2
36
Gla‐100 0.4 U/kg‐1
Gla‐300 0.4 U/kg‐1
24181260 30
0
INS
[µU/m
L‐1]
25
5
15
20
10
N=30
1. Becker RH, et al. Diabetes Care. 2014;pii:DC_140006.
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U‐100 and U‐200 Insulin Degludec
• Available only in a pen– U‐200: 600 units/pen, max 160 units/inj– U‐100: 300 units/pen, max 80 units/inj
• Can be used for patients on small and larger volumes of insulin
• Provides flatter and prolonged pharmacokinetic and pharmacodynamic profiles and more consistency– Duration of action >42 hours– Half‐life ~25 hours
• Detectable for at least 5 days
– Steady state in 3‐4 days
1. Garber AJ. Diabetes Obesity Metab; published online 31 Oct 2013]. 2. Owens DR, et al. Diabetes Metab Res Rev. 2014;30(2):104‐19.
Basal Insulin DegludecFlat, stable profile of both 100 unit/mL
and 200 unit/mL formulations
GIR = glucose infusion rate.
1. Heise T, et al. ADA. 2012, Oral 349 Abstract (Trial: NN1250‐1987).
2. Nosek L, et al. IDF 2011: P‐1452; Diabetologia. 2011;54(suppl. 1):S429 (1055‐P); Diabetes. 2011;60(suppl. 1A):LB14.
Glu
co
se
Infu
sio
n R
ate
2
0
Day 6 Day 7
4
1
3
5
IDeg 100 U/mL 0.4 U/kg
IDeg 100 U/mL 0.8 U/kg
IDeg 100 U/mL 0.6 U/kg
IDeg 200 U/mL 0.6 U/kg
Mean 24‐Hour GIR Profile of the Two Insulin DegludecFormulations at Steady State
Half‐life atSteady State
IDeg 200 U/mL0.6 U/kg
MeanHalf‐life(hours)
26.2 h
n = 21
n = 37n = 16n = 22
Side Effects and Contraindications
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Adverse ReactionSitagliptin100 mg†1
Saxagliptin2.5 mg‡2
Saxagliptin5 mg‡2
Linagliptin5 mg‡3
Alogliptin25 mg‡§4
Headache 5.1–5.9 6.5 6.5 – 4.2
Nasopharyngitis 5.2–6.3 – – 7.0 4.4
URTI 5.5–6.3 – 7.7 – 4.2
UTI – – 6.8 – –
Frequently Reported ADEs in Patients Receiving a DPP‐4i
Adverse Reactions Reported Core Phase 3 Placebo-Controlled Studies, %*
*Excluding hypoglycemia. †Data from multiple core studies. ‡Pooled data from core studies.§URTI = upper respiratory tract infection; UTI = urinary tract infection.
1. Januvia® (sitagliptin). Prescribing information.2. Onglyza® (saxagliptin). Prescribing information..3. Tradjenta® (linagliptin). Prescribing information.
4. Nesina™ (alogliptin). Prescribing information. 5. Deacon. Diabetes Obes Metab. 2011;13:7–18.
No differences in the overall safety profiles of the various DPP-4 inhibitors have so far emerged.5
Agent
Approximate ex VivoDPP-4 Inhibition, %1
Metabolism EliminationMaximum24 H
Postdose
Sitagliptin 97 80 Not appreciably metabolized2
Primarily renal (~79% excreted unchanged by kidney)2
Saxagliptin 80 70 Hepatically transformed toactive metabolite, chiefly by CYP3A4/53
Primarily renal (24% as parent compound, 36% as metabolite); also hepatic3
Linagliptin 80 70 ~90% eliminated unchanged; exposure decreased by strong CYP3A4 or P-gp inducers4
Primarily enterohepatic (80%); renal, 5%4
Alogliptin 90 75 Not appreciably metabolized5
Primarily renal (up to 71% excreted unchanged by kidney)5
Pharmacologic and PK Characteristics of DPP‐4i
1. Deacon. Diabetes Obes Metab. 2011;13:7–18. 2. Januvia® (sitagliptin). Prescribing information.. 3. Onglyza® (saxagliptin). Prescribing information.
