medication make-over: contemporary pharmacotherapy options for type 2 diabetes il cb... · 2017....
TRANSCRIPT
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Medication Make-Over: Contemporary Pharmacotherapy
Options for Type 2 Diabetes
Susan Cornell, BS, PharmD, CDE, FAPhA, FAADE
Associate ProfessorMidwestern University - Chicago College of Pharmacy
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Objectives
• Describe recent updates in the pharmacotherapy management recommendations for type 2 diabetes.
• Discuss the rationale regarding therapeutic decision making when adding on to, or replacing metformin in type 2 diabetes.
• Assess the appropriateness of SGLT-2 inhibitors, DPP-4 inhibitors, GLP-1 agonists, and newer concentrated insulins based on specific patient characteristics.
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PATIENT CASE #1
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Case #1: GL• GL is a 60-year-old African-American male returning to his
primary care clinic for routine follow-up. He has had T2D for 5 years, hypertension and dyslipidemia for 8 years and GERD for 3 years.
• Current Medications
– Metformin 1000 mg PO BID
– Lisinopril 20 mg PO daily
– Atorvastatin 40 mg PO daily
– Omeprazole 20mg PO daily
• SMBG:
– Fingersticks three times a week in the morning
– FPG = average 155 mg/dL (range 130-199 mg/dL)
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Case #1: GLSocial History
▪ Employed full time as accountant
▪ Nonsmoking with no illicit drug use
▪ Occasional alcohol use (~3 drinks per week)
▪ Self-reported hectic and inconsistent eating schedule. Usually eats breakfast and dinner, but often times skips lunch during busy work day. Largest meal of day is dinner.
▪ Married with 2 grown children. His wife does the cooking.
Physical Exam, Vitals & Labs
▪ A1C 8.2%
▪ Weight - 194 lb
▪ BMI - 27 kg/m2
▪ BP - 132/80 mmHg
▪ HR - 70 bpm
▪ Slightly decreased sensation in both feet bilaterally
▪ Lipid panel – WNL
▪ Urinary albumin/creat - 215
▪ SCr - 1.0 mg/dL
▪ eGFR - > 100 mL/min/1.73 m2
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Metformin is CURRENTLY most commonly used as “first line”
therapy
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Neurotransmitter Dysfunction
Biguanides (Metformin)
DeFronzo R A. Diabetes. 2009;58(4):773-795.7
Islet b-cell
ImpairedInsulin Secretion
Decreased GlucoseUptake
Islet a-cell
IncreasedGlucagon Secretion
IncreasedLipolysis
Increased GlucoseReabsorption
IncreasedHepatic Glucose Production
GI tract/Decreased
Incretin Effect
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Tips for Use: Metformin• Dosing
– Metformin immediate release
• Start with 500mg daily to BID
• Max effective dose is 2000mg/day
• Individualize titration based on GI side effects
– Metformin XR
• May be helpful if immediate release GI effects are bothersome
• Start XR 500mg – XR 750mg QD
– Take with food to reduce GI side effects
– Ideally take in evening/bedtime
– Monitor: A1C, Serum Creatinine, eGFR, B12 levels
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Metformin
• Historically, serum creatinine was the measure used to determine if a patient could be prescribed metformin.
• More recent studies support the use of the glomerular filtration rate estimating equation (eGFR).
Diabetes Guidelines, Endocr Pract. 2015;21(Suppl 1), Diabetes Care 2017;40(Suppl. 1):S57-S634http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm494829.htm accessed 4/13/17
General Practice Recommendations
eGFR 45 – 60 ml/min
Continue therapy, monitor renal function every 3 – 6 months
eGFR 30 – 45 ml/min
Avoid initiation of metforminIf already using, consider dose adjustment to max of 500mg BID
eGFR < 30Ml/min
Do not use / discontinue use
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What comes after metformin?
How do you choose a second agent?
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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). .
