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Keeping UP on Diabetic
Medications and Complications  Apply current clinical practice standards to optimize pharmacologic treatment outcomes and non-pharmacological management strategies for an adult patient with type 2 diabetes.  Recognize patient situations where the utilization of a new or novel pharmacological agent appropriately optimizes type 2 diabetes management.  Apply current standards of medical care to perform appropriate patient assessments, and suggest appropriate monitoring parameters and goals of therapy or an adult patient with type 2 diabetes Results primarily from insulin resistance in muscle and liver, which could lead to defect in pancreatic insulin secretion Accounts for 90-95% of diabetes Prevalence in the US is 7.8% (about 23.6 million and growing) Formerly known as non-insulin-dependent diabetes (adult-onset diabetes) Often asymptomatic with a slow onset over 5-10 years Disturbing increased trends in children and adolescents due to rise in obesity CDC. National Diabetes Statistics Report 2014: Estimates of diabetes and its burden in the United States, 2014. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Diseas e Control and Prevention, 2011. Available at CDC 2014. Summary Health Statistics for U.S. Adults: 2012. Table 8. Available at FAST FACTS ON DIABETES
Diabetes affects 29 million people—
9.3% of the U.S. population
DIAGNOSED
21.0 million people
UNDIAGNOSED
8.1 million people
American Indian/Native American 17.9%
Non-Hispanic White 7.3%
CDC. National Diabetes Statistics Report 2014: Estimates of diabetes and its burden in the United States, 2014. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2011. Available at CDC 2014. Summary Health Statistics for U.S. Adults: 2012. Table 8. Available at ADA Data-Native Americans


Every 24 hours…  4557 adults are diagnosed with diabetes.  136 people begin treatment for end-stage
renal disease.
 200 nontraumatic lower-limb amputations
 641 people die from diabetes, or diabetes is a contributing cause of their death.
CDC. National Diabetes Statistics Report 2014: Estimates of diabetes and its burden in the United States, 2014. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2011. Available at ACCE 2016
<8% - Elderly, frail, brittle >6.5% - Concurrent serious illness and high hypoglycemic risk Monotherapy A1c <9%: Metformin
A1c <7.5%: Met, SGLT2i, DPP4i, or
GLP-1 RA
A1c >9%: Dual Therapy –
A1c >7.5%: Dual Therapy –
Metformin + SU, TZD, DPP-4i, Metformin + (Preferred: DPP-4i, SGLT2i, GLP-1 RA, Insulin SGLT2i, GLP-1 RA, Colesevelam, A1c >10% and symptomatic:
Bromocriptine, Agi, Use caution: Metformin +Basal + Prandial Insulin SU/GLN, TZD, Insulin) Triple Therapy Metformin + 2 others Metformin + 2 others AACE/ACE Comprehensive Type 2 Diabetes Management Algorithm 2016 Published in Endocr Pract.2016;22:84-113 ACCE 2016
A1c >10% + Symptoms : Metformin + A1c <8%: Basal TDD 0.1-0.2 U/kg Basal Insulin (Start 10 U/day or 0.1- A1c >8%: Basal TDD 0.2-0.3 U/kg 0.2 U/kg/day) + Add Prandial Insulin *Add Prandial Insulin or GLP-1 RA if or GLP-1 RA if goal not achieved (1 goal not achieved (Plus 1, 2, 3 or meal or Premixed) Goal <140/90 mmHg Goal <130/80 mmHg 1st line: ACEi/ARB 1st line: ACEi/ARB *Add CCB or Thiazide if needed Dual Therapy: BP >150/90 use ACEi/ARB + CCB, BB, Thiazide <40 yo w/o ASCVD Risk – no statin >40 yo – Moderate/High Intensity AACE/ACE Comprehensive Type 2 Diabetes Management Algorithm 2016 Published in Endocr Pract.2016;22:84-113 Goals of Diabetes Management  Primary goal – prevent onset of acute or chronic complications  Acute complications:  Hypoglycemia, DKA, hyperglycemic hyperosmolar nonketotic  Chronic complications:  Microvascular: Retinopathy, nephropathy, and neuropathy  Macrovascular: Cardiovascular, cerebrovascular, and peripheral vascular diseases  Glycemic therapy goals: A1C <7% and <8% (elderly)  FPG or premeal 80-130mg/dL (change in 2015 by ADA)  Peak postprandial glucose (1-2 hours after meal) <180mg/dL ADA 2016 Clinical Practice Recommendations: http://care.diabetesjournals.org/content/39/Supplement_1 Goals of Diabetes Management Cont.  