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8/10/17

One Size does not fit all !!! Advanced Therapeutic Options for Management of the Type II Diabetic Patient in Primary Care

Carole Mackavey DNP, MSN, APRN, RN FNP-C University of Texas Health Science Center@ Houston Texas

Outcomes Type II Prevalence

• Recognize and implement the best • In 2012, 29.1 million Americans, or 9.3% of the population, had diabetes. therapeutic options for advanced • 1.4 million Americans are diagnosed with diabetes every year. • Understand the mechanism of action • Prevalence in Seniors: The percentage of Americans age 65 and older remains and side effects for the most common high, at 25.9%, or 11.2 million seniors (diagnosed and undiagnosed). - See diabetic agents more at: • Examine several case scenarios and discuss a plan of care for the patient. • Undiagnosed: Of the 29.1 million, 21.0 million were diagnosed, and 8.1 million were undiagnosed • Examine and discuss the role of the patient in the management of diabetes • In 2012, 86 million Americans age 20 and older had prediabetes; this is up from 79 million in 2010.

http://www.diabetes.org/diabetes-basics/statistics/?referrer=https://www.google.com/

Complications/Co-Morbid Conditions

• Hypoglycemia older • Hypertension

• Dyslipidemia

• CVD Death • Heart Attack

• Stroke • Blindness and Eye Problems: retinopathy

• Kidney Disease • Amputations

http://www.diabetes.org/diabetes- basics/statistics/?referrer=https://www.google.com/#sthash.iSimJp8y.dpuf

1 8/10/17

Diabetes by Race/Ethnicity Things to keep in mind

• Diabetes is primarily a self managed disease • The rates of diagnosed diabetes by race/ethnic background are: • Treatment decisions should be timely, rely on evidence-based guidelines, and

• 7.6% of non-Hispanic whites be made collaboratively with patients based on individual preferences, • 9.0% of Asian Americans prognoses, and comorbidities. • 12.8% of Hispanics • 13.2% of non-Hispanic blacks • The patient MUST be involved in the decisions made regarding the • 15.9% of American Indians/Alaskan Natives management of their diabetes

http://www.diabetes.org/diabetes-basics/statistics/?referrer=https://www.google.com/

Alpha-Glucosidase Inhibitors

So Lets Review Diabetes • Inhibit enzyme at intestinal brush border How do they work? • Slow absorption of • Usually starts working after the first dose

Alpha-Glucosidase Inhibitors Examples of alpha-glucosidase inhibitors include:

• (Precose) • Acarbose- Precose. • (Glyset) • Miglitol - Glyset. • Average A1C reduction: 0.5% to 0.8% • .

• SE: Flatulence, diarrhea, abdominal bloating • Precautions: Avoid when creatinine clearance < 25 mL per minute per 1.73 m2 (0.42 mL per second per m2) • Most effective when given with a starchy, high-fiber diet • Reverse hypoglycemia with glucose, not sucrose

Alpha-glucosidase inhibitor - Wikipedia https://en.wikipedia.org/wiki/Alpha-glucosidase_inhibitor

2 8/10/17

Alpha-Glucosidase Inhibitors

• Acarbose is able to reduce body weight, improve blood pressure, lower • Decrease hepatic glucose production; increase sensitivity glucose levels, decrease in the incidence of newly diagnosed cardiovascular peripherally events and attenuate both fasting and post prandial hypertriglyceridemia. • Decrease intestinal absorption of carbohydrates • Usually works after 1-2 weeks • AGIs delays complex digestion. This mechanism of action leads to both wanted (lowering of glycemia) and unwanted (osmotic) effects. Undigested disaccharides which remain in the intestinal lumen may cause flatulence, diarrhea and abdominal pain.

Kalra, S. (2014)Alpha glucosidase inhibitors Journal of the Pakistan Medical Association, retrieved http://jpma.org.pk/full_article_text.php?article_id=6311,

Biguanides • Metformin- first line drug in treatment of type II diabetes • A1C reduction: 1.0% to 1.3% • The use of metformin as first-line therapy was supported by findings from a • SE: Nausea, diarrhea, abdominal bloating • Extended-release preparations have fewer gastrointestinal adverse large meta-analysis, with selection of second-line therapies based on effects patient-specific considerations • Precautions: Estimated GFR 30 to 44 mL per minute per 1.73 m2: review use of metformin • Metformin is effective and safe, is inexpensive, and may reduce risk of • Estimated GFR < 30 mL per minute per 1.73 m2: discontinue use • Discontinue during acute illness or procedure that could predispose cardiovascular events and death patient to lactic acidosis

• American Diabetes Association. Standards of medical care in diabetes—2014. Diabetes Care. 2014;37(suppl 1):S14-S80.

• Powers AC, D'Alessio D. Chapter 43. Endocrine pancreas and pharmacotherapy of diabetes mellitus and hypoglycemia. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman & Gilman's Pharmacological Basis of Therapeutics. 12th ed. New York, NY: McGraw-Hill; 2011

Metformin Metformin

Liquid Metformin (Metformin Hydrochloride 500mg/5ml Oral Solution) can be • Metformin is associated with vitamin B12 deficiency, with a recent report given to improve tolerance in patients experiencing side effects at 500 mg from the Diabetes Prevention Program Outcomes Study (DPPOS) You can start of with ½ or 1 cc and gradually increase to 500 mg. suggesting that periodic testing of vitamin B12 levels should be considered

in metformin-treated patients, especially in those with anemia or

peripheral neuropathy.

