Diabetes Topic DiscussionNicholas England & Dylan Hotham

October 2, 2018Introduction

● Diabetes is a complex, chronic illness requiring continuous medical care with several risk-reduction strategies beyond blood glucose monitoring

● Insulin - A hormone secreted from pancreatic β-cells when plasma glucose levels are increased○ Suppresses the release of glucagon (normally secreted by pancreatic α-cells when plasma glucose

levels are reduced)○ 3 main functions:

■ Signals the liver to convert glucose into glycogen, and prevents glycogen breakdown when higher levels of blood glucose are present

■ Required for glucose uptake by muscle cells, which use glucose as energy■ Regulates fat storage in adipose tissue, where excess glucose is converted into fat, thus

preventing fat breakdown for energy○ Stimulates the cellular uptake of glucose

■ Acts as a key to unlock a specific cell in order for glucose molecules to be absorbed, thus causing a decreased plasma glucose level

● Oral glucose intake leading to a dysfunctional release of pancreatic insulin○ This causes an increase in hepatic glucose release, and a subsequent decrease in glucagon

suppression○ Decreased glucose uptake into muscle cells due to insulin resistance, or no insulin production

Classification

Type 1 Diabetes Mellitus (T1DM) Type 2 Diabetes Mellitus (T2DM)

Age of Onset Usually <30 yoa Usually >30 yoa

Body Type Usually lean Usually obese

Family History Generally not strong Strong

Time of Onset Abrupt Gradual

● Prediabetes - A patient who has an increased risk of developing DM○ Annual monitoring for the development of DM and treatment of any modifiable cardiovascular

disease (CVD) risk factors are recommended for these patients● Gestational Diabetes (GDM)

○ A female patient who develops DM during pregnancy, or had a diagnosis of DM before becoming pregnant

○ Target blood glucose levels are more stingy than that of a non-pregnant DM patient○ First step in management of GDM is lifestyle modifications

■ If this can’t be managed, than insulin is the preferred treatment○ Goals for GDM patients:

■ Fasting plasma glucose = <95 mg/dL■ 2-hour post-prandial glucose = <120 mg/dL

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Diabetes Topic DiscussionNicholas England & Dylan Hotham

October 2, 2018Risk Factors for T2DM

Physical inactivity History of CVD 1st-degree relative with DM

Women with polycystic ovarian syndrome

Overweight (BMI >25 kg/m2; BMI >23 kg/m2 in Asian American patients)

History of GDM HbA1c >5.7%, impaired glucose tolerance, or impaired fasting glucose

HDL <35 mg/dL &/or Triglycerides >250 mg/dL

Hypertension High-risk race/ethnicity (African American, Latino, Asian American, etc.)

Other clinical conditions associated with insulin resistance

Complications● Microcytic

○ Retinopathy○ Nephropathy○ Neuropathy

● Macrocytic○ Coronary Artery Disease○ Myocardial Infarction○ Peripheral Vascular Disease○ Cerebrovascular Disease (Stroke)

Presentation and Diagnosis

● Polydipsia, polyphagia, and polyuria are the three hallmark symptoms of hyperglycemia. Other symptoms include blurred vision and fatigue.

● Initial presentation of most type 1 diabetics is diabetic ketoacidosis

● Type 2 diabetes develops over time, so patients may live undiagnosed until symptoms are noticeable.

Prediabetes is defined by one or more of the following:

● FPG 100-125 mg/dL● 2 hour plasma glucose of 140-199

mg/dL after 75-g OGTT● A1C 5.7-6.4%

Diagnosis of Diabetes: ● Classic symptoms of hyperglycemia or hyperglycemic crisis AND random fasting blood glucose ≥200 mg/dL

OR one or more of the following:● FPG ≥ 126 mg/dL*● 2 hour plasma glucose ≥ 200 mg/dL after 75-g OGTT*● A1C ≥ 6.5%* *must confirm w/ repeat testing

C-Peptide: A byproduct of the conversion of proinsulin to insulin that can be measured to determine if the pancreas is producing insulin and can be used to differentiate between type 1 and type 2 diabetes.

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Screening Criteria for