Blood Pressure  BP <150/90 mmHg for >60 years old; <140/90 mmHg for everyone else (change in 2015 by ADA to match with JNC8)  For younger patients consider treating to <130/80 to prevent long term complications  No specific LDL-C, HDL-C, or TG goal are currently recommended  Lowering LDL-C by 30%-49% in pt with diabetes 40-75 years old and by at east 50% if 10-year risk of cardiovascular event is >7.5% (ACC/AHA 2013) ADA 2016 Clinical Practice Recommendations: http://care.diabetesjournals.org/content/39/Supplement_1


 Insulin Deficiency- lack of secretion  Insulin Resistance  Glucagon Secretion  Increased gastric motility  Decrease GLP/GIP  Leptin & Ghrelin UKPDS: β-Cell Function over Time Decline to insulin deficiency 12 yrs after Dx! Insulin loss starts 10 yrs before Dx. Half gone by Dx. Insulin loss is part of T2 DM 51% residual secretion 28% residual insulin secretion Years After Diagnosis Diabetes 44: 1249-1258, 1995 Primary Mechanism of Action  Decrease hepatic glucose production (HGP) Increase glucose uptake in muscle Mean drop in A1c  Side effects:  weight neutral, moderate GI symptoms (N/V, flatulence, diarrhea), B‐12 deficiency Contraindicated: eGFR<45ml/min due to lactic acidosis, CKD (stage 3B, 4, and 5) Benefit in CVD pt? Primary Mechanism of Action  Increase insulin secretion Glipizide (better option for older adults and those with renal impairment) Glyburide (BEER's list) Mean drop in A1c  Dose titration: can increase weekly Side effects:  Moderate/severe hypoglycemia (more risk in renal disease patients), weight gain Thiazolidinediones Primary Mechanism of Action  Increase glucose uptake in muscle and fat Decrease hepatic glucose production (HGP) Mean drop in A1c  Slow dose titration and may not see effect until 8-12 weeks Side effects:  May worsen fluid retention (caution with CHF patients), weight gain, moderate bone loss, possible bladder cancer risk a-Glucosidase Inhibitors Primary Mechanism of Action  Delay carbohydrate absorption from intestine Mean drop in A1c  Side effects:  Moderate GI symptoms (bloating, flatulence, diarrhea, abdominal pain), rash Contraindications & Precautions: Inflammatory bowel disease, colonic ulcerations, intestinal obstruction Primary Mechanism of Action  Decrease glucagon secretions Slow gastric emptying Increase satiety Mean drop in A1c  0.5-1% (very effective at controlling postprandial glucose) Side effects:  High risk of hypoglycemia, moderate GI symptoms (N/V, diarrhea, abdominal pain), fatigue, dizziness, modest weight loss Bile Acid Sequestrant  Primary Mechanism of Action Remove bile acid from the body, so lower cholesterol. Mechanism to reduce serum glucose: unknown (Decrease HGP? Increase incretin levels?) Colesevelam (Welchol)  Mean drop in A1c 0.5% when added to metformin, sulfonylurea, or insulin  Side effects: Mild GI symptoms (constipation, indigestion, and nausea), fatigue, headache, myalgia Contraindicated in pts with a history of bowel obstruction, TG concentration Dopamine-2 Agonist Primary Mechanism of Action  Activates dopaminergic receptors; "reset" biological clock to improve metabolism Bromocriptine (Cycloset) Mean drop in A1c  Side effects:  Moderate GI symptoms, fatigue, headache/syncope, dizziness, somnolence, and possible cardiovascular