final updated prasad-reddy ipha diabetes slides › 5752152618172416 › 565316480401… · õ l í...
TRANSCRIPT
9/15/2018
1
Navigating the Diabetes Armamentarium: New Options for
Glycemic ControlLalita Prasad-Reddy, PharmD, MS, BCPS, BCACP, CDE
Clinical Assistant Professor Chicago State University
Clinical Pharmacy Specialist – Rush University Medical Center
• Dr. Prasad declares no conflicts of interest, real or apparent, and no financial interests in any company, product, or service mentioned in this program, including grants, employment, gifts, stock holdings and honoraria.
Disclosures and Conflict of Interest
At the conclusion of the program, the pharmacists will be able to:
• Describe recent updates in pharmacotherapy management of diabetes as it relates to cardiovascular disease.
• Discuss advantages and disadvantages of the various medication classes used to treat type 2 diabetes.
• Describe which factors guide therapeutic decision making when adding on to, or replacing metformin in type 2 diabetes.
• Compare and contrast the appropriateness of SGLT-2 inhibitors, DPP-4 inhibitors, and GLP-1 agonists for glycemic management based on specific patient characteristics.
Pharmacist Objectives
9/15/2018
2
Questions to Consider in Guiding Treatment Management of Diabetes
What patient and drug factors direct choice of agent? What patient and drug factors direct choice of agent?
What drug(s) are most appropriate to add to metformin for BG control? What drug(s) are most appropriate to add to metformin for BG control?
Are there specific disease-related conditions that dictate patient therapy? Are there specific disease-related conditions that dictate patient therapy?
Patient Case• KP is a 49yo F with type 2 diabetes for 3 years. Denies any symptoms of polyuria,
polyphagia, polydipsia. A1C increased from 7.4% to 8.4% today. She is concerned about the weight gain with insulin
• PMH• Diabetes• Hypertension• Depression• Unstable angina• Hypothyroidism• Frequent UTI’s• CKD
• Medications• Metformin 1000mg BID,• Metoprolol tartrate 50 mg bid• Lisinopril 20 mg daily• Levothyroxine 88mcg daily • Citalopram 20mg daily • Atorvastatin 20mg daily
• Social History• (-) Alcohol/tobacco• Exercise: none• Insurance: Private PPO• Diet: 1 – 2 meals/day + snacks (not watching
carbohydrates or diet)• Lives at home with husband and 3 kids
• Physical examination/Laboratory• Ht: 5’2’’, Weight 180 lbs, BMI: 32.9• BP: 128/78 mm HG• A1C 8.4% today • Notable labs:
• Potassium: 4.5 mEq/L• Serum creatinine: 1.3 mg/dL• eGFR: 44 ml/min• Albumin: Creatinine ratio: 32
– SMBG: 130 - 200 mg/dL
• Which of the following medications would be the best option to add to KP’s medication regimen?
• Liraglutide (Victoza®)
• Pioglitazone (Actos®)
• Sitagliptin (Januvia®)
• Empaglifozin (Jardiance®)
Pre-Test Question # 1 Pre-Test Question # 2
• True/False. Based upon KP’s current condition of CKD, and current estimate of kidney functioning, she is no longer a candidate for metformin therapy.
• True
• False
9/15/2018
3
Type 2 diabetes mellitus (T2DM)
DiabetesDek 2002 by Infodek
Insulin Deficiency
↓ Glucose-Induced Insulin Secretion
Decreased TissueResponse to Insulin
Insulin Resistance
↑Hepatic Glucose Production
↓Cellular Glucose Uptake
Impaired Beta Cell Function
Post receptor Defect
Hyperglycemia
Pathogenesis of Type 2 Diabetes
Liver
Pancreas
Gut
Muscle
Hyperglycemia
AdiposeTissue
T2DM: A Multisystem Disorder
Increased gluconeogenesis
Decreased glucose uptake
Decreased insulinsecretion
Decreased glucose uptake
Brain
Increasedglucagon secretion
Graphics courtesy of Robb Malone, PharmD, CPP, CDE
Increased glucagon, decreased glucose-dependent insulin
secretion
The Egregious 11
Diabetes Care 2016;39:179–186Schwartz SS, et al. Diabetes Care 2016;39:179-86.