3 8/10/17

Dipeptidyl-peptidase-4 inhibitors (DPP4)

• Increase glucagon-like peptide-1 • Increase insulin secretion from β-cells and decrease glucagon secretion from α-cells in the pancreas • Medication starts to work after 1-2 weeks

http://www.f6publishing.com/Pub/10.3748/v19/i15/WJG-19-2298-g001.jpg

Dipeptidyl-peptidase-4 inhibitors List of FDA-approved DPP-4 inhibitors

• (Nesina)* • Brand name Active ingredient(s) • (Tradjenta)* • Janumet XR and metformin extended release • (Onglyza)* • Onglyza saxagliptin • Sitagliptin (Januvia)* • Kombiglyze XR saxagliptin and metformin extended release • AIC reduction 0.5% to 0.9% • Tradjenta linagliptin • SE: Headache, pancreatitis (rare) • 7 more rows • Precautions: Linagliptin does not require dosage adjustment in renal insufficiency • Saxagliptin dosage adjustment required when administered with concomitant CYP3A4 • FDA Drug Safety Communication: FDA warns that DPP-4 inhibitors inhibitors • https://www.fda.gov/Drugs/DrugSafety/ucm459579.htm

DPP4 Glucagon-like peptide-1 receptor agonists (GLP1)

• Increase insulin secretion from β-cells and • DPP-4 inhibitors are taken orally with or without food and have once a day decrease glucagon secretion from α-cells in the dosing. pancreas • They are safer than when comparing the rate of • Suppress hepatic glucose production; delay gastric hypoglycemic episodes. emptying •They do not affect weight. • Medication starts to work after 1st dose if short acting • In patients with impaired renal function, linagliptin is the only DPP-4 inhibitor and after 2 weeks if long acting like exenitide that does not require a dose adjustment. extended (Bydurion) & (Trulicity) • Rare hypoglycemia events

http://ftp.rxeconsult.com/healthcare-articles/New-Drugs-for-Diabetes-Treatment-509/2

4 8/10/17

Glucagon-like peptide-1 receptor agonists Approved GLP-1 agonists:

• (Tanzeum)* • Dulaglutide (Trulicity)* (Once-weekly) • (Byetta/Bydureon), approved in 2005/2012. • Exenatide (Byetta, Bydureon)* (Bydueon once weekly) • (Victoza)* • liraglutide (Victoza, Saxenda), approved 2010. • A1C reduction: 0.8% to 2.0% • (Lyxumia), approved in 2016. • SE: Nausea, vomiting, sense of fullness • albiglutide (Tanzeum), approved in 2014 by GSK. • Weight loss of 1 to 4 kg (2.2 to 8.8 lb) is likely • Precautions: Pancreatitis (rare) • dulaglutide (Trulicity), approved in 2014—manufactured by Eli Lilly. • Exenatide is not recommended if creatinine clearance < 30 mL per minute per 1.73 m2 (0.50 mL per second per m2) • Boxed warning for personal or family history of medullary thyroid carcinoma; patients with multiple endocrine neoplasia type 2

American Diabetes Association. Standards of medical care in diabetes—2014. Diabetes Care. 2014;37(suppl 1):S14-S80. Glucagon-like peptide-1 receptor agonist - Wikipedia Powers AC, D'Alessio D. Chapter 43. Endocrine pancreas and pharmacotherapy of diabetes mellitus and hypoglycemia. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman & Gilman's Pharmacological Basis of Therapeutics. 12th ed. New York, NY: McGraw-Hill; 2011 https://en.wikipedia.org/wiki/Glucagon-like_peptide-1_receptor_ agonist

GLP1

• Exenatide is injected under the skin twice a day or once-weekly (Bydureon) within 60 minutes prior to meals. • Close potassium channels in β-cells; • Liraglutide is injected under the skin once daily at any time of the day. • Stimulate release of insulin from the pancreas • When GLP-1 receptor agonists are used in combination with a , the risk of hypoglycemia increases. • Medication starts to work after 1st dose • Clinical trial data for GLP-1 receptor agonists have shown a weight loss of 2.3 to 2.8 kg when used as monotherapy and a range of 2.6 to 2.9 kg when used in combination with metformin. • Clinical results have demonstrated liraglutide’s potential as a weight loss drug for non- diabetic, obese patients. • After 1 year, liraglutide subjects lost 5.8 kg compared to 3.8 kg in the placebo group. The liraglutide group maintained a 2-year weight loss of 7.8 kg.

Meglitinides Metiglitinides

• (Starlix)* • (Prandin) • Decrease post prandial glucose excursion • A1C reduction: 0.5% to 1.0% • Dose flexibility

• Hypoglycemia • Increased weight • Metabolized primarily by the liver (CYP3A4 and CYP2C9)

5 8/10/17

Sodium-glucose co-transporter 2 inhibitors Sodium-glucose co-transporter 2 inhibitors (SGLT2)

• Lower renal threshold for glucose and reduce • (Invokana)* reabsorption of filtered glucose from tubular lumen • (Farxiga)* • (Jardiance)* • Increase urinary glucose excretion • A1C Reduction: 0.5% to 0.9% • SE: Increased urinary tract and genital infections, increased low-density lipoprotein cholesterol level • Weight loss of 0.7 to 3.5 kg (1.5 to 7.7 lb) is typical • Precautions: Dosage adjustment required in renal insufficiency • Medication starts to work after 1-2 weeks

List of SGLT2 inhibitors SGLT2

Brand name Active ingredient(s • In addition to acidosis, other possible side effects of SGLT2 inhibitors include: Invokana canagliflozin Invokamet canagliflozin and metformin • dehydration Farxiga dapagliflozin • kidney problems Xigduo XR dapagliflozin and metformin extended- release • low blood sugar when this class of medicines is combined with other Jardiance empagliflozin prescription medicines used to treat diabetes, Glyxambi empagliflozin and linagliptin • increased cholesterol in the blood, and yeast infections

SGLT2 SGLT2

• Canagliflozin is taken orally once daily before the first meal of the day. • SGLT2 Inhibitors and Weight Loss • Dapagliflozin is taken orally once daily in the morning, with or without food. • Researchers found that actual weight loss was 2.7 times less than • Dapagliflozin has no known drug interactions. predicted in patients with (T2DM) on SGLT2 inhibitors. • Why? Any ideas? • Clinical trial data for SGLT2 inhibitors have shown a weight reduction range of 2.2 to 3.9 kg when used as monotherapy and a range of 2.6 to 4.2 kg when used in combination with metformin.