benefit Contraindications & Precautions: pt with syncopal migraines; can limit effectiveness of agents used to treat psychosis or exacerbate psychotic disorder; Primary Mechanism of Action Remove bile acid from the body, so lower cholesterol. Mechanism to reduce serum glucose: unknown (Decrease HGP? Increase incretin levels?) Increase insulin secretion (similar to Sulfonylurea but more rapid onset and shorter duration of activity) Repaglinide (Caution: level greatly increased when use with gemfibrozil) Mean drop in A1c Mild hypoglycemia (more risk for renal disease patients), weight gain, and upper respiratory infection/bronchitis  Glucagon-like peptide 1 receptor agonists (GLP-1 agonist)  Dipeptidyl peptidase 4 inhibitors (DPP-4 Inhibitors)  Sodium glucose cotransporter 2 inhibitors (SGLT2 Inhibitors)  Inhaled Insulin - Afrezza  Concentrated Insulin  U200 and U300 GLP-1 Receptor Agonist  Injectable non-insulin medication for T2DM  Works in the small intestine  Stimulates glucose-dependent stimulation of insulin secretion  Slows gastric emptying  Prevents inappropriate glucagon secretion  Promotes weight loss GLP-1 Receptor Agonist  Trulicity (dulaglutide) 0.75mg-1.5mg SQ weekly  Tanzeum (albiglutide) 30mg-50mg SQ weekly+  Bydureon (exenatide) 2mg SQ weekly+**  Victoza (liraglutide) 0.6mg-1.8mg SQ daily**  Byetta (exenatide) 5-10mcg SQ bid within 60 minutes of meal** +Requires dilution and mixing prior to use ** Caution in renal failure GLP-1 Receptor Agonist  Injection Site Reaction  Pancreatitis  Acute pancreatitis has been reported but the FDA has found insufficient evidence  Discontinue if pancreatitis occurs  Do not start if history of pancreatitis GLP-1 Receptor Agonists  Contraindicated in pts with or family history of:  Thyroid C-cell type cancer including medullary thyroid carcinoma  Multiple endocrine neoplasia syndrome type 2 (MEN 2) GLP-1 Receptor Agonists Lower A1c 1-1.5% Weight loss 2-3 kg Little hypoglycemia  Disadvantages Gastrointestinal side effects may limit use 10-50% Risk of thyroid c-cell tumors Risk of pancreatitis Worsening renal function DPP-4 Inhibitors  Oral medication for T2DM  Inhibits the enzyme DPP-4, prevents the deactivation of GLP-1  Stimulates insulin release from the pancreatic islets  Slows gastric emptying  Inhibits post-meal glucagon release  Reduces food intake DPP-4 Inhibitors  Januvia (sitagliptin) 100mg po daily*  Onglyza (saxigliptin) 2.5 – 5mg po daily*  Nasina (alogliptin) 25mg po daily*  Tradjenta (linagliptin) 5mg po daily *Requires renal adjustments All are Pregnancy Category B and can be taken with/without food DPP-4 Inhibitors  Pancreatitis  All DPP-4 Inhibitors  Hepatic Function  Aloglipitin – baseline LFTs and every 3 months for first year  Saxaglipitin – serious skin reactions  All DPP-4 Inhibitors – Stevens-Johnson syndrome DPP-4 Inhibitors  Cardiovascular Effect  Saxigliptin and aloglipitin – increased risk of hospitalization for  July 2015, Meta-Analysis 14,735 patients with DMT2 and history of CVD on sitagliptin or placebo showed no differences in CVD outcomes. DPP-4 Inhibitors  No hypoglycemia (monotherapy)  Weight neutral  Well tolerated  Disadvantages  May be associated with Pancreatitis  Risk of Heart failure (saxagliptin) SGLT2–Inhibitors  Oral medication for adults with T2DM  Increase glucose excretion by inhibiting sodium-glucose co- transporter 2 (SGLT2) in the kidney  Independent of insulin  Potential for lowering blood pressure and weight loss (2-3 kg)  Canagliflozin may also decrease post-prandial hyperglycemia by delaying glucose absorption SGLT2–Inhibitors  Canagliflozin (Invokana)  100mg-300mg po daily before breakfast*  Canagliflozin/Metformin (Invokamet) 50/500mg-150/1000mg bid  