9/15/2018
4
T2DM Pathogenesis
• Decreased insulin secretion
• Blunted “incretin effect”
• GLP-1 levels decreased in T2DM
• Less glucose-dependent insulin release and more post-prandial glucagon release
• Increased hepatic glucose production
• Insulin resistance
• Muscle
• Adipose tissue
Diabetes Mellitus in the US: Health Impact of the Disease
DiabetesLeading cause of blindness
Leading cause of renal failure
Leading cause of non-traumatic
amputation
Seventh leading cause of death
Cardiovasculardisease 2X to 4X
Healthcare costs $245 billion
30.3 million people affected
Centers for Disease Control and Prevention. National diabetes statistics report, 2017. Atlanta, GA: National Center for Chronic Disease Prevention and .
Metformin is #1• Why metformin?
• Longstanding evidence for efficacy and safety, inexpensive, generally well tolerated
• MOA: Decreases hepatic glucose production, improves insulin sensitivity
• FDA modified renal thresholds – no longer serum creatinine, based upon GFR
• Previously Scr 1.4 mg/dL (women) and Scr 1.5 mg/dL (men)
• Risk of lactic acidosis far less than originally feared
• GI issues(N/V/D): consider long-acting formulation, dose reduction, slow titration
• Monitor vitamin B12 levels and renal functionGeneral Practice Recommendations
eGFR 45 – 60 ml/min
Continue therapy, monitor renal function q 3 – 6 months
eGFR 30 – 45 ml/min
Avoid initiation of metforminConsider dose adjustment, max 500mg BID
American Diabetes Association. Standards of Medical Care in Diabetes –2018. Diabetes Care 2018;41(suppl. 1):S1-159.
But what comes next???
9/15/2018
5
Management of Hyperglycemia in T2DM
• Metformin remains the first-line option
• Controversial on what is next!!!• Lack of comparative data on different regimens
• Concerns about benefits/risks of intensive control on macrovascular events
• Increasing complexity of therapeutic options
• Potential adverse effects
• Individualization of treatment
• Patient preferences and tolerance
American Diabetes Association. Standards of Medical Care in Diabetes –2018. Diabetes Care 2018;41(suppl. 1):S1-159.
American Diabetes Association (ADA) Treatment Approach
Initial Treatment
• Lifestyle interventions + Metformin are 1st line for most• If A1C≥9%, consider dual therapy (utilize CV risk to determine agent)• IF A1C≥10% or BG>300mg/dL, consider combination or injectable therapy
Not at Goal at 3
months?
• Assess medication taking behavior• Add a 2nd oral agent or long-acting insulin or a GLP-1 receptor agonist
Not at Goal at 6
months?
• Assess medication taking behavior• Add a 3rd oral agent or long-acting insulin or a GLP-1 receptor agonist
cost, potential side effects, weight, comorbidities, Use a patient-centered approach taking into account cost, potential side effects, weight, comorbidities,
hypoglycemia risk, patient preferences, cardiovascular effects
American Diabetes Association. Standards of Medical Care in Diabetes –2018. Diabetes Care 2018;41(suppl. 1):S1-159.
American Diabetes Association (ADA) Treatment Approach
American Diabetes Association. Standards of Medical Care in Diabetes –2018. Diabetes Care 2018;41(suppl. 1):S1-159.
9/15/2018
6
Metformin
Sulfonylureas
GlyburideGlipizide
Glimeperide
Thiazolidinediones
PioglitazoneRosiglitazone
SGLT-2 Inhibitors
CanagliflozinDapagliflozinEmpagliflozinErtugliflozin
DPP-4 Inhibitors
SitagliptinSaxagliptinLinagliptinAlogliptin
Insulin
Nasal
InsulinRapid, Short
IntermediateBasal
Premixed Nasal
Available Antihyperglycemic Therapies (1st or 2nd line)
GLP-1 RA ExenatideLiraglutide
LixisenatideDulaglutideSemaglutide
And many combinations…
American Diabetes Association. Standards of Medical Care in Diabetes –2018. Diabetes Care 2018;41(suppl. 1):S1-159.