4. Tradjenta® (linagliptin). Prescribing information. .5. Nesina™ (alogliptin). Prescribing information.
CYP = cytochrome P450; P-gp = P-glycoprotein.
• Rare cases of acute pancreatitis and HSRs have been reported during clinical trials and the postmarketing period1–5
• Acute pancreatitis– Meta‐analysis did not detect increased incidence vs comparators in core
trials5
– Patients should be monitored for signs and symptoms, especially at start of therapy1,2,4
– If pancreatitis is suspected, DPP‐4 inhibitor should be discontinued promptly and management initiated1,2,4
• HSRs– Often occur within first 3 months of treatment1,2
– Discontinue agent and do not restart if serious HSR is suspected1–4
– Use caution when prescribing a DPP‐4 inhibitor for a patient who had a HSR during treatment with a previous DPP‐4 inhibitor1,2,4
Safety Issues with DPP‐4i
HSR = hypersensitivity reaction.
1. Januvia® (sitagliptin). Prescribing information.2. Onglyza® (saxagliptin). Prescribing information. 3. Tradjenta® (linagliptin). Prescribing information.
4. Nesina™ (alogliptin). Prescribing information. 5. Monami et al. Curr Med Res Opin. 2011;27:57–64.
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Head-to-Head Trial, Active Comparators
Incidence of Adverse Event, %
Nausea Vomiting Diarrhea
LEAD-6: liraglutide 1.8 mg, exenatide 10 μg 26, 28 6, 10 12, 12
DURATION-1: exenatide extended release 2 mg, exenatide 10 μg 26, 35 11, 19 14, 13
DURATION-5, exenatide extended release 2 mg, exenatide 10 μg 14, 35 5, 9 9, 4
DURATION-6, exenatide extended release 2 mg,liraglutide 1.8 mg
9, 21 4, 11 6, 13
HARMONY-7, albiglutide 50 mg, liraglutide 1.8 mg 10, 29 5, 9 15, 14
AWARD-1, dulaglutide 0.75 & 1.5 mg, exenatide 10 μg 16, 28, 26 6, 17, 11 8, 11, 6
AWARD-6, dulaglutide 1.5 mg, liraglutide 1.8 mg 20, 18 7, 8 12, 12
GLP-1 agonist : GI Adverse Events
Buse. Lancet. 2009. Drucker. Lancet. 2008. Blevins. J Clin Endocrinol Metab. 2011. Buse. Lancet. 2013. Pratley. Lancet
Diabetes Endocrinol. 2014. Wysham. Diabetes Care. 2014. Dungan. Lancet. 2014. Handelsman. Endocr Pract. 2015.
In clinical practice, GI disturbances often resolve over time, but 5–10% of patients discontinue treatment due to adverse effects.Following dose titration instructions reduces risk of GI disturbances.Patients with preexisting severe GI disease (eg, gastroparesis) should not use a GLP-1 agonists.
• Pancreatitis has been reported in association with GLP-1 agonist treatment
• Until more is known, providers should– Observe patients carefully for pancreatitis signs
and symptoms– Discontinue agent if pancreatitis is suspected– Not restart treatment if pancreatitis is confirmed– Consider other glucose-lowering agents in
patients with pancreatitis history
Pancreatic Safety for GLP-1 agonists
Byetta®. PI. Feb. 2015. Victoza®. PI. Mar. 2015. Bydureon®. PI. Mar. 2015. Tanzeum™. PI. Mar. 2015.
Trulicity™. PI. Mar. 2015. Egan. N Engl J Med. 2014. Butler. Diabetes Care. 2013.
• Currently unknown whether GLP-1 agonists cause thyroid C-cell tumors in humans
• Liraglutide, exenatide extended release, albiglutide, and dulaglutide– Have boxed warning on thyroid C-cell tumor risk– Are contraindicated in patients with personal or family history
of MTC and in patients with MEN 2
• Prescribers should– Counsel patients about potential MTC risk– Inform them about thyroid tumor symptoms
• Stipulations do not apply to exenatide (twice daily)
Thyroid C-Cell Tumors
MEN 2 = multiple endocrine neoplasia syndrome type 2;MTC = medullary thyroid carcinoma
Byetta®. PI. Feb. 2015. Victoza®. PI. Mar. 2015.