Dapagliflozin (Forxiga)  5mg-10mg po daily*  Dapagliflozin/Metformin (Xigduo XR) 5/500mg-10/2000mg daily  Empagliflozin (Jardiance)  10mg-25mg po daily  Empagliflozin/Linaglipitin (Glyxambi) 10mg/5mg daily *Requires dose adjustment for renal function All ar e Pregnancy category C and only canagliflozin should be take with regard to a meal but should be taken in the morning as they have a diuretic effect SGLT2–Inhibitors  Vulvovaginal Candidiasis Canagliflozin 10-11% Dapagliflozin 7-8% Empagliflozin 4-6%  Urinary Tract Infections Canagliflozin 4-6% Dapagliflozin 4-6% Empagliflozin 9%  Hypoglycemia Low with monotherapy, elevated when combined with insulin or other oral DM medication SGLT2–Inhibitors  Diabetic Ketoacidosis FDA Black Box Warning
SGLT2 inhibitors alone or in combination products, may lead to ketoacidosis Signs or symptoms of ketoacidosis (ex. difficulty breathing, nausea, vomiting, abdominal pain, confusion, unusual fatigue or sleepiness) Glucose may not be elevated as typically seen with DKA Major illness, reduced food and fluid intake, and reduced insulin dose may contribute to ketoacidosis in patients taking SGLT2 inhibitors.  Bladder Cancer Dapagliflozin – 10 cases reported Prompted FDA to require post-marketing surveillance studies SGLT2–Inhibitors Little hypoglycemia (as monotherapy) Mild weight loss Reduced Blood pressure  Disadvantages Vulvovaginal infections Urinary tract infections Can't be used in severe renal failure Risk of bladder cancer (dapagliflozin)


1921 Insulin "Discovered" 1923 Eli Lilly manufactures Insulin 1973 U-100 Insulin Developed 1978 Engineered "human" insulin developed 1986 Insulin Pen Developed 2006 First Approved Inhaled Insulin Developed


Pharmacokinetics Primary Mechanism of Action  Stimulate peripheral glucose uptake Decrease hepatic glucose production (HGP) Inhibits proteolysis, enhances protein synthesis, and inhibits lipolysis in adipocytes Short acting (Regular human insulin) Rapid acting (Novolog, Humalog, Glulisine) Intermediate acting: NPH Long acting: Lantus and Levemir (can not be mixed with other insulins) Mean drop in A1c  1.5-3% (most effective treatment for hyperglycemia) Side effects:  Hypoglycemia, injection site reaction, rash, weight gain, peripheral edema Nathan DM, Buse JB, Davidson MB, et al. Diabetes Care. 2009; 32(1): 193-203) Insulin Medications Starting Insulin Starting Insulin  Basal 0.1-0.2 Units/kg/day or 10 units Adjust 1-2/week by 10-15% or 2-4 units Goal pre-prandial 80-130mg/dL Adding Bolus Prandial Insulin  Start if FBG reached, but A1c not controlled or TDD >0.5 U/kg/day Bolus 4 units or 0.1 U/kg or 10% of Basal dose with largest meal Adjust 1-2/week by 1-2 U or 10-15% Add additional "bolus" with >2 meals Adding Premixed  Divide Basal dose: 2/3 in am and 1/3 in pm Adjust 1-2/week by 1-2 U or 10-15% Adjusting Insulin Blood Sugar
Insulin Dose
Breakfast
Levemir 30 units hs Levemir 30 units hs Levemir 30 units hs  FBG controlled – Lunch pre-prandial BS above goal  Start: Bolus Insulin with Breakfast  Dose: 4 units, 0.1 U/kg (weight 100kg = 10 units), 10% = 3 unit Switching Between Insulin  Intermediate to Basal  Once daily – convert 1:1  Twice daily – Use 80% of dose  Converting to U500  Use 80% of TDD insulin dose, given 30 minutes before meals  TDD = 200-300 units/day divide dose bid  TDD = 300-750 units/day divide dose tid  TDD = 750-2000 units/day divide dose four times daily  TDD >2000units/day consider insulin pump  Inhaled Insulin - Afrezza  Concentrated Insulin  U200  U300  Ultra Long-Acting Insulin Inhaled Insulin - Afrezza Second Generation Inhaled Insulin  Approved June 2014  Ultra Rapid-acting inhaled insulin for adults at least 18 years of age with T1DM or T2DM.  