American Diabetes Association. Standards of Medical Care in Diabetes –2018. Diabetes Care 2018;41(suppl. 1):S1-159.
Sulfonylureas
• Second generation: glipizide, glimepiride, glyburide
• MOA: Stimulate beta cells in the pancreas to release insulin
• Adverse effects
• Hypoglycemia
• Weight gain
• Rash
• Beta cell burnout? - Decreased longevity
• Cardiovascular risk?
• Inhibition of myocardial ischemic preconditioning
• Low cost, effective A1C lowering
American Diabetes Association. Standards of Medical Care in Diabetes –2018. Diabetes Care 2018;41(suppl. 1):S1-159.
9/15/2018
7
Thiazolidendiones(TZD’s)• TZD’s include pioglitazone, rosiglitazone
• MOA: Activates the nuclear transcription factor PPAR-gamma, increases peripheral insulin sensitivity
• Adverse effects
– Bone fractures
– Edema/fluid retention
– Weight gain
– Reported cases of liver failure
• Avoid in NYHA Class III or IV heart failure
• Clinical considerations
• Cardiovascular disease, Bladder Cancer
American Diabetes Association. Standards of Medical Care in Diabetes –2018. Diabetes Care 2018;41(suppl. 1):S1-159.
Incretin Physiology
Plasma Glucose
Tissues
GlucoseDisposal
Rate ofglucose
appearance
Rate ofglucose
disappearance
Stomach
BrainFoodIntake—
GastricEmptying
—
Liver
GLP-1
Gut
PostprandialGlucagon
Pancreas
Insulin
Illustration courtesy of Amylin PharmaceuticalsGedulin BR, et al. Endocrinology 2005; 146:2069-76.
De Leon DD, et al. The International Journal of Biochemistry & Cell Biology 2005 Sep 29Kruger DF. Drugs 2004; 64:1419-32.
DPP-4 Enzyme
Dipetidyl Peptidase-4 (DPP-4) Inhibitors
4 available agents
Sitagliptin(Januvia®)
Saxagliptin(Onglyza®)
Linagliptin(Tradjenta®)
Alogliptin(Nesiba®)
Well tolerated Most common ADR’s: headache, upper respiratory infections, urinary tract infections FDA alerts: pancreatitis, joint pain, heart failure
MOA: Inhibits DPP-4 activity, increasing postprandial incretin (GLP-1, GIP)
concentra ons: ↑ Insulin secre on, ↓ glucagon secre on (glucose dependent)
American Diabetes Association. Standards of Medical Care in Diabetes –2018. Diabetes Care 2018;41(suppl. 1):S1-159.
DPP-IV Agent Comparison
Sitagliptin (Januvia®) Saxagliptin (Onglyza®) Linagliptin(Tradjenta®)
Alogiptin(Nesiba®)
High selectivity for DPP-4 enzyme
Moderate selectivity for DPP-4 enzyme
High selectivity for DPP-4 enzyme
High selectivity for DPP-4 enzyme
DPP-4 inhibition ~97% (24 hours post-dose)
DPP-4 inhibition ~80% (24 hours post-dose)
DPP-4 inhibition > 80%
(24 hours post-dose)
DPP-4 inhibition ~ 75% (24 hours post dose)
Dose not undergo appreciable metabolism
Metabolized by CYP3A4 enzyme system
Weak – Moderate Inhibitor of CYP3A4
enzyme system
Not appreciably metabolized
Renal excretion Renal excretion Non-renal excretion Renal excretion
Deacon C.F. Diabetes, Obesity and Metabolism. 2011. 13:7-18.
9/15/2018
8
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 agonists
Pancreatitis
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
Glucagon-Like-1 Receptor Agonists (GLP-1 RA)
• MOA: Activates GLP-1 Receptors
– ↑ Insulin secretion (glucose dependent)
– ↓ Glucagon secretion (glucose dependent)
– Slows gastric emptying
– ↑ Sa ety
• Supra-therapeutic levels of GLP-1
– Higher levels achieved compared to DPP-4 inhibitors
• Common adverse effects
• Nausea/vomiting, injection site reactions, weight loss, increased heart rate
• Bydureon®: SQ nodules
• Warnings include pancreatitis, thyroid C-cell tumors, gallstonesDiabetes Care 2017;40(Suppl. 1):S64–S74.
