15 erm2 17 diabetesmgmt noninsulinmed kulasa
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Diabetes management: Non-insulin medications
Kristi Kulasa, MD
Assistant Clinical Professor of Medicine
Director, Inpatient Glycemic Control
Department of Endocrinology, Diabetes and Metabolism
November 10, 2015
Learning Objectives
1. Describe the role of diet, exercise, and patient education in the treatment of diabetes
2. Know the mechanism of action, dosing schedule, indications, percent A1c reduction, and side effects for common medications to treat type 2 diabetes including biguanides, sulfonylureas, thiazolidinediones, alpha-glucosidase inhibitors, incretins, and SGLT-2 inhibitors
3. Explain the clinical rationale for choosing a particular medication to treat type 2 diabetes in terms of A1c reduction, adverse effects, and co-morbidities
4. Differentiate key points in the treatment of type 1 and type 2 diabetes
Outline
• Mechanisms of Hyperglycemia
• Available Treatment Options
• Published algorithms for treatment of type 2 diabetes
• Case Discussions
COLESEVELAM
ACARBOSE
GLP-1R AGONISTS
DPP-4 INHIBITORS
INSULIN SU
DPP-4 INH MEGLITINIDES
GLP-1R AGONISTS
GLP-1 R
AGONISTS
MET
TZD
TZD
SGLT-2
RECEPTOR
BLOCKERS
HYPERGLYCEMIAReabsorb
Filtered
Glucose
Derangements at the Level of the
Hypothalamus Lead to Appetite
Dysregulation and Obesity
Increased Lipolytic Activity
Leading to Deleterious
Effects in Both Insulin
Secretion and Action
Inappropriate
Hepatic
Glucose
Production
Impaired Insulin – Mediated
Glucose Disposal
β
Reduced
Insulin
Secretion
α
Increased Post-
Prandial Secretion
of Glucagon
Decreased Incretin Action
Leads to Glucose
Stimulated Insulin ReleaseGut
Glucose
Absorption
Lifestyle
• Diet and Exercise
– A1C reduction 1-2%
– Weight loss
– Improved utilization of insulin
– Compliance difficult
• Patient Education
– Survival skills- meds, meter, hypoglycemia
– Who to call
Biguanide
• Generic: Metformin
• US Brand: Fortamet®, Glucophage®, Glucophage® XR, Glumetza®, Riomet®
• MOA: decreases hepatic gluconeogenesis and improves insulin sensitivity in peripheral tissues
• A1C lowering: 1.0-2.0%
• Advantages: weight neutral, no hypoglycemia
• Disadvantages: GI s/e (diarrhea, nausea, vomiting). Contraindicated with serum creatinine ≥1.5 mg/dL in males or ≥1.4 mg/dL in females. More recent studies OK w/ Clcr down to 30 mL/minute w/ dose reduction < 45 mL/minute. Avoid use in patients with impaired liver function due to potential for lactic acidosis.
Sulfonylurea
• 1st generation:
– Acetohexamide
– Chlorpropamide (Diabinese)
– Tolbutamide (Orinase)
• 2nd generation:
– Glipizide (Glucotrol) (Glucotrol XL)
– Gliclazide (Diamicron R) (Diamicron MR)
– Glyburide (Glibenclamide) (Diabeta) (Micronase) (Glynase)
– Glimepiride (Amaryl)
Sulfonylurea
• MOA: stimulates insulin secretion
• A1C lowering: 1-2%
• Advantages: rapid acting, low cost
• Disadvantages: weight gain, hypoglycemia, effectiveness
decreases over time. Use with caution in elderly patients,
malnourished patients and in patients with impaired renal
or hepatic function
Thiazolidinediones
• Pioglitazone - Actos®
• Rosiglitazone - Avandia®
• MOA: improves insulin sensitivity in
adipose tissue, skeletal muscle and liver
• A1C lowering: 0.5-1.4%
• Advantages: improved lipid profile (Pioglitazone), potential decrease MI (Pioglitazone), no hypoglycemia
• Disadvantages: fluid retention, CHF, weight gain, bone fractures, bladder CA, potential to increase MI (rosiglitazone)
SGLT-2 Inhibitors
• Canagliflozin - Invokana®
• Dapagliflozin – Farxiga®
• Empagliflozin – Jardiance®
• MOA: blocks reabsorption of glucose by the kidney
• A1C lowering: 0.7-1.0%
• Advantages: weight loss and no hypoglycemia
• Disadvantages: UTI, genital infections, increased urination, intravascular volume contraction/symptomatic hypotension, hyperkalemia, cannot use in renal impairment (contraindicated GFR < 30 ml/min, not rec GFR <45-60 ml/min), euglycemicDKA.