6 8/10/17

Sulfonylureas Sulfonylureas

• Bind to potassium channels in β-cells • (Amaryl) • Stimulate release of insulin from the pancreas • (Glucotrol) • Medication starts to work after 1st dose • Glyburide (Micronase) • A1C Reduction: 0.4% to 1.2% • SE: Hypoglycemia, weight gain • Precautions: Dosage adjustment required in renal insufficiency • Administer with meals

Thiazolidinedione's (TZD) 's

• (Actos) • Increase hepatic glucose uptake; decrease hepatic • (Avandia) glucose production • A1C Reduction: 0.5% to 1.4%

• increase insulin sensitivity in the muscle, adipose • Weight gain, edema tissue • Contraindicated in patients with New York Heart Association Class III or IV congestive heart failure • Medication starts to work after 2 weeks • Decrease concomitant insulin dose at initiation

Classification Average A1C reduction Precautions

Alpha-Glucosidase Inhibitors A1C reduction: 0.5% to 0.8% Avoid when creatinine clearance < 25 mL per minute per 1.73 m2 TZD’s (0.42 mL per second per m2) Biguanides A1C reduction: 1.0% to 1.3% Estimated GFR 30 to 44 mL per minute per 1.73 m2: review use of metformin

Dipeptidyl-peptidase-4 inhibitors AIC reduction 0.5% to 0.9% Saxagliptin - dosage adjustment required when administered with • Rosiglitazone and pioglitazone are used as monotherapy or with a (DPP4) concomitant CYP3A4 inhibitors sulfonylurea, metformin, or insulin. Glucagon-like peptide-1 receptor A1C reduction: 0.8% to 2.0% Exenitide is not recommended if creatinine clearance < 30 mL per • However, there are concerns with combined thiazolidinedione and insulin agonists minute per 1.73 m2 (0.50 mL per second per m2) therapy because of an increased incidence of heart failure (HF). Metglitinides A1C reduction: 0.5% to 1.0% Hypoglycemia

• In addition, thiazolidinedione's have several other potential side effects, Sodium-glucose co-transporter 2 A1C Reduction: 0.5% to 0.9% Dosage adjustment required in renal insufficiency which make them less appealing as initial or second step therapy inhibitors (SGLT2) Sulfonylureas A1C Reduction: 0.4% to 1.2% Dosage adjustment required in renal insufficiency • USE WITH CAUTION Thiazolidinedione's (TZD) A1C Reduction: 0.5% to 1.4% Contraindicated in patients with New York Heart Association Class III or IV congestive heart failure

7 8/10/17

Progressive disease LETS review Cliff

• Type 2 diabetes is progressive, most patients will eventually need insulin • VS 98.9, 84, 16, 126/82 Wgt 180 Hgt 5’6’’ BMI • A hallmark of type 2 diabetes is a decline in β-cell function, which begins • HgbA1C 14.6 as early as 12 years before diagnosis and continues throughout the • FBS 448 disease process. • Lipids: total 180, HDL 54, LDL 82, trigs 156 • β-cell function continued to deteriorate in association with progressively increasing despite treatment

Current Medication

• Trintellix 10 mg 1 tab(s) orally once a day • Lipitor 20 mg tablet 1 tab(s) orally once a day (at bedtime)

• Losartan-HCTZ 25 mg-100 mg tablet 1 tab(s) orally once a day

• Metoprolol Succinate ER 50 mg tablet, extended release 1 tab(s) orally once a day • Diabetes related

• Metformin 1000 mg tablet 1 tab(s) orally BID • Glipizide 10 mg tablet 1 tab(s) orally BID, • Victoza 18 mg/3 mL solution 1.8 subcutaneously once a day

• NovoTwist Insulin Needle 32 G needle as directed injection sub Q • Accu-Check Test Strips & Lancet strips & lancet strips & lancet check blood sugar finger stick twice a day

Why Consider Starting Insulin Patient concerns when starting insulin

• In patients with extreme hyperglycemia, insulin should be started immediately • Pain to lower glucose levels. The patient may present with any of the following: • Pain is associated with injection therapy and glucose monitoring • Weight gain and hypoglycemia • Fasting plasma glucose (FPG) levels >250 mg/dL • with insulin therapy is due to the anabolic effects of insulin, increased appetite, • Random plasma glucose consistently >300 mg/dL defensive eating from hypoglycemia, and increased caloric retention related • Glycated hemoglobin (A1C) >10%; to decreased glycosuria • Ketonuria • Symptomatic diabetes with polyuria, polydipsia, and weight loss.[2,3]

8 8/10/17

Starting insulin in a type 2 diabetic Adding

• Each person’s basal insulin requirement is unique. It’s affected by factors • Goals of insulin therapy such as body size, activity level, stage of growth, hormone levels, and the • ADA goal of A1C < 7.0 amount (if any) of internal insulin production from one’s own pancreas • AACE goal of A1C < 6.5 • The initial dosage of insulin is individualized based on the patient's insulin • Optimal glycemic control without causing undue hypoglycemia or sensitivity. excessive weight gain • Insulin therapy may be started with a set dosage, such as 10 units of glargine daily, or by using weight-based equations

Basic Recommendations: Types of Insulin

• If FPG is elevated, start with long-acting (basal) insulin • Rapid-acting insulin -a type of insulin that starts to lower blood glucose within 5 to 10 minutes after injection • may be started with a set dosage, such as 10 units of glargine daily, or by using and has its strongest effect 30 minutes to 3 hours after injection, depending on the type used. weight-based equations • Insulin therapy may be initiated as augmentation, starting at 0.2- 0.3 unit per kg, or • Aspart insulin and lispro insulin, begins to work about 15 minutes after injection, peaks in about 1 hour, and as replacement, starting at 0.6 to 1.0 unit per kg. continues to work for 2 to 4 hours. Types: (Apidra), (Humalog), and (NovoLog) • If postprandial glucose (PPG) is elevated, rapid-acting (prandial or bolus) can be used • Regular or Short-acting insulin usually reaches the bloodstream within 30 minutes after injection, peaks anywhere from 2 to 3 hours after injection, and is effective for approximately 3 to 6 hours. Types: Humulin R, • If FPG and PPG are elevated, any of the following would be appropriate: Novolin R • Oral agents with basal insulin • Premixed insulin analogs • Basal/bolus as in multiple daily injections (MDI) or an insulin pump. http://www.diabetes.org/living-with-diabetes/treatment-and-care/medication/insulin/insulin-basics.html