Technosphere Insulin, dry powdered insulin for prandial coverage in non-smoking adults without pulmonary diseases  In patients with T1DM, Afrezza must be used in combination with long-acting insulin. Inhaled Insulin – Afrezza  Administration Give immediately prior to meal, reaches peak plasma in 12-15 minutes Sealed foil packages refrigerated, once opened may be out of fridge for 10days Inhaler must be replaced every 15 days Risk of acute bronchospasm in patients with chronic lung disease Contraindicated in patients with Asthma, COPD, lung cancer, current smokers or cessation smokers within last 6 months



Inhaled Insulin – Afrezza



Inhaled Insulin - Afrezza Inhaled Insulin – Afrezza  Reduces number of insulin injections  Can be used immediately before meal  Disadvantages  Contraindicated in pts with respiratory problems, lung cancer or  Multiple inhalations for higher insulin doses  Risk of lung function decreasing  Dosing increments of 4 and 8 units Concentrated Insulin U-200  Humalog Kwikpen  Rapid acting mealtime insulin, identical to Humalog U100 except contains 200units/ml  Could be considered for people on >20 units/day of rapid acting Concentrated Insulin U-300 Toujeo (Insulin glargine)  Available in SoloStar pen, which only delivers up to 80 units per  Longer duration of action than Lantus (slower absorption)  Higher doses may be required to get same glycemic efficacy as Lantus  5 days to achieve maximum benefit, titrate every 3-4 days  Conversions: Daily Lantus, Levemir or NPH 1:1 conversion Twice daily Lantus 1:1, Levemir or NPH use 80% of total daily dose Insulin Degludec  Approved September 2015  Ultra Long-acting insulin approved for adults at least 18 years of age with T1DM or T2DM.  Available in Flextouch pen U100 or U200 with dosing up to 160 Tresiba [package insert]. Plainsboro, NJ: Novo Nordisk Inc; September 2015. Insulin Degludec Dosing and Administration  Once daily SQ dose, start at 10 units, 0.2-0.4mg/kg Daily Lantus, Levemir or NPH 1:1 conversion Pharmacokinetics  Half-life 25 hours, Duration of Action 42 hours Unopened - Refrigerator Opened – Unrefrigerated, stable for 8 weeks below 86°F Similar rates of hypoglycemia to Insulin Glargine Lower rates of nocturnal hypoglycemia compared to Insulin Glargine (not significant) Tresiba [package insert]. Plainsboro, NJ: Novo Nordisk Inc; September 2015.  Biosimilars are close to the original "reference" drug and produce similar therapeutic outcomes but are made differently and by different companies and will cost less than the original  First Insulin Biosimilars approved by FDA in 2014  Basaglar – similar to Lantus (under 30 month automatic stay due to patent infringement filed by Sanofi)  Abasria – European product New DM Medications On the Horizon Medication
Expected Approval
Insulin peglispro LA basal insulin 5-10 units SQ daily 0.8-1.6mg po weekly 2016 10-25mg po weekly 10-40mg po daily Glucagon receptor 5-200mg po daily 75 yo female has T2DM, her HgA1c is 10.1 with SCr 0.9 and she is on Metformin 1000mg bid and glyburide 10mg . Select the best treatment plan. Continue metformin, glyburide and add pioglitizone 15mg daily Continue metformin, glyburide and add sitagliptin 5mg daily Continue metformin, glyburide and add Levemir 10 units hs Continue metformin, stop glyburide and add Levemir 10 units hs  35 yo female with T2DM her HgA1c 9.1, BMI 44kg, BP 137/88, SCr 0.7. She is currently on Levemir 45 unit SQ bid, Novolog 10 units SQ AC, Lisinopril 20mg daily, omeprazole 20mg daily, metoclopramide 10mg TID, calcium/vit D. Intolerant to metformin. What would be the best option for her DM? Add a DPP-IV inhibitor Add a GLP1-agonist Add SGLT-2 inhibitor 35 yo female with T2DM her HgA1c 