Detail-Document, Comparison of GLP-1 Agonists. Pharmacist’s Letter/Prescriber’s Letter. December 2014Lixisenatide. Micromedex 2.0. Available at: http://www.micromedexsolutions.com. Accessed April, 2017.
AvailableGLP-1RAsGLP-1 RA Dosing (All SQ) Clinical Considerations
Exenatide (Byetta®)
5 – 10 mcg BID • Primarily affects postprandial glucose due to delays in gastric emptying• High risk of GI adverse effects, may take longer than long-acting GLP-1 agonists to become
nausea free• Dose escalation precautions required for CKD
Liraglutide(Victoza®)
0.6 – 1.8 mg daily
• More pronounced effects on fasting blood glucose• Administer at anytime of the day• Dose adjustments not recommended
Lixisenatide(Aldyxin®)
10 – 20 mcg daily
• Administer 1 hour prior to first meal of day• Although administered once daily, half life is short with most robust effect on postprandial
glucoses• Dose adjustments not recommended, but gastrointestinal disturbances and dehydration can
worsen renal concerns
Exenatide QW (Bydureon®)
2 mg once weekly
• Available as two formulations - one prefilled pen, and one that requires patient reconstitution• Steady state concentrations are not reached until week 7• Dose escalation precautions required for CKD
Dulaglutide(Trulicity®)
0.75 – 1.5 mg weekly
• Achieves therapeutic concentrations faster than other agents (3 - 7 days)• Less efficacy in reducing satiety (presumably due to less effect on CNS through limited passage
in the blood-brain barrier
Semaglutide (Ozempic®)
0.25 mg weekly • Potential concerns of progression of diabetic retinopathy with this agent• Dose adjustments not required
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.
9/15/2018
9
Sodium-Glucose Co-Transportor-2 (SGLT-2) Inhibitors
Pros• Unique MOA
• Lowers BP
• Weight loss
• Low risk of hypoglycemia
• Positive CV outcome data (Jardiance®, Canagliflozin®)
Cons
PL Detail-Document, Drugs for Type 2 Diabetes. Pharmacist’s Letter/Prescriber’s Letter. September 2016
MOA: Inhibits SGLT-2 in the proximal renal tubule; blocks glucose reabsorption by the kidney, increasing glucosuria
Canagliflozin(Invokana®)
Dapagliflozin(Farxiga®)
Empagliflozin (Jardiance®)
Ertugliflozin(Steglartro®)
• Genitourinary tract infections
• Hypovolemia
• Bone fractures
• Leg/foot amputations
• Acute kidney injury
• Euglycemic DKA
SGLT2-Inhibitors: Adverse Effects
• FDA warning added to canagliflozin in Sept 2015• A pooled analysis of 9 trials over 85 weeks compared canagliflozin to placebo: more bone fractures
with Cnagligflozin (1.5 vs. 1.1) per 100 patient-years
Bone loss
• FDA warning updated June 2016 for canagliflozin, dapagliflozin• 2013-2015, FDA received 101 confirmed cases of acute kidney injury
Acute Kidney Injury
• FDA warning added Dec 2015• 19 cases of life-threatening urosepsis and pyelonephritis with canagliflozin(n=10) and
dapagliflozin(n=9)
Urosepsis
• FDA warning added May 2015 (updated Dec 2015)• 73 cases of DKA reported in FAERS
Diabetic Ketoacidosis
Amputations
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 4/13/17
FDA Drug Safety Alert. Available at: https://www.fda.gov/Drugs/DrugSafety/ucm446845.htm. Accessed: 3/20/17
Drug Selection: A Balancing Act
Clinical Outcomes
Patient Safety
Considerations in Drug Selection
Mechanism of Action
Effects on A1C, FBG,
PPG
Cost Effects on Weight
Hepatic/Renal Thresholds
Medication Adherence
Adverse Effects
Risk of Hypoglycemia
Patient Preferences
9/15/2018
10
Impact on A1C and Glucose
•Think: how low do you need to go? Ex: More A1C lowering with GLP-1 RA vs. DPP4 inhibitor
• Insulin has the most A1C lowering potentialA1C Lowering
•Metformin, TZD’s, SGLT-2 inhibitors, long acting GLP-1 RA’s, long acting insulinFBG Coverage
PPG Coverage
•Sulfonylureas, long acting GLP-1 RA’s FBG/PPG Coverage
• DPP-4 inhibitors, short-acting GLP-1 RA’s, alpha-glucosidase inhibitors, meglitinides, rapid/short-acting insulin
A. American Diabetes Association. 9. Cardiovascular disease and risk management: Standards of Medical Care in Diabetes-2018. Dibetes Care 2018;41(uppl. 1):S86-104.