Incretins
Lipidsonline.org
• Gut hormones that are secreted from enteroendocrine
cells into the blood within minutes of eating
DPP-IV inhibitors
• Sitagliptin – Januvia®
• Saxagliptin – Onglyza®
• Linagliptin - Tradjenta®
• Alogliptin – Nesina®
• MOA: glucose mediated insulin release, decreases glucagon, slows gastric emptying
• A1C lowering: 0.6-0.9%
• Advantages: weight neutral, can use with renal impairment, glucose dependent action, no hypoglycemia
• Disadvantages: expensive (now covered on most plans)
Glucagon-like peptide 1 agonists
• Exenatide - Byetta®
• Liraglutide - Victoza®
• Exenatide Once Weekly - Bydureon®
• Albiglutide – Tanzeum®
• Dulaglutide – Trulicity®
• MOA: glucose mediated insulin release, suppresses glucagon secretion, slows gastric emptying, reduces food intake
• A1C lowering: 0.9-1.9%
• Advantages: weight loss, glucose dependent action, no hypoglycemia
• Disadvantages: injections, GI s/e (nausea, vomiting), expensive
Insulin
http://www.medicalcriteria.com/criteria/dbt_insulin.ht
m
Insulin
Category/Name of Insulin Brand Name
(manufacturer)
Onset, Peak, Duration Appearance
Rapid-Acting
Insulin Lispro
Insulin Aspart
Insulin Glulisine
Humalog (Lilly)
Novolog (Novo Nordisk)
Apidra (Sanofi-Aventis)
w/in 15 min, 1-3h, 3-5h
w/in 15 min, 1-3h, 3-5h
15-30 m, 30-60 m, 4h
Clear
Clear
Clear
Short-Acting
Regular Humulin R (Lilly)
Novolin R (Novo Nordisk)
30-60 min, 2-4h, 5-8h Clear
Intermediate-Acting
NPH Humulin N (Lilly)
Novolin N (Novo Nordisk)
1-2h, 4-10h, 14+ hrs Cloudy
Long-Acting
Insulin Detemir
Insulin Glargine
Levemir (Novo Nordisk)
Lantus (Sanofi-Aventis)
3-4h, 6-8h, 20-24h
1.5h, flat, 24h
Clear
Clear
Insulin Mixtures
NPH/Reg (70%/30%)
LisproProtamine/Lispro (50%/50%)
LisproProtamine/Lispro (75%/25%)
AspartProtamine/Aspart (70%/30%)
Humulin 70/30 (Lilly)
Novolin 70/30 (Novo)
Humalog Mix 50/50 (Lilly)
Humalog Mix 75/25 (Lilly)
Novolog Mix 70/30 (Novo)
15-30m, 30m-3h, 14-24h
5-10m, 1-4h, 18-24h
Cloudy
Cloudy
Cloudy
Cloudy
Cloudy
Insulin
• A1C lowering: unlimited
• Advantages: no dose limit, rapidly effective, improved lipid
profile
• Disadvantages: weight gain, hypoglycemia, injections
(Qday-QID), monitoring
Type 1 vs Type 2
Type 1 Diabetes
• 5-10% of patients with DM
• Autoimmune destruction of pancreatic islets destroying ability to make insulin
• Absolute insulin deficiency
• Treatment MUST include insulin
Type 2 Diabetes
• 90-95% of patients with DM
• Metabolic disorder characterized by insulin resistance
• Relative insulin deficiency
• Treatment CAN include insulin, esp late in disease process
ADA/EASD Consensus Statement for Treatment of Type 2 Diabetes
Inzucchi et al, Diabetes Care, 2015
Case 1
• 45 y/o male with newly diagnosed type 2 diabetes. He Has been symptomatic with 2 months of polyuria, polydipsia and unintentional weight loss of 20 lbs.
• A1C 10.7%
• Cr 0.8
• Weight 85 kg (BMI 30)
• What is the most appropriate initial treatment regimen?A. Lifestyle change only, patient is very motivated
B. Lifestyle + metformin
C. Lifestyle + metformin + acarbose
D. Lifestyle + metformin + glipizide + basal insulin
ADA/EASD Consensus Statement for Treatment of Type 2 Diabetes
Inzucchi et al, Diabetes Care, 2015
Case 2
• 56 y/o male with long-standing uncontrolled type 2 diabetes
x15yrs, CAD s/p MI 2003, class IV CHF and sleep apnea.