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ADA Standards of Medical Care (2017)
American Diabetes Association. Diabetes Care 2017;40:(Suppl 1).
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Drug Selection: A Balancing Act
Clinical Outcomes
Patient Safety
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Considerations in Drug Selection
• Patient factors to consider
– Synergistic / complimentary mechanism of action
– A1c lowering needed• Fasting, post-prandial
– Weight/Obesity• High levels of insulin resistance
– Cardiovascular disease• Hypoglycemia
– Ease of medication administration• Side effect profile
– Renal impairment
– Cost, available medication coverage
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Neurotransmitter Dysfunction
Sulfonylureas
DeFronzo R A. Diabetes. 2009;58(4):773-795.15
Islet b-cell
ImpairedInsulin Secretion
Decreased GlucoseUptake
Islet a-cell
IncreasedGlucagon Secretion
IncreasedLipolysis
Increased GlucoseReabsorption
IncreasedHepatic Glucose Production
GI tract/Decreased
Incretin Effect
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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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Tips for Use
• Take in morning before/with breakfast
• If dosed BID, take with breakfast and supper.
– Patient should check bedtime BG and have snack if needed
• Patients need to eat on schedule
– Do not skip meals/snacks
• Risk of hypo
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Neurotransmitter Dysfunction
TZD’s (Glitazones)
DeFronzo R A. Diabetes. 2009;58(4):773-795.18
Islet b-cell
ImpairedInsulin Secretion
Decreased GlucoseUptake
Islet a-cell
IncreasedGlucagon Secretion
IncreasedLipolysis
Increased GlucoseReabsorption
IncreasedHepatic Glucose Production
GI tract/Decreased
Incretin Effect
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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.
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Tips for Use
• Takes 4-8 weeks before effect is noticed.
• Patients need to give TZD’s 2-3 months use
• Best used early in the disease process
• Good combination with:
– GLP-1 agonists
– Metformin
– SGLT-2i (?)
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Neurotransmitter Dysfunction
DPP4 Inhibitors (gliptins)
DeFronzo R A. Diabetes. 2009;58(4):773-795.21
Islet b-cell
ImpairedInsulin Secretion
Decreased GlucoseUptake
Islet a-cell
IncreasedGlucagon Secretion
IncreasedLipolysis
Increased GlucoseReabsorption
IncreasedHepatic Glucose Production
DecreasedIncretinEffect
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DPP4 Inhibitors (gliptins)
• Inhibits DPP-4 enzyme in the GI tract that breaks down GLP-1 resulting in ↑ endogenous GLP-1. – glucagon suppression results in ↓ liver glucose production– Enhances appropriate insulin and amylin secretion from the
pancreas– 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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DPP-4 Inhibitors: Comparisonssitagliptin saxagliptin linagliptin alogliptin
Dose/frequency
100 mg once daily
5 mg once daily
5 mg once daily
25 mg once daily
Efficacy (A1C lowering): monotherapy 0.6% 0.7% 0.4% 0.8%
Efficacy (A1C lowering): combination therapy 0.7% 1.2% 0.7% 0.9%
Renal dosing
50 mg daily (moderate)25 mg daily
(severe)
2.5 mg daily (moderate-severe)
**No dose adjustmentnecessary
12.5 mg daily (moderate)
6.25 mg daily (severe)
Approximate ex VivoDPP-4 Inhibition, %
(maximum)97 80 80 90
Baetta R. Drugs 2011;71:1441-1467, Deacon. Diabetes Obes Metab. 2011;13:7–18.
Januvia® (sitagliptin). Prescribing information.. Onglyza® (saxagliptin). Prescribing information.