Macrovascular Complications
Patients with DM have 2 – 6 times higher risk of development of CV diseaseCHD risk equivalent
Treatment may be less efficacious than general population
Poorer prognosis than individuals without clinically apparent DM Protective effect for females is lost in women
with DM
Landmark TrialsStandards of Care, 2018 Guidelines
9/15/2018
11
Objective Study Design Results
To assess the long-term effects of liraglutide on cardiovascular outcomes and other clinically important events in patients with T2DM and high risk of cardiovascular disease• Primary outcome:
composite of CV death, nonfatal MI, nonfatal stroke
Multicenter, double-blind, placebo-controlled trial at 410 sites in 32 countries
Patients randomized to 2 week placebo run in period, then randomized 1:1 to liraglutide 1.8mg or placebo once daily + standard of care
The primary composite outcome occurred in fewer patients in the liraglutide group 13.0% than in the placebo group 14.9% (hazard ratio, 0.87; 95% confidence interval [CI], 0.78 to 0.97; P<0.001 for noninferiority; P=0.01 for superiority)
Death from cardiovascular causes occurred in fewer patients in the liraglutide group (hazard ratio, 0.78; 95% CI, 0.66 to 0.93; P=0.007)
The rate of death from any cause was also lower in the liraglutidegroup than in the placebo group ( (hazard ratio, 0.85; 95% CI, 0.74 to 0.97; P=0.02)
LEADER Trial
Marso SP, et al. N Engl J Med. 2016:375:311-322.
Hazard ratio (95% CI) P value
Primary composite endpoint* 0.87 (0.78-0.97) 0.01
Expanded composite endpoint† 0.88 (0.81-0.96) 0.005
Death from any cause 0.85 (0.74-0.97) 0.02
CV death 0.78 (0.66-0.93) 0.007
Fatal or nonfatal MI 0.86 (0.73-1.00) 0.046
Nephropathy 0.78 (0.67-0.92) 0.003
Clinical Outcomes with Liraglutide
LEADER(N=9340)
Marso SP, et al. N Engl J Med. 2016:375:311-322.
0.00 0.20 0.40 0.60 0.80 1.00 1.20
Median follow-up: 3.5 years
LEADER Trial –OUTCOMES
Marso SP, et al. N Engl J Med. 2016:375:311-322.
LEADER: Selected Safety Results
Adverse Event Liraglutide (%) Placebo (%) P-Value
Any ADE 62.3 60.8 0.12
Serious ADE 49.7 50.4 0.51
Confirmedhypoglycemia
43.7 45.6 0.06
Severe hypoglycemia 2.4 3.3 0.02
Acute gallstone disease 3.1 1.9 < 0.001
Injection site reaction 0.7 0.3 0.002
ADE leading to discontinuation of trial
9.5 7.3 <0.001
Marso SP, et al. N Engl J Med. 2016:375:311-322.