Bydureon®. PI. Mar. 2015. Tanzeum™. PI. Mar. 2015.
Trulicity™. PI. Mar. 2015.
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Effect1GLP-1
AgonistsDPP-4
Inhibitors
Increase beta-cell mass and proliferation ++ +
Reduce beta-cell apoptosis ++ +
Enhance glucose-dependent insulin secretion ++ +
Reduce hepatic glucose production ++ +
Improve fasting glucose ++ +
Improve postprandial glucose ++ +
Delay gastric emptying ++ –
Increase satiety and reduce food intake ++ –
Promote weight loss ++ –
Comparing the Effects of GLP‐1 Agonists and DPP‐4i
GLP-1 agonists are administered by subcutaneous injection; DPP-4 inhibitors are administered orally.
1. Cornell. J Clin Pharm Ther. 2012;37:510–524.– = negligible effects; + = modest effects; ++ = pronounced effects.
• Most common side effects– Weight loss– Vaginal and male genital infections– Rash– UTI– Frequent urination– Increased thirst– GI problems (when combined with metformin)
SGLT‐2 Inhibitors Adverse Effects
List JF et al. Diabetes Care. 2009; 32:650-7.Wilding JP et al. Diabetes Care. 2009; 32:1656-62.
Mean difference Upper 95% CI Lower 95% CI
Canagliflozin ‐0.640 ‐0.768 ‐0.513
Dapagliflozin ‐0.592 ‐0.692 ‐0.491
Empagliflozin ‐0.564 ‐0.745 ‐0.384
SUMMARY ‐0.591 kg ‐0.663 ‐0.519 P<0.001
SGLT‐2i ‐ Weight EffectsMeta‐analysis
‐ Mechanism: 1 gram glucose = 4 kcal. Loss of potentially 200‐300 kcal/day‐ Maximum weight loss at approximately 6 months‐ Weight loss is, in general, maintained
Berhan A et al. BMS Endocr Disord. 2013; 13:58‐69.
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Mean 95% CI
Systolic BP
SGLT2i vs. placebo ‐3.77 ‐4.65 to ‐2.90
SGLT2i vs. active comparator
‐4.45 ‐5.73 to ‐3.18
Diastolic BP
SGLT2i vs. placebo ‐1.75 ‐2.27 to ‐1.23
SGLT2i vs. other antidiabetics
‐2.01 ‐2.62 to ‐1.39
Odds Ratio
Hypotension 2.68 114 to 6.29
SGLT‐2i – Blood PressureMeta‐analysis
Vasilakou D et al. Ann Int Med. 2013; 159:262-74.
• BP Lowering Mechanism• Not fully determined but
likely due to osmotic diuresis
• Orthostatic changes possibleupon initiation• Early 24‐48 hour
increased sodium excretion
• Caution in combination with other diuretics
CV Effects of DPP‐4i, GLP‐1 agonists and SGLT‐2I
Results of CV Outcomes Trials in T2DM
Drug Class Study Drug vs. placebo N Results (year published)
DPP‐4i EXAMINE Alogliptin 5400 Neutral (2013)
SAVOR‐TIMI Saxagliptin 16500 Neutral (2013)
TECOS Sitagliptin 14000 Neutral (2015)
CARMELINA Linagliptin 8300 Expected (2017)
GLP‐1 agonist ELIXA Lixisenatide 14000 Neutral (2015)
LEADER Liraglutide 16500 Positive (2016)
EXSCEL Exenatide QW 5400 Expected (2018)
REWIND Dulaglutise 8300 Expected (2019)
SGLT‐2i EMPA‐REG Empagliflozin 7300 Positive (2015)
CANVAS Canagliflozin 4300 Expected (2017)
DECLARE dapagliflozin 22200 Expected (2019)
DPP4i = dipeptidyl peptidase 4 inhibitor GLP‐1 = glucagon like peptide ‐1 SGLT‐2i = sodium glucose cotransporter 2 inhibitor Adapted from: Handelsman Y. Endocrine Today. 2016
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LEADER Results
• 9340 patients randomized and followed for 3.8 years.
– Fewer patients died from CV causes in the liraglutide group (219 patients) than in the placebo group (278) P=0.007.