9.1, BMI 44kg, BP 137/88, SCr 0.7. She is currently on Levemir 45 unit SQ bid, Novolog 10 units SQ AC, Lisinopril 20mg daily, omeprazole 20mg daily, metoclopramide 10mg TID, calcium/vit D. Her pooled cohort is 7%. What is the best option for the patient. Add simvastatin 20mg HS Wait until she is 40 then add statin Add atorvastatin 20mg Add atorvastatin 80mg 35 yo female with T2DM her HgA1c 9.1, BMI 44kg, BP 137/88, SCr 0.7. She is currently on Levemir 45 unit SQ bid, Novolog 10 units SQ AC, Lisinopril 20mg daily, omeprazole 20mg daily, metoclopramide 10mg TID, calcium/vit D. Intolerant to metformin. What else should be done to manage to optimize her therapy? Add amlodipine 10mg daily Increase Lisinopril to 30mg daily Add Vitamin D3 1000units daily  64 yo male on Levemir 50 units SQ HS and Novolog 15 units SQ AC. The chart displays his BS. How would you adjust his insulin? Patient Case cont. Change Levemir to 30 units SQ QAM and HS Increase Novolog to 17 units SQ AC Increase Novolog to 17 units qam, 15 units before lunch and dinner Increase Novolog to 15 units qam and dinner and 17 units before lunch  Metformin is still the first-line medication treatment option for  GLP-1 agonists may be an alternative for patient's who doesn't tolerate metformin as first-line.  Choosing second or third line DM medications must depend on patient preference, patient's medical history and cost.  Several new medications are on the horizon but no new novel  Preventing and treating macrovascular and microvascular complications are vital in reducing mortality and morbidity  Blood Pressure goals for Diabetics are <140/90mmHG  All diabetics should be on statin therapy if tolerated and maximized to moderate or high intensity depending on their ASCVD risk ADA 2016 Clinical Practice Recommendations: http://care.diabetesjournals.org/content/39/Supplement_1 Management of hyperglycemia in type 2 diabetes, 2016: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2016 AACE/ACE Comprehensive Type 2 Diabetes Management Algorithm 2016 Published in Endocr Pract.2016;22:84-113 Micromedex® Solutions [online]. Updated periodically. Truven Health Analytics, Inc. Accessed July 30, 2015. Insulin. Facts and Comparisons® eAnswers. Drug Facts and Comparisons® [online]. Updated periodically. Clinical Drug Information, LLC. Accessed July 30, 2015. Hajheydari Z, Kashi Z, Akha O, Akbarzadeh S. Frequency of lipodystrophy induced by recombinant human insulin. European Review for Medical and Pharmacological Sciences. 2011; 15(10): 1196-1201. Toujeo®, insulin glargine injection 300 Units/mL [package insert]. Sanofi-Aventis, LLC. Bridgewater, NJ. 2015. Afrezza®, human insulin inhalation powder [package insert]. Sanofi-Aventis, LLC. Bridgewater, NJ. 2015. Farxiga (dapagliflozin) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; Jardiance (empagliflozin) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; American Diabetes Association (ADA). Standards of medical care in diabetes--2015. Diabetes Care. 2015;38(Suppl 1):S1-94. FDA Safety Communication. FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood. Food and Drug Administration website. Invokana (canagliflozin) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation, 2013 Nov 12. With Full Report Supplement. Rising tide of cardiovascular disease in American Indians: the Strong Heart Study Howard BV, Lee ET, Cowan LD, Devereux RB, Galloway JM, Howard WJ, Rhoades ER, Robbins DC, Sievers ML, Welty TK. Circulation. 1999;99:2389 –2395. Racial Misclassification and Disparities in Cardiovascular Disease Among American Indians and Alaska Natives Dorothy A. Rhoades. Circulation. 2005;111:1250-1256.

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