9/15/2018
12
Objective Study Design
To assess the effects of empagliflozin an in addition to standard care, on cardiovascular morbidity and mortality in patients with type 2 diabetes at high cardiovascular risk
Multicenter, randomized, double blind, placebo controlled at 590 sties in 42 countries
The primary outcome occurred in 10.5% in the pooled empagliflozin group and in 12.1% in the placebo group (hazard ratio in the empagliflozin group, 0.86; 95.02% confidence interval, 0.74 to 0.99; P=0.04 for superiority)
Empagliflozin was associated with significantly lower rates of death from cardiovascular causes (3.7%, vs. 5.9% in the placebo group; 38% relative risk reduction), hospitalization for heart failure (2.7% and 4.1%, respectively; 35% relative risk reduction), and death from any cause (5.7% and 8.3%, respectively; 32% relative risk reduction)
EMPA-REG (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes)
Hazard ratio (95% CI) P value
Primary composite endpoint* 0.86 (0.74-0.99) 0.04
Secondary composite endpoint† 0.89 (0.78-1.01) 0.08
Death from any cause 0.68 (0.57-0.82) <0.001
CV death 0.62 (0.49-0.77) <0.001
Fatal or nonfatal MI 0.87 (0.70-1.09) 0.23
Hospitalization for HF 0.65 (0.50-0.85) 0.002
Hospitalization for HF or CV death 0.66 (0.55-0.79) <0.001
Clinical Outcomes with Empagliflozin
EMPA-REG OUTCOME Pooled Analysis(N=7020)
Zinman B, et al. N Engl J Med. 2015;373:2117-2128.
0.00 0.20 0.40 0.60 0.80 1.00 1.20
Primary Outcome Results – EMPA-REGSafety Outcomes with Empagliflozin
Zinman B, et al. N Engl J Med. 2015;373:2117-2128.
Event Pooled Empagliflozin (%) Placebo (%)
Any adverse event 90.2 91.7
Serious adverse event 38.2 42.3
Death 3.8 5.1
Any hypoglycemia 27.8 27.9
Severe hypoglycemia 1.3 1.5
Urinary tract infection Male 18.0 18.1
Genital infection 6.4 1.8
Volume depletion 5.1 4.9
Diabetic ketoacidosis 0.1 <0.1
Bone fracture 3.8 3.9
Acute kidney failure 5.2 6.6
9/15/2018
13
Objective Study Design Results
To assess the effects of empagliflozin an in addition to standard care, on cardiovascular,renal, and safety outcomes in patients with type 2 diabetes at high cardiovascular risk• Primary outcome
composite of CV death, nonfatal MI (excluding silent MI), or nonfatal stroke
Multicenter, randomized, double blind, placebo controlled at 667 sites in 30 countries
The primary outcome was significantly lower with patients treated with canagliflozin than with placebo (occuring in 26.9 vs. 31.5 participants per 1000 patient years; HR 0.86, 95% CI (0.75-0.97), p <0.001 for noninferirotiy; p = 0.02 for superiority)
Canagliflozin was associated lower progression of albuminuria,the need for renal-replacement therapy, and death from renal causes.
Canagliflozin was associated with an increased risk of amputation at the toe or metatarsal
Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes
Neal B, et al. NEJM 2017;377:644-657
Hazard ratio (95% CI)
Primary composite endpoint* 0.86 (0.75-0.97)
CV death 0.87 (0.72-1.06)
Nonfatal MI 0.85 (0.69-1.05)
Nonfatal stroke 0.90 (0.71-1.15)
Fatal or nonfatal MI 0.89 (0.73-1.09)
Fatal or nonfatal stroke 0.87 (0.69-1.09)
HF hospitalization 0.67 (0.52-0.87)
CV death or HF hospitalization 0.78 (0.67-0.91)
All-cause death 0.87 (0.74-1.01)
Progression of albuminuria 0.73 (0.67-0.79)
40% reduction in eGFR, renal replacement therapy, or renal death
0.60 (0.47-0.77)
Clinical Outcomes with Canagliflozin
0.00 0.50 1.00 1.50
Neal B, et al. NEJM 2017;377:644-657
Adverse Events with Canagliflozin
Event Canagliflozin Placebo P value
Events per 1000-patient years
All serious adverse events 104.3 120.0 0.04
Adverse events leading to discontinuation 35.5 32.8 0.07
Diabetic ketoacidosis (adjudicated) 0.6 0.3 0.14
Amputation 6.3 3.4 <0.001
Bone fracture (adjudicated) 15.4 11.9
Infection of male genitalia 34.9 10.8 <0.001
Osmotic diuresis 34.5 13.3 <0.001
Volume depletion 26.0 18.5 0.009
Mycotic genital infection in women 68.8 17.5 <0.001
Urinary tract infection 40.0 37.0 0.38
Acute kidney injury 3.0 4.1 0.33
Neal B, et al. NEJM 2017;377:644-657American Diabetes Association. 9. Cardiovascular disease and risk management: Standards of Medical Care in Diabetes-2018. Dibetes Care 2018;41(uppl. 1):S86-104.