– The rate of death from any cause was lower in the liraglutide group (381 patients) than in the placebo group (447) P=0.02.
– The rates of nonfatal MI, nonfatal stroke, and hospitalization for heart failure were nonsignificantly lower in the liraglutide group than in the placebo group.
• Is this reproducible? – Is this a class effect? Will this change guideline recommendations?
Marso S et al. N Engl J Med 2016; 375:311‐322
EMPA‐REG Results• 7300 randomized to empagliflozin vs. placebo.
– Primary outcome was 3‐point MACE: Time to first occurrence of CV death, non‐fatal MI or non‐fatal stroke
– Key secondary outcome was 4‐point MACE: Same as primary + hospitalization for unstable angina
• Treatment duration 2.6 years, Observation time 3.2 years
• Results were impressive and unexpected– ↓ CV death by 38%
– ↓ all cause mortality by 32%
– ↓ heart failure hospitaliza on by 35%
– Number Needed to Treat to prevent one death in 3 years = 39
• Is this reproducible? – Is this a class effect? Will this change guideline recommendations?
Zinman B, et al. NEJM 2015.
Dosing Considerations
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Biguanides (Metformin)
• Decreases liver glucose production– Can be used throughout duration of disease; if no contraindication– Good durability
• Lowers fasting glucose• Decreases A1c by 1.5‐2% (~45‐60 mg/dl)
• Most common side effects• Stomach and intestine distress• May reduce B‐12 levels after long‐term use• Favorable lipid profile improvements
– ↑ good cholesterol (HDL)– ↓ bad cholesterol (LDL) & ugly cholesterol (triglycerides).
• Caution in patients with renal & hepatic dysfunction– CrCl < 1.4 in women and < 1.5 in men
Cornell S, Lullo A. Diabetes Trends 2009.
Metformin: Labeling changes
• eGFR between 30 to 45 mL/minute/1.73 m2.
– Not recommended
• eGFR below 30 mL/minute/1.73 m2
– Contraindictaed
• If a patient is already on metformin
– eGFR falls below 45 mL/minute/1.73 m2,
• Weigh benefits of continuation verse discontinuation.
– eGFR falls below 30 mL/minute/1.73 m2
• Discontinue metformin
• Stimulates insulin release from the pancreatic beta cell
– Long acting stimulation (>6 hours)– Requires endogenous insulin to be affective; therefore better used early in the disease; if necessary
– Short durability
• Most common side effects• Hypoglycemia• Weight gain
• may inhibit ischemic pre‐conditioning
Sulfonylureas
Cornell S, Lullo A. Diabetes Trends 2009.
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AgentDose Frequency and
Timingtmax
t1/2
Initial Dose (Duration)
Regular Dose
Elimination
Exenatide BIDBID; within 60 minutes
before morning and evening meals
2.1 hours2.4 hours
5 µg (1 month)
5 µg or 10 µg
Mainly renal; not recommended for patients with ESRD or severe renal
impairment
Liraglutide QD; any time of day8-12 hours13 hours
0.6 mg (1 week)
1.2 mg or 1.8 mg
Mainly metabolized by proteolyticdegradation; use caution in patients
with renal impairment
Exenatide QW QW; timing not specified2-7 weeks
N/A2 mg 2 mg Renal
Albiglutide QW; timing not specified3-5 days6-7 days
30 mg 30 mg N/A
Dulaglutide QW; timing not specified~70 hours~4 days
N/A0.75 mg or
1.5 mgN/A
LixisenatideQD; within 60 minutes
before breakfast~2 hours~3 hours
10 µg (2 weeks)
20 µg Renal
Pharmacologic and Pharmacokinetic Differences among GLP‐1 Agonists
Byetta [package insert]. 2015. Victoza [package insert]. 2015.
Bydureon [package insert]. 2015. Gilbert MP, et al. Am J Med. 2009;122(suppl 6):S11-S24.
Bischoff LA, et al. Expert Opin Pharmacother. 2011;12(8):1297-1303. St Onge EL, et al. Expert Opin Biol Ther. 2010;10(5):801-6.
Umpierrez GE, et al. Diabetes Obes Metab. 2011;13(5):418-425. Christensen M, et al. Expert Opin Investig Drugs. 2011;20(4):549-557.