Intermediate and long acting Premix insulin

• Intermediate-acting insulin generally reaches the bloodstream about 2 to • Premixed insulin similarly reduces A1C compared with basal-bolus insulin 4 hours after injection, peaks 4 to 12 hours later, and is effective for about • patients are more restricted in their eating habits and schedule. 12 to 18 hours. Types: NPH (Humulin N, Novolin N) • Patients must eat breakfast, lunch, dinner, and possibly midmorning and bedtime snacks to prevent hypoglycemia. • Long-acting insulin reaches the bloodstream several hours after injection and tends to lower glucose levels fairly evenly over a 24-hour period. Types: (Levemir) and (Lantus)

9 8/10/17

New combinations of injectable degludec/liraglutide (Xultophy 100/3.6)

• SOLIQUA 100/33 (insulin glargine and lixisenatide injection) 100 Units/mL and 33 mcg/mL • Xultophy 100/3.6 can be taken at the same time each day with or without • LixiLan, is the first market worldwide for this combination of its GLP-1 receptor agonist food and will be available in a prefilled pen. It delivers doses from 10 to 50 lixisenatide (Lyxumia/Adlyxin) and insulin glargine (Lantus). units with each injection, and each unit of Xultophy 100/3.6 contains 1 unit • It is indicated for the treatment of adults with type 2 diabetes inadequately controlled on basal insulin (less than 60 units a day) or lixisenatide. of and 0.036 mg of liraglutide. • Insulin glargine The primary activity of insulin, including insulin glargine, is regulation of • The starting dose is 16 units (16-units insulin degludec and 0.58-mg glucosemetabolism. Insulin and its analogs lower blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose liraglutide), and the maximum dose of 50 units corresponds to 50 units of production. Insulin inhibits lipolysis and proteolysis, and enhances protein synthesis. insulin degludec and 1.8 mg of liraglutide. • Lixisenatide is a GLP-1 receptor agonist that increases glucose-dependent insulin release,decreases glucagon secretion, and slows gastric emptying.

AFREZZA New Inhaled Insulin Afrezza

• In 2015 an inhaled insulin product, Afrezza, became available in the U.S. • Afrezza can cause serious side effects, including:• Sudden lung problems • Afrezza is a rapid-acting inhaled insulin (bronchospasms). • that is administered at the beginning of each meal and can be used by adults with type 1 or type 2 diabetes. • Not recommended or people with long-term (chronic) lung problems such • Afrezza is not a substitute for long-acting insulin. as asthma or chronic obstructive pulmonary disease (COPD). • Afrezza must be used in combination with injectable long-acting insulin in patients with type 1 • Before starting Afrezza A Pulmonary function test to assess lung function is diabetes and in type 2 patients who use long-acting insulin. indicated • Inhaled insulin begins working within 12 to 15 minutes, peaks by 30 minutes, and is out of your system in 180 minutes. Types: Technosphere insulin-inhalation system (Afrezza) (ADA 2015)

10 8/10/17

Adding Insulin to orals

• Many oral are safe and effective when combined with insulin therapy. • Consider the mechanism of action for different therapies • Insulin sensitizers have been proven safe and effective when combined with insulin therapy. • Metformin is usually continued because it reduces cardiovascular risk in overweight patients with type 2 diabetes. • Metformin combined with insulin helps with weight control • Metformin may allow for a lower insulin dosage, and less hypoglycemia compared with insulin alone.

Insulin and TZD’s Insulin and Alpha-glucosidase inhibitors

• improve insulin sensitivity but may increase weight gain, • Alpha-glucosidase inhibitors delay absorption of carbohydrates in the fluid retention, and risk of congestive heart failure when combined with gastrointestinal tract to decrease postprandial hyperglycemia. insulin.

• Not been shown to reduce macrovascular complications or all-cause • These medications are safe and effective when combined with insulin. mortality.

Insulin and sulfonylureas and glitinides Practice Pearls:

• Insulin secretagogues (sulfonylureas and glitinides) can be combined with • 11,000 patients were evaluated who were using insulin and sulfonylurea and 16,910 patients receiving metformin insulin, especially when only basal augmentation is being used. with insulin to determine the differences in outcomes of treatment combinations were evaluated.

• However, there is a possible increased risk of hypoglycemia that needs to • There was a two to five times greater risk for mortality among the sulfonylurea group compared with the metformin group. be monitored closely. • Hypoglycemia was more frequent with [sulfonylurea plus insulin] compared with [metformin plus insulin] and was • Usually by the time insulin is required for meals, insulin secretagogues are associated with an increased risk. • Mogensen UM. Diabetologia. 2014;58:50-58. not effective or necessary.

11 8/10/17

Insulin and incretins Insulin and sodium glucose co-transporter 2 (SGLT2) inhibitor

• Dipeptidyl-peptidase IV inhibitors (DPP4) (sitagliptin [Januvia] and saxagliptin [Onglyza]) • Adding an SGLT2 inhibitor to multiple daily doses of insulin improved • This combination is associated with improved fasting and postprandial glucose control glycemic control, benefited weight loss, lowered insulin doses, and no • Glucagon-like peptide-1(GLP1) agonists (exenatide [Byetta] and liraglutide [Victoza]

• Exenatide combined with insulin has been associated with improved glycemic control, weight loss, and no increased increase in hypoglycemia was seen risk of hyperglycemia.

DO NOT GIVE DPP4 with a GLP1! GLP-1 agonists or DPP-4 inhibitors are not FDA approved for use in combination with one another, nor do treatment guidelines recommend use of the combination “Diabetes Care.” Improved Glucose Control With Weight Loss, Lower Insulin Doses, and No Increased Hypoglycemia With Empagliflozin Added to Titrated Multiple Daily Injections of Insulin in Obese Inadequately Controlled Type 2 Diabetes. N.p., n.d. Web. 13 Oct. 2014.