Tradjenta® (linagliptin). Prescribing information. Nesina™ (alogliptin). Prescribing information
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DPP-4 Inhibitors: Adverse Effects
• FDA Alert (Aug, 2015): 33 cases from 2006-2013 in FAERS
• Occurred 1 day to years after initial use
• After discontinuation, symptoms relieved
Joint Pain
• FDA update April 2016 for alogliptin and saxagliptin
• EXAMINE: Alogliptin increased HF hospitalizations (3.9% vs 3.3%)
• SAVOR-TIMI: Saxagliptin increased hospitalization rates for HF (3.5% vs. 2.8%,)
Heart Failure
• FDA alert in 2009 due to post-market reports
• Higher rates in clinical trials compared to placebo
• Also seen with GLP-1 receptor agonistsPancreatitis
https://www.fda.gov/Drugs/DrugSafety/ucm459579.htmPL Detail-Document, DPP-4 Inhibitors (Gliptins) and Risk of Heart Failure. Pharmacist’s Letter/Prescriber’s Letter. June 2016.https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm494252.htm Accessed 4/13/17
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Tips for Use
• Best used for patient with A1c near normal
– Minimal A1c lowering
– PPG target
• Minimal side effects
• Good combination with:
– Metformin
– SGLT-2i
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Neurotransmitter Dysfunction
SGLT-2i
DeFronzo R A. Diabetes. 2009;58(4):773-795.26
Islet b-cell
ImpairedInsulin Secretion
Decreased GlucoseUptake
Islet a-cell
IncreasedGlucagon Secretion
IncreasedLipolysis
Increased GlucoseReabsorption
IncreasedHepatic Glucose Production
GI Tract/Decreased
Incretin Effect
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SGLT-2i
• ↓ renal glucose reabsorption in the early proximal tubule of the kidney
– body fat - Possibly due to ↑ water and fat urination (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.
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SGLT2 Inhibitors: ComparisonsCanagliflozin 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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SGLT-2i: Post Market - Adverse Effects
Bone LossFDA warning added to canagliflozin in Sept 2015A pooled analysis of 9 trials over 85 weeks compared canagliflozin to placebo: more bone fractures with Canagliflozin (1.5 vs. 1.1) per 100 patient-years
Acute Kidney InjuryFDA warning updated June 2016 for canagliflozin, dapagliflozin2013-2015.FDA received 101 confirmed cases of acute kidney injury
UrosepsisFDA warning added Dec 2015 19 cases of life-threatening urosepsisand pyelonephritis with canagliflozin(n=10) and dapagliflozin(n=9)
Diabetic KetoacidosisFDA warning added May 2015 (updated Dec 2015)73 cases of DKA reported in FAERScanagliflozin(n=48) , dapagliflozin(n=21) , empagliflozin(n=4)
FDA Drug Safety Communication:. Available from:https://www.fda.gov/Drugs/DrugSafety/ucm461449.htm Accessed 4/13/17https://www.fda.gov/Drugs/DrugSafety/ucm505860.htm Accessed 4/13/17FDA Drug Safety Alert. Available at: https://www.fda.gov/Drugs/DrugSafety/ucm446845.htm. Accessed: 3/20/17
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Tips for Use
• Educate patients on proper GU hygiene, importance of hydration, signs/symptoms of DKA, increase frequency of urination
• Use caution in patient on volume depleting drugs (e.g diuretics)
• Good combination with:
– Metformin
– DPP-4i
– GLP-1 agonist
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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
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Neurotransmitter Dysfunction
GLP-1 Agonists
DeFronzo R A. Diabetes. 2009;58(4):773-795.32
Islet b-cellImpaired
Insulin Secretion
Decreased GlucoseUptake
Islet a-cell
IncreasedGlucagon Secretion
IncreasedLipolysis
Increased GlucoseReabsorption
IncreasedHepatic Glucose
Production
GI Tract/Decreased
Incretin Effect
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GLP-1 Agonists
• GLP-1 agonists “fix” 6 dysfunctional organs in T2DM– glucagon suppression
• Results in ↓ liver glucose production
– Enhances appropriate insulin and amylin secretion from the pancreas• Results in brain satiety
– Regulates the GI tract to slow gastric emptying time– Can improve insulin uptake in peripheral tissue via weight loss
– 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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GLP-1 RA: Adverse Effects
Gallbladder Disease• Increased risk of bile duct and
gallbladder disease possibly due to rapid weight loss
• Higher rates seen in the SCALE and LEADER studies
• Patient counseling
– Diet modifications and warning signs of right upper quadrant pain that can radiate to the shoulder
Thyroid Disease• Thyroid C-cell tumors have
occurred in rats and mice at clinically relevant exposures
– Black Box Warning
– Higher rates with increased dose and duration
– Avoid use in multiple endocrine neoplasia syndrome type 2 or personal or family history of medullary thyroid carcinoma
Professional Resource, GLP-1 Agonists and Gallbladder Disease. Pharmacist’s Letter/Prescriber’s Letter. October 2016. Liraglutide package insert, Dulaglutide package insert.