Hirsch IB. N Engl J Med. 2005; 352:174‐83.
Flood TM. J Fam Pract. 2007; 56(suppl 1):S1‐S12.
Becker RH et al. Diabetes Care. 2015; 38:637‐43.
Pharmacokinetic Profile of Currently Available Basal Insulins
Plasma Insulin Levels
0 12 16 20 24842 14 18 22106
Intermediate (NPH)
Long (detemir)
Long (U‐100 glargine)
Time (hr)
26 28 30 32 34 36
Ultra‐long (degludec & glargine U‐300)
Insulin Onset (hr) Peak (hr) Duration (hr) Appearance
Insulin Lispro U100 & U200 within 15 min 0.5- 1.5 3-5 Clear Insulin Aspart within 15 min 1-3 3-5 Clear Insulin Glulisine 0.25-0.5 0.5-1 4 Clear Regular U100 0.5 – 1 2-4 5-8 Clear
Regular inhaled Within 5 min 20-40 minutes 3 Powder Regular U-500 30 min 2-4 Up to 24 hr Clear
NPH 1-2 4-10 14+ Cloudy Insulin Detemir 3-4 6-8 (though relatively flat) up to 20-24 Clear
Insulin Glargine U100 1.5 flat 24 Clear
Insulin Glargine U300 1.5 flat 26 Clear
Insulin Degludec U100 & U200 0.5 – 1 flat >30 Clear Lispro Mix 50/50 0.25-0.5 0.5-3 14-24 Cloudy Lispro Mix 75/25 0.25-0.5 0.5-2.5 14-24 Cloudy Aspart Mix 70/30 0.1-0.2 1-4 18-24 Cloudy Degludec/aspart Mix 70/30 0.23 – 1.2 2.3 >24 Cloudy
Note: Patient specific onset, peak, duration may vary from times listed in table, Peak and duration are often very dose dependent with shorter duration of actions with smaller doses and vice versa
Insulin Comparison
11/2/2016
19
Weight Effect
Hypoglycemiaβ-Cell
ProtectionCVD
BenefitsCost Other Considerations
AGIs Neutral Low risk Possible Possible $ to $$GI adverse effects (gas),
dose frequency
Amylinomimetic Loss Low risk Possible Yes $$GI adverse effects (nausea), injectable, dose frequency
Bile acid sequestrant
Neutral or loss
Low risk Possible Yes $$GI adverse effects (constipation),
dose frequency
Biguanides Loss Low risk Possible Yes $GI adverse effects (diarrhea), renal and hepatic impairment
DPP-4 inhibitors (gliptins)
Neutral Low risk Possible Yes $$$ Minimal adverse effects
Dopamine agonistNeutral or loss
Low risk Unknown Yes/no $$$GI adverse effects (nausea),
hypotension, dizziness
GLP-1 agonists Loss Low risk Possible Yes $$$GI adverse effects (nausea),
injectable
InsulinGain or
loss Risk—bolus
Low risk—basalPossible Possible $ to $$
Injectable, dose frequency (bolus), increased SMBG
Secretagogues sulfonylureas and glinides
Gain Risk No No $ to $$Immediate short-term response,
increased SMBG,
dose frequency (glinides)
SGLT-2 inhibitors Loss Low risk ?? Yes $$$Urinary tract and urogenital
infections
TZDs (glitazones) Gain Low risk Possible Yes/no $$
4-8 weeks for response, redistribution of SC/visceral fat,
edema, bone loss, fracture, bladder cancer
FPG = fasting plasma glucose; PPG = postprandial glucose; GI = gastrointestinal; SMBG = self-monitoring of blood glucose. Unger J, et al. Postgrad Med. 2010;122(3):145-157. Cornell S, et al. Postgrad Med. 2012;124(4):84-94.
• Metformin is recommended as initial therapy for most patients with type 2 diabetes, but most patients require additional therapy, particularly as the disease progresses.
• Guidelines recommend several second‐line treatment options including insulin, sulfonylureas, thiazolidinediones, DPP‐4 inhibitors, GLP‐1 agonists, and SGLT‐2 inhibitors.
• A patient‐centered approach to decision making is recommended including an evaluation of the mechanism of action, efficacy, unique benefits and safety of each option.
Key Points