Basal Insulin Pearls

• The goal of basal insulin is to suppress hepatic glucose production and • Proceed with caution when using sulfonyureas and starting insulin to prevent hypoglycemia!!! improve fasting hyperglycemia. • Starting Basal insulin at night allows for patient self management using • ****If basal insulin is titrated too high, it will also partially cover meals and dosing adjustment scale lead to hypoglycemia during the night or if a meal is missed**** • GO slow! Patients are terrified on hypoglycemic episodes. They say “ it feels like I’m dying”. This is also one of the key reasons for non- compliance.

Self management of Basal insulin Self Management Lantus or Levemir once daily at bedtime instructions FBS goal 90 FBS goal 100 • Patients make decision regarding their diabetes everyday. • Start at 10 IU/day >180 increase Basal insulin by 8 > 190 increase Basal insulin by 8 • The dose will be adjusted units units • Nutritional education and regular physical activity are critical for weekly based on SMBG 141-180 increase Basal insulin by 151-190 increase Basal insulin by 6 managing diabetes. average over the last 5 6 units units days of the morning fasting BS 121-140 increase Basal insulin by 131-150 increase Basal insulin by 4 • Consider the patients ethnicity and location when developing a plan of • If SMBG is <70 or if you 4 units units care this includes nutritional education and physical activity. experience hypoglycemia 101-120 increase Basal insulin by 111-130 increase Basal insulin by • Ethnic foods resume previous dose and 2 units units STOP adjustments for one 80-100 no change 90-100 no change • Access to grocery stores week • Safety of their environment <70 resume previous dose <70 resume previous dose

12 8/10/17

Interesting tidbits from Diabetes Self Interesting tidbits from Diabetes Self Management Management

• African-American women have said that they are happier adopting • Researchers from the University of Otago in New Zealand found that when the participants walked for 10 minutes after each meal, their blood sugar diabetes-friendly diets if the eating plan includes healthier versions of levels were an average of 12% lower than when they took a single 30- community favorites minute walk each day. • Diabetic education must be culturally appropriate • Taking a short walk after dinner showed the greatest benefit on blood glucose, particularly when the meal contained a lot of carbohydrate, lowering blood sugar levels by 22% compared to taking a single daily walk.

Hypoglycemia Hypoglycemia

• No matter how high the blood sugar to much insulin to fast can cause • Among patients with type 2 diabetes, the median time from the first hypoglycemia episode of hypoglycemia to the first CV event was 1.5 years • Hypoglycemia is link to an increased risk for CV mortality • Hypoglycemia is associated with an increased risk of CV events and all- cause mortality in insulin-treated patients with diabetes. The relationship between hypoglycemia and CV outcomes and mortality exists over a long period.

Anyone out there still awake?

CASE STUDIES

Image from http://custom-writing.org/blog/wp-content/uploads/custom-writing.org/2012/04/case-study-method.jpg

13 8/10/17

Troy Troy’s office visit

• 48 year old African American Male • “I’m here because the last time I had these symptoms they said I had diabetes and I think it is back”. • Patient comes to the clinic with polydipsia and polyuria • Patient is currently on no medication • PMH: BP 166/94. HR 88, Hgt 5.8 Weight 215 BMI 32.7 Obese • Diagnosed two years ago with diabetes. He was told to lose weight and given medication Hemoglobin A1C 12.6 • He lost 20 pounds and his lab work returned to normal FBS 276 • Medication: metformin -told to take 2 tabs twice a day BUN 24 • Stopped taking it because it gave him nausea and severe diarrhea Creatinine 1.4 • Didn’t return to the doctor • Where should we start?

What’s the best course of action? Troy

• He was started on Onglyza 2.5 mg and metformin 1000mg bid • Have a honest discussion about diabetes (the metformin was started 500mg po qhs times 5 days; then 500 mg po bid, increasing by 500 mg every 5 days until 1000mg po bid) • Diabetes has not disappeared- it is here to stay • Make it our best friend. • Lisinopril 20mg po qd (to reduce proteinuria and delay CKD progression) • The more you know the more control you have! • Lipitor 10mg po qd (CV protection) • You will need to manage this disease. (Assign accountability) • 3 months later Return lab: • HGBA1C: 6.9 • Creat 1.2

TIM Current treatment • 65 year old salesman who is on the road most of the day. He comes for a physical exam. • ACE inhibitor , HCTZ, and Statin • PMH: hypertension and dyslipidemia since age 55 • Diagnosis • FH: father T2DM. Passed away a age 59 from MI • Controlled hypertension • Patients obese BMI 30kg/m2, , BP 138/88 • Dyslipidemia • Total cholesterol 180 TG 220, HDL-C-38, LDL C95 • New onset hyperglycemia • Fasting Glucose 160mg/dL Hemoglobin A1C 8.5% • Insurance: Medicare Advantage Plan

14 8/10/17

What is the best initial treatment for this patient? Answer

1. Lifestyle modification only ( diet and increase exercise) re-evaluate in 6 months • Lifestyle modification ( diet and increase exercise) plus metformin 2. Lifestyle modification ( diet and increase exercise) plus metformin and plus SGLT2. 3. Lifestyle modification only ( diet and increase exercise) plus metformin plus GLP1 4. Lifestyle modification ( diet and increase exercise) plus metformin 5. Lifestyle modification ( diet and increase exercise) plus metformin plus a DPP4

Mr. Rob Mr. Rob

• Rob Is a 44 year old man of Hispanic ancestry with a history of type II DM, hypertension, and obesity, who presents for a routine follow up visit to the • He has been reluctant to make any medication changes. He is a landscaper clinic. with a family of five to support. He has Medicaid insurance, money is tight and Today 3 months ago 6 months ago in the past he has told you he sometimes skips meals so that his mother and sister with Type I DM can eat.

BMI 34.6 Kg/m2 33.9 33.7 • He is highly motivated to increase his activity and modify his diet. He therefore refuses to discuss changes to his medication BP 155/87 149/83 146/86 HG A1C 9.4% 8.9% 8.6% • Metformin 1000 mg bid Creatinine 1.6 mg/dL 1.4 1.3 • Lisinopril 20 mg qd (serum) • Hctz 25 mg po qd eGFR 47mL/min/1.73M2 55 60

Diabetes Treatment. Yale Office-based Medicine Curriculum, Ninth Edition, Volume 3, 2016. Diabetes Treatment. Yale Office-based Medicine Curriculum, Ninth Edition, Volume 3, 2016.