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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 = fasting plasma glucose; PPG = postprandial plasma glucose
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Tips for Use
• Educate and monitor injection technique
• Discuss/prepare patient on how to minimize nausea, GI side effects
• Good combination with:
– Metformin
– TZD
– SGLT-2i
– Basal insulin
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Neurotransmitter Dysfunction
Insulin
DeFronzo R A. Diabetes. 2009;58(4):773-795.37
Islet b-cell
ImpairedInsulin Secretion
Decreased GlucoseUptake
Islet a-cell
IncreasedGlucagon Secretion
IncreasedLipolysis
Increased GlucoseReabsorption
IncreasedHepatic Glucose Production
GI Tract/Decreased
Incretin Effect
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Pharmacokinetic Profile of Currently Available Basal Insulins
Pla
sma
Insu
lin L
eve
ls
0 12 16 20 24842 14 18 22106
Intermediate (NPH insulin)
Long (Insulin detemir)
Long (Insulin glargine)
Time (h)
26 28 30 32 34 36
Ultralong
(glargine U300)
Ultralong degludec U100, U200
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Concentrated Insulin Glargine (U-300)
• “Ultra long-acting” basal insulin
– Smaller depot surface area
– Reduced rate of absorption
• Relatively flat and prolonged PK/PD profiles
– Half-life ~23 hours
– Steady state in 4 days
– Duration of action < 36 hours
• Available only in pen– 450 units/pen (1.5 mL)
– Maximum 80 units/injection
– 3 pens per box
Purple label
Green label
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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.
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Fixed Combination Products
Insulin glargine + lixisenatide (Soliqua™) – iGlarLixi
Image available at: http://www.pharmasay.com/2016/12/12/insulin-soliqua-10033-glargine-lixisenatide-available-january-2017/Image available at: https://www.diabetesdaily.com/blog/fda-approves-novo-nordisks-xultophy-combination-drug-for-type-2-diabetes-322527/
Insulin degludec + liraglutide (Xultophy®) - iDegLira
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Neurotransmitter Dysfunction
Insulin + GLP-1 agonist
DeFronzo R A. Diabetes. 2009;58(4):773-795.42
Islet b-cell
ImpairedInsulin Secretion
Decreased GlucoseUptake
Islet a-cell
IncreasedGlucagon Secretion
IncreasedLipolysis
Increased GlucoseReabsorption
IncreasedHepatic Glucose Production
GI Tract/Decreased
Incretin Effect
Insulin Insulin
InsulinInsulin
Insulin
GLP-1GLP-1
GLP-1
GLP-1
GLP-1
GLP-1
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Fixed Combination Products
iGlarLixi ---- Administer within 1 hour before breakfast• Prime dose before every use (2 units)
• Starting dose
• 15 units/5 mcg – previously treated with GLP-1RA or <30 units basal insulin
• 30 units/10 mcg – previously treated with 30-60 units basal insulin
• Titrate by 2-4 units every week
iDegLira----Administer once daily (anytime of day)• Prime dose before every use (priming symbol)
• Starting dose
• 16 units/0.58 mcg
• May be down titrated to 10 units/0.36 mcg
• Titrate by 2 units every 3-4 days
Sanofi-Aventis U.S. LLC. Soliqua (insulin glargine/lixisenatide) package insert. Bridgewater, NJ; 2016.Novo Nordisk A/S. Xultophy (insulin degludec/liraglutide) package insert. Bagsvaerd, Denmark; 2016.