9/15/2018
14
CVDCVD CKDCKD ObesityObesity
Heart FailureHeart Failure OsteoporosisOsteoporosis
Drug-Disease Considerations • KP is a 49yo F with type 2 diabetes for 3 years. Denies any symptoms of polyuria,
polyphagia, polydipsia. A1C increased from 7.4% to 8.4% today. She is concerned about the weight gain with insulin
• PMH• Diabetes• Hypertension• Depression• Unstable angina• Hypothyroidism• Frequent UTI’s• CKD
• Medications• Metformin 1000mg BID• Metoprolol tartrate 50 mg bid• Lisinopril 20 mg daily• Levothyroxine 88mcg daily • Citalopram 20mg daily • Atorvastatin 20mg daily
• Social History• (-) Alcohol/tobacco• Exercise: none• Insurance: Private PPO• Diet: 1 – 2 meals/day + snacks (not watching
carbohydrates or diet)• Lives at home with husband and 3 kids
• Physical examination/Laboratory• Ht: 5’2’’, Weight 180 lbs, BMI: 32.9• BP: 128/78 mm HG• A1C 8.4% today • Notable labs:
• Potassium: 4.5 mEq/L• Serum creatinine: 1.3 mg/dL• eGFR: 44 ml/min• Albumin: Creatinine ratio: 32
– SMBG: 130 - 200 mg/dL
Back to the Patient Case
• Which of the following medications would be the best option to add to KP’s medication regimen?
• Liraglutide (Victoza®)
• Pioglitazone (Actos®)
• Sitagliptin (Januvia®)
• Empaglifozin (Jardiance®)
Liraglutide is the only appropriate option for KP in this case. Given her history of ASCVD, liraglutide or empaglifozin are both options. However, she has a frequent history of UTI’s, so in this case, the GLP-1 agonist would provide the greatest benefit to
her A1C, as well as prevent CVD mortality.
Post-Test Question # 1 Post-Test Question # 2
• True/False. Based upon KP’s current condition of CKD, and current estimate of kidney functioning, she is no longer a candidate for metformin therapy.
• True
• False
The guidelines for metformin dosing have changed! While previously metformin was dosed based upon Serum Creatinine as an index, GFR now serves as the dosing guide for metformin. Given her degree of CKD, it would be prudent to decrease the overall dose to decrease the overall risk of lactic acidosis.
9/15/2018
15
Individualization for therapy after metformin should be based upon current disease state, degree of A1C lowering desired, and other co-morbid conditions.
For patients with history of ASCVD, SGLT-2 inhibitors, as well as GLP-1 agonists have demonstrated reduction in overall cardiovascular mortality.
Clinicians should utilize an individual approach when selecting add-on therapy to patients’ diabetes regimens.
Medications should never substitute appropriate patient counseling on self-care behaviors.
TAKE HOME POINTS References ADA Standards of Care. American Diabetes Association. Standards of Medical Care in Diabetes – 2018. Diabetes Care 2018;41(suppl. 1):S1-159.
AACE . Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Management Algorithm. Endocrine Practice. 2018;24(1): 91- 120.
Cefalu et al. Cardiovascular Outcomes Trials in Type 2 Diabetes: Where Do We Go From Here? Reflections from a Diabetes Care Editors’ Expert Forum. Diabetes Care. 2018;41(1): 14-31.
Chaudhury et al. Clinical Review of Antidiabetic Drugs: Implications for Type 2 Diabetes Mellitus Management. Front Endocrinol (Lausanne). 2017;8(6).
Lalita Prasad-Reddy, PharmD, MS, BCPS, BCACP, CDE