Mr. Rob Glomerular Filtration Rate (eGFR)

• His history of albuminuria which has been controls to <30 ug/mg on his • used instead of serum creatinine as the more accurate measure of renal current regime. He has no evidence of retinopathy or neuropathy. function to determine whether or not it is safe for a patient to take metformin • What should his goal be for his HGA1C? • Assess eGFR before starting metformin; follow at least annually in patients • What concerns do you have regarding his current use of metformin as it on metformin relates to his renal function? • It is not recommended to start metformin if the eGFR is between 30 and 45 mL/min/1.73m2 • Metformin is contraindicated if the eGFR is below 30 mL/min/1.73m2

Diabetes Treatment. Yale Office-based Medicine Curriculum, Ninth Edition, Volume 3, 2016. Diabetes Treatment. Yale Office-based Medicine Curriculum, Ninth Edition, Volume 3, 2016.

15 8/10/17

Case continues Case continues

• Mr. Rob looks upset when you walk into the room. “I’ve seen the numbers, • What classes of oral medications would Mr. Rob need to avoid (given his and I know that everything’s going in the wrong direction. I’m not able to concerns about hypoglycemia)? lose weight and control my blood sugar on my own, but I know I can’t do insulin yet.” • Rob reminds you his mother is on insulin for type 2 diabetes and has had a • What other treatment options exist for Mr. Rob, and what is the average number of episodes of severe hypoglycemia requiring intramuscular reduction in hemoglobin A1C that you could expect for each? glucagon and hospitalization. He is adamant that, if he does not absolutely have to, he does not want to take any medications that would carry a risk of low blood sugar.

Diabetes Treatment. Yale Office-based Medicine Curriculum, Diabetes Treatment. Yale Office-based Medicine Curriculum, Ninth Edition, Volume 3, 2016. Ninth Edition, Volume 3, 2016.

Answer

• The key oral medication classes that he would need to avoid are the • Mr. Rob is not interested in discussing the possibility of an α-glucosidase secretagogues: sulfonylureas and meglitinides. inhibitor (a friend had a bad experience with excessive flatulence). • With regard to this patient, the key medication options and corresponding • In the spirit of shared decision-making, What are the pros and cons of the average A1C reduction for each are: remaining options? • Glucagon-like Peptide (GLP)-1 agonists = -1.0% • Thiazolidinediones (TZDs) = -1.0% • Sodium-Glucose Co-transporter 2 (SGLT2) inhibitors = -0.6-0.8% • Dipeptidyl peptidase (DPP)-4 inhibitors = -0.6-0.8% • α-glucosidase inhibitor = -0.8%

Diabetes Treatment. Yale Office-based Medicine Curriculum, Ninth Edition, Volume 3, 2016. Diabetes Treatment. Yale Office-based Medicine Curriculum, Ninth Edition, Volume 3, 2016.

MARY

• 42 year old female, 5’ 4”, 275 lbs, BMI 47.2 kg/m2. • History of hypertension, chronic low back pain, severe gastroesophageal reflux disease, depression and type 2 diabetes (diagnosed 2 years ago), and anxiety/depression. • Medications include lisinopril 10 mg daily, oxycodone 5 mg TID prn, omeprazole 20 mg daily, metformin 500 mg BID, and paroxetine 20 mg daily. • She has been actively working with her PCP on losing weight with diet modification and water aerobics but has only lost about 4% of her weight in the past 6 months. • Current labs: • fasting blood glucose 154 mg/dl, • Hgb A1C 6.7 • Creatinine 1.7, mg/dl • TSH of 5.6 U/ml.

Submitted by: Dr. Melissa M. Davis, DNP, ANP-BC, CNS, CBN, CNOR, RNFA

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What’s the best course of action? Mr. Frank

• Mr. Frank is an overweight, Caucasian 63-year-old patient who comes in for a 6-month • Change paroxetine to wellbutrin, check-up. • Discontinue metformin • He has a 12-year history of type 2 diabetes. He was diagnosed at age 33 with high blood pressure, but had never really done much about it as it was “too much of a hassle” and he • Consider Liraglutide, linagliptin, pioglitazone, glimiperide felt “just fine.” • Refer to renal for evaluation • At the time his diabetes was diagnosed, he was referred to a diabetes education program and was started on metformin, lovastatin, losartan and aspirin. • Verify insurance benefit for bariatric surgery with subsequent referral • He has an individualized A1C goal of 7%. • Four years after diagnosis, pioglitazone was added to Mr. Frank’s diabetes regimen.

• Three years ago, he came in for an appointment complaining of polyuria, polydipsia and fatigue with an Hemoglobin A1C of 9.3%.

More on Mr. Frank Labs on Mr. Frank

• At that time, he was started nightly on basal insulin detemir. • Labs taken last year show Mr. Frank: • Since that time, he has made concerted efforts to eat a healthy diet and get to the gym. • Serum creatinine 1.2mg/dL with an eGFR 61mL/min. • Today, he reports his SBGM fasting plasma glucose levels are on target (FPG<130mg/dL). • He also states that his feet always feel a little bit swollen. • Today, his serum creatinine is 1.6 mg/dL and his eGFR is 44 mL/min.

• BP 128/78, HR 73, RR 19. • Because guidelines indicate when a patient’s eGFR falls below 60mL/min, • Physical exam is remarkable for peripheral edema and mildly decreased pedal pulses. dose reduction of medications should be considered, you decide to adjust Mr. • Current medications: metformin, pioglitazone, insulin detemir, lovastatin, losartan, aspirin. At today’s visit, his Hemoglobin A1C is 8.1%. Frank’s medication. • A rapid-acting insulin analogue was added to his largest meal of the day.