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Comparison of Renal Considerations and CV Effects of
DPP-4i, GLP-1 agonists and SGLT-2I
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Renal Impairment
• Complicates treatment choices– Often result of poor glycemic control
– Produces higher risk when using many medications
• Hypoglycemia rate increases in CKD stage III-V
– Can alter A1c interpretation
• Shortens erythrocyte life span as eGFR decreases
• Falsely lowers A1c values
1. Gosmanov AR, et al. Nephrol Dial Transplant 2016; 31 (1): 8-15. 2. Chujo K, et al. J Med Invest 2006; 53 (3-4): 223-2283. Fukami K. Journal of Diabetes and its Complications 2015; 29 (7): 913-917.
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Renal Impairment: Modified Algorithms
eGFR 30-60 ml/min
Metformin (reduced dose)
DPP-4 (reduced dose), GLP-1 agonists meglitinidespioglitazone glipizide
Insulin
eGFR <30 ml/min
DPP-4 (reduced dose) GLP-1 agonists meglitinides
pioglitazone
glipizide
Insulin
Modified from: Ioannidis I. World J Diabetes 2014; 5 (5): 651-658
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Drug class Drug/Dose Reduce dose if: Contraindicated if:
GLP-1 agonist
ExenatideIR: 5-10 mcg BIDER: 2 mg weekly
--- Clcr <30ml/min
Liraglutide0.6-1.8mg daily
--- ---
Lixisenatide10-20 mcg daily
--- Clcr < 15ml/min
Dulaglutide0.75-1.5mg weekly
--- ---
Albiglutide30-50 mg weekly
--- ? <15ml/min
Micromedex® 2.0, (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com/ (cited: May 12, 2017).
GLP-1 Agonists
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Drug class
Drug/Dose Reduce dose if: Contraindicated if:
DPP-4 inhibitors
Sitagliptin25-100mg daily
eGFR 30-50: 50mg dailyeGFR <30: 25mg daily
---
Saxagliptin2.5-5mg daily
eGFR<50: 2.5mg daily ---
Alogliptin25mg daily
eGFR 30-60: 12.5mg dailyeGFR <30: 6.25mg daily
---
Linagliptin5mg daily
--- ---
Micromedex® 2.0, (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com/ (cited: May 12, 2017).
DPP-4i
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Drug class Drug/Dose Reduce dose if: Contraindicated if:
SGLT2 inhibitors
Canagliflozin100-300 mg daily
eGFR 45-59: 100 mg daily
eGFR <45ml/min
Dapagliflozin5-10 mg daily
--- eGFR <60ml/min
Empagliflozin10-25 mg daily
--- eGFR <45ml/min
Micromedex® 2.0, (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com/ (cited: May 12, 2017).
SGLT-2i
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Renal Protection
• EMPA-REG OUTCOME
– Empagliflozin: 39% relative risk reduction in incident or worsening nephropathy compared to placebo
• LEADER
– Liraglutide: 22% relative risk reduction in new onset or worsening kidney disease compared to placebo