• Home regimen: metformin 1000mg bid, glipizide 5mg bid
• A1C 10%
• Cr 0.6
• Weight 95 kg (BMI 35)
• Which of the following medication should be added next?
A. Lifestyle change only, patient is very motivated
B. Pioglitazone (Actos®, TZD)
C. Liraglutide (Victoza®, GLP-1 R agonist)
D. Sitagliptin (Januvia®, DPP-IV inhibitor)
ADA/EASD Consensus Statement for Treatment of Type 2 Diabetes
Inzucchi et al, Diabetes Care, 2015
Case 3
• 75 y/o female with long-standing type 2 diabetes and osteoporosis recently admitted to the hospital with a hip fracture s/p fall at home in the setting of hypoglycemia.
• Home regimen: metformin 1000mg bid and glipizide 2.5mg bid
• A1C 6.5%
• Cr 0.4
• Weight 40 kg (BMI 19)
• Which of the following medication adjustment is most appropriate?A. No change necessary, A1C at goal
B. Stop glipizide and start sitagliptin (Januvia®, DPP-IV inhibitor)
C. Stop metformin and start canagliflozin (Invokana®, SGLT-2 inhibitor)
D. Stop glipizide and start pioglitazone (Actos®, TZD)
ADA/EASD Consensus Statement for Treatment of Type 2 Diabetes
Inzucchi et al, Diabetes Care, 2015
Case 4
• 45 y/o male with newly diagnosed DM2 w/ A1C 8.3%. Denies polyuria, polydipsia or blurry vision.
• Home regimen - none
• A1C 8.3%
• Cr 0.85
• Weight 95 kg (BMI 30)
• What is the most appropriate initial treatment regimen?A. Lifestyle change only, patient is very motivated
B. Lifestyle + metformin (Glucophage®, biguanide)
C. Lifestyle + sitagliptin (Januvia®, DPP-IV inhibitor)
D. Lifestyle + canagliflozin (Invokana®, SGLT-2 inhibitor)
ADA/EASD Consensus Statement for Treatment of Type 2 Diabetes
Inzucchi et al, Diabetes Care, 2015
Case 5• 45 y/o female with uncontrolled DM2 w/ A1C 10.2% as well as
heartburn, HTN and hyperlipidemia needs medication escalation for DM, but is very concerned about weight gain and will not take any medication that will cause weight gain.
• Home regimen – metformin 1000mg bid
• A1C 10.2%
• Cr 0.6
• Weight 90 kg (BMI 34)
• Which of the following medication(s) should be added next?A. Lifestyle change only, patient is very motivated
B. Liraglutide (Victoza®, GLP-1 R agonist) + glipizide (SU)
C. Sitagliptin (Januvia®, DPP-IV inhibitor) + canagliflozin (Invokana®, SGLT-2 inhibitor)
D. Canagliflozin (Invokana®, SGLT-2 inhibitor) + Liraglutide (Victoza®, GLP-1 R agonist)
ADA/EASD Consensus Statement for Treatment of Type 2 Diabetes
Inzucchi et al, Diabetes Care, 2015
Case 6• 65 y/o female with longstanding DM2 c/b retinopathy, neuropathy and
nephropathy w/ chronic kidney disease (Cr 1.7) as well as coronary artery disease and congestive heart failure admitted to the hospital with CHF exacerbation and acute kidney injury, noted to have hypoglycemia at home 3x/week.
• Home regimen: glipizide 5mg bid
• A1C 7.2%
• Cr 2.2 (GFR 24)
• Weight 80 kg (BMI 28)
• Which of the following medication adjustment is most appropriate?A. No change necessary, A1C at goal given age and co-morbidities
B. Stop glipizide and start pioglitazone (Actos®, TZD)
C. Stop glipizide and start sitagliptin (Januvia®, DPP-IV inhibitor)
D. Stop glipizide and start canagliflozin (Invokana®, SGLT-2 inhibitor)
E. Stop glipizide and start metformin (Glucophage®, biguanide)
ADA/EASD Consensus Statement for Treatment of Type 2 Diabetes
Inzucchi et al, Diabetes Care, 2015
Questions?
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