In type 2 diabetes, which one of the following Rationale medications does not need to be considered for dose reduction in Mr. Frank’s regime? • 20-30% of patients with type 2 diabetes develop moderate-severe renal disease (GFR<60mL/min). • Pioglitazone does not undergo renal elimination and can therefore be used • A. Glyburide without restriction in chronic kidney disease. • • Metformin undergoes renal elimination and current U.S. guidelines suggest B. Metformin caution using in individuals with creatinine 1.5 mg/dL (males) and creatinine • C. Insulin 1.4 mg/dL (females) as its use has been associated with lactic acidosis in patients with CKD. • D. Pioglitazone • U.K. guidelines advise dose reduction of metformin at GFR of 45 ml/min and • E. Exenatide cessation with GFR of 30 ml/min. • Exenatide is renally eliminated and its use should be discontinued at GFR of 30ml/min

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Insulin and GFR Insulin and GFR

• The study for the first time quantified the required dose reduction of long- • The most distinct dose reduction was found for insulin lispro. Referring to a acting insulin analogues. Given a person of 70 kg body weight and eGFR person with normal renal function (eGFR > 90 ml/min) and 70 kg of body greater than 90 ml/min, the mean daily dosage was 19 IU of insulin weight the mean total dosage of insulin lispro was about 32 IU/day. glargine and 23 IU of insulin detemir. Provided that the eGFR was less than • Assuming that the filtration rate was then reduced to less than 60 ml/min, 60 ml/min, the doses would have to be reduced to 13 IU of glargine and the mean dosage of insulin lispro would have to be reduced to about 22 17 IU of detemir. IU/day. • For short-acting human insulin the dose reduction would be 7 IU/day (30 IU/day versus 23 IU/day).

What is the best option Q and A

• A 59-year-old patient who was diagnosed with type 2 diabetes five years ago presents • Compared to insulin NPH, what would you expect Mr. Frank to experience to your clinic for an appointment. while taking detemir? • He has a history of hypertension and dyslipidemia, both currently well controlled with medication. • Less weight gain • He has been taking metformin and a DPP-4 inhibitor. He tells you he is concerned • More hypoglycemia about a sore on his foot that is taking a long time to heal. • More weight gain • At today’s visit, BP 130/76 HR 80 RR 16 Wgt 230 Hgt 5’9” his Hemoglobin A1C is 8.8%. • After discussing his options, you decide to add basal insulin analogue detemir to his • No weight gain or hypoglycemia difference regimen.

Answer

• Less weight gain • Determir states is weight neutral • Something to keep in mind- Patients often gain weight when put on insulin Just a few questions for review!

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Ms. T is a 52-year-old woman with a history of Type 2 What are the key safety issues that you need to be aware of diabetes, obesity (BMI 32), and hyperlipidemia. and counsel her about prior to initiating a medication from this class?

Although she has been successful with making dietary changes to reduce a. These drugs are contraindicated in patients with multiple endocrine neoplasia added sugar in her diet, regularly exercises with family members, and syndrome type 2 (MEN2) or a personal or family history of medullary thyroid carcinoma. faithfully adheres to metformin 1000mg BID, her hemoglobin A1C has crept b. These drugs should not be used in patients with a history of pancreatitis. up from 7.2% to 8.5% over the past six months. She is committed to achieving a goal A1C of <7% and is interested in learning more about the c. Patients may experience nausea, bloating, or diarrhea when taking these medications. injectable GLP-1 agonists, given the anticipated weight loss side effect. d. These medications should not be used in combination with medications in the DPP-4 inhibitor class. e. All of the above

Diabetes Treatment. Yale Office-based Medicine Curriculum, Ninth Edition, Volume 3, 2016. Diabetes Treatment. Yale Office-based Medicine Curriculum, Ninth Edition, Volume 3, 2016.

Question

• This oral drug class slows the intestinal digestion and absorption of carbohydrates:

• 1. Sulfonylureas • 2. DPP-4 Inhibitors • 3. Alpha-glucosidase inhibitors • 4. Bile Acid sequestrates

http://www.diabetesincontrol.com/resources/test-your-knowledge/

Answer Question

• Clinicians treating patients with type 2 diabetes should include lifestyle interventions when developing diabetes management plans. Which of the following is NOT appropriate? •DPP-4 Inhibitors • 1. Weight reduction, if necessary • 2. A minimum of 150 minutes/week of moderate-intensity aerobic physical activity, spread over at least 3 days/week with no more than 2 consecutive days without exercise • 3. Diabetes Self-Management Education & Support (DSME/DSMS) • 4. A calorie fixed ADA diet • 5. Individualized plan of calories including recommended amounts carbohydrates, fats, and proteins

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Answer Mr. Q is a 49-year-old man with Type 2 diabetes and hypertension

• Mr. Q comes to your office, excited about a television commercial that he saw for an SGLT-2 inhibitor. •A calorie fixed ADA diet • He currently takes lisinopril 10mg daily and hydrochlorothiazide 25mg daily; he also takes metformin 1000mg BID, but he likes the idea of a once-daily medication for • Instead try Individualized plan of calories including recommended diabetes. amounts carbohydrates, fats, and proteins • His hemoglobin A1C is 7.8% (goal <7%) and blood pressure is 143/78; • he does not feel that he can realistically make any additional changes to his diet or exercise regimen to further control his blood sugar. • What are some of the key risks and benefits regarding SGLT-2 inhibitor medications do you not need to address with him?

Diabetes Treatment. Yale Office-based Medicine Curriculum, Ninth Edition, Volume 3, 2016.

What are some of the key risks and benefits regarding SGLT-2 Answer inhibitor medications do you not need to address with him?

• a. Mr. Q may notice some additional improvement in his blood pressure • The FDA has issued warnings regarding associations between SGLT- after starting an SGLT-2 inhibitor, due to the diuretic properties. inhibitors and bladder cancer. • b. If adding an SGLT-2 inhibitor to his medication regimen, he will need to pay attention to his hydration status as he is already on a thiazide diuretic. • c. The FDA has issued warnings regarding associations between SGLT- inhibitors and bladder cancer. • d. Common side effects include urinary tract infections and genital mycotic infections

Diabetes Treatment. Yale Office-based Medicine Curriculum, Ninth Edition, Volume 3, 2016.