1. Wanner C, et al. N Engl J Med 2016;375:323-34.2. Marso SP, et al. N Engl J Med 2016; 375:311-322.
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Cardiovascular Disease(from AACE 2017)
Beailnefit Neutral Caution Risk
ASCVD GLP-1 agonistsTZD (stroke risk)
Metformin SGLT-2iDPP-4i InsulinPramlintide AGI
SUGLN
Heart Failure
GLP-1 agonistsSGLT-2i
Metformin AGIPramlintide
DPP-4iTZD
SUGLNInsulin
AACE. Endocr Pract 2017ASCVD = atherosclerotic cardiovascular disease
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Cardiovascular Disease – Clinical Trials
Drug class Drug Impact on CVD Study
GLP-1 agonist Exenatide Ongoing trial EXSCEL
Liraglutide ↓ Risk of CV death and total death
LEADER
Dulaglutide Ongoing trial REWIND
Albiglutide No ↑ CV Risk HARMONY program meta-analysis
Lixisenatide No ↑ CV Risk ELIXA
Adapted from: Handelsman Y. Endocrine Today. 2016
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Cardiovascular Disease – Clinical Trials
Drug class Drug Impact on CVD Study
SGLT2 inhibitors Canagliflozin ↓ Risk of CV death CANVAS
Dapagliflozin Ongoing trial DECLARE-TIMI
Empagliflozin ↓ Risk of CV death EMPA-REG
Adapted from: Handelsman Y. Endocrine Today. 2016
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Cardiovascular Disease – Clinical Trials
Drug class Drug Impact on CVD Study
DPP-4 inhibitors Sitagliptin No ↑ CV RiskNo ↑ HF hospitalization
TECOS
Saxagliptin No ↑ CV Risk↑ HF hospitalization
SAVOR-TIMI
Alogliptin No ↑ CV Risk EXAMINE
Linagliptin Ongoing trials CAROLINA*CARMELINA
Adapted from: Handelsman Y. Endocrine Today. 2016
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Weight Considerations
Gain Neutral Loss
SUMeglitinidesInsulinTZD
MetforminDPP-4 inhibitorAG inhibitorBile acid sequestrants Dopamine agonist
GLP-1 agonistSGLT-2 inhibitAmylin mimetic
Cornell S, D’Souza J. Postgrad Med 2014; 126 (2): 100-109.
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*Indicates that < 50% of subjects have intensified treatment.Mean time between HbA1c measurements was 6.2 to 7 months.Khunti K, et al. Diabetes Care. 2013;36:3411-3417.
Clinical Inertia Leaves Patients Unnecessarily Exposed to Hyperglycemia
Median Time to Addition of Another OAD or Insulin
Patients taking 1 OAD
Patients taking 3 OADs > 7.1 y*; mean HbA1c : 9.7%
Patients taking 2 OADs > 7.2 y*; mean HbA1c : 9.1%
Time, y
0 1 2 3 4 5 6 7 8
2.2 y; mean A1c: 8.7%
56
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Combination & Co-formulation Considerations
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Do NOT Use Combinations
• Duplicate Mechanisms of Action• Sulfonylurea + meglitinide
• GLP-1 agonist + DPP4 inhibitor
• 2 long acting/intermediate insulins
• 2 rapid/short acting insulins
• Sulfonylurea/meglitinide + rapid/short acting insulin
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Effective Metformin Combinations
• Need FPG lowering
– Met + SU
– Met + TZD
– Met + SGLT-2i
– Met + GLP-1 agonist (long)
– Met + Basal
• Need PPG lowering
– Met + DPP-4i
– Met + SGLT-2i
– Met + GLP-1 agonist (short)
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Effective Non-Met Combinations
• Modest A1c reduction (primarily PPG)
– DPP-4i + SGLT-2i
• High A1c lowering (FPG + PPG)
– GLP-1 agonist + TZD
– GLP-1 agonist + SGLT-2i
– GLP-1 agonist + Basal insulin
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• Diabetes guidelines encourage individualizing therapy
• Several factors guide drug therapy selection including:
– patient safety,
– blood glucose lowering potential
– weight effects
– cost
– adherence
– patient preferences
•
Key Points
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• Metformin is currently recommended as initial therapy for most patients with type 2 diabetes.
– Although, most patients will require additional therapy, particularly as the disease progresses.
• Newer medications offer additional treatment options with other positive effects
• Liraglutide and empagliflozin have cardiovascular benefits.
• More data on other (newer) drugs to come soon
Key Points
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