Final Case Scenario Grace D • Grace D is a 63 year old African American female with poorly controlled HTN, DM, increased lipids, obesity, GERD , gout, and sleep apnea. She has not had an MI (yet) She smokes ½ PPD • BP is 150/86; • Medications include: • Labs: HbA1C is 10.4; Hb is 9.5, HDL is 35, LDL is 115, triglycerides are 295; Ca • Amlodipine 10mg qd • HCTZ 25mg qd, is 9.8; Microalbumin/creatinine ratio is 54.5; Creatinine is 1.7: GFR = 39 • Clonidine 0.3mg bid • GD has stage 3 CKD and most of it’s complications. • Atorvastatin 10 MG PO qd, • Metoprolol 100mg po bid, • What should we do for this patient? • Insulin glargine 30units sc at HS • Metformin 1000mg po bid • Allopurinol 300mg po qd, • Omeparazole 20mg po qd • CPAP at 12 cm (Note: she is not on an ACE)

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Grace D She has complications!

• Problems: • Microalbumin/Creatinine >30 • GFR < 60 • GD has Stage 3B;A2 CKD • This puts her at moderately high risk

Medication Review

• There are meds that are dangerous to her: Stop them or modify dose • GD is taking OTC NSAIDS for her back pain • Stop this and all NSAIDS and Cox-2 • Metformin can cause lactic acidosis. • Stop if GFR < 30 • Reduce her Allopurinol • Avoid Bisphosphonates

Diabetes hypertension

• She starts a diet and exercise program • ACE is added to reduce proteinuria and delay CKD progression. • We encourage patient centered goal setting (Motivational Interviewing) • GFR decreases to 32 but stays there. Creat is 2.1 • We intensify her insulin regimen • K+ is good at 4.0

• We add Sitagliptin, liraglutide, or glypizide to her insulin • Leave her on the ACE Results: • Her HbA1C drops to 6.8 over 6 months • Her BP goes down to 130/70 • Stop her clonidine as it is no longer need

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Heart Anemia

• Increase her statin to Atorvastatin 40 mg qd • Colonoscopy is normal • MCV is nl at 85 • Start ASA 81 mg qd • Fe is 50; TIBC is 200 for a saturation of 25% • Give her the ACS quit smoking line number • Start Erythropoieitin 20,000 units q 2 weeks • Start oral iron • Add Niaspan 500 qd or Omega 3’s One gram bid to raise HDL and • √CBC ,Fe/TIBC monthly. We hold EPO if Hbg > 12.0

decrease Triglycerides Results: Results: • Hbg rises to 11.5 and she feels much better • Transferrin saturations stay normal at above 20% • She quits smoking, Her HDL is now 43, LDL 68 and Triglycerides 130

Check for Bone Disease things to remember

• We √ Ca++; PO4=; and PTH and 25 OH Vit D • Refer to nephrology when GFR < 30- co manage levels • Ca++ is 9.8 (nl) • If the GFR <20; refer for transplant evaluation even before she needs • PO4= is 3.1 (nl) dialysis • PTH is 60 (nl) • Vitamin D is 7 (low) • Start her Vitamin D 50,000 units once per month or 1,000-2,000 units Vitamin D 3 daily • Follow these labs yearly and refer if PTH > 100 or PO4= rises above 4.5

Key Points Diabetes Distress

• Glycemic targets and glucose-lowering therapies must be individualized. • Diabetes has a strong psychological impact on many patients • Diet, exercise, and education remain the foundation of any type 2 diabetes treatment program.

• Unless there are prevalent contraindications, metformin is the optimal first-line drug. • Providers need to remember this and screen people on a regular basis, • After metformin, there are limited data to guide us. Combination therapy with an additional 1–2 oral or especially when treatment targets are not met and/or at the onset of injectable agents is reasonable, aiming to minimize side effects where possible. diabetes complications. • Ultimately, many patients will require insulin therapy alone or in combination with other agents to maintain glucose control. • Remember to ask if life situations have changed. • All treatment decisions, where possible, should be made in conjunction with the patient, focusing on his/her preferences, needs, and values. • Providers develop relationships when managing care over time. This can • Comprehensive cardiovascular risk reduction must be a major focus of therapy. be extremely beneficial

Inzucchi, S.E., Bergenstal, R.M., Buse, J.B., Diamant, M., Ferrannini, E., Nauck, M., Peters, A.L.,…..Matthews, D.R.(2013). Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 36(2): 490-490. http://dx.doi.org/10.2337/dc13-er02

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Have you had more than enough?

THANK YOU AND HAVE A GREAT DAY!

References

• American Diabetes Association (2017) Standards of Medical Care in Diabetes.

• American Diabetes Association (2014) Standards of Medical Care. Diabetes Care, 37(suppl 1):S14-S80

• American Diabetes Association ( 2015) Insulin Basics

• Fennell, D. (2016). How to Lower Blood Sugar? Take a 10-Minute Walk After Meals, Study Says. Diabetes Self Management retrieved from http://www.diabetesselfmanagement.com/blog/lower-blood-sugar-take-10-minute-walk-meals-study-says/

• Fox, C (nd). Key points in the treatment of Chronic Kidney disease. Department of Family Medicine; University of Buffalo. Powepoint,

• Inzucchi, S.E., Bergenstal, R.M., Buse, J.B., Diamant, M., Ferrannini, E., Nauck, M., Peters, A.L.,…..Matthews, D.R.(2013). Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 36(2): 490-490. http://dx.doi.org/10.2337/dc13-er02

• Padigus, J.L. (2014) New Drugs for Diabetes Treatment retrieve from http://ftp.rxeconsult.com/healthcare-articles/New-Drugs-for- Diabetes-Treatment-509/4

• Peason, T.L. (2016). Initiating insulin in type 2 diabetes patients, retrieved from http: www.Medscape.org/viewarticle/567952

• Power, A.C., D’Alessio, D. (2011) Endocrine, Pancreas and pharmacotherapy of diabetes and hypoglycemia In Bruntib L.L. Knollman, B.C (Ed) (2011) Goodman and Gilman’s Pharmacological Basis of Therapeutics 12th edition. New York NY McGaw Hill

• Scheiner, G. (2006 update 2014) Getting down to basaI. Diabetes Self Management Retrieved from http://www.diabetesselfmanagement.com/managing-diabetes/treatment-approaches/getting-down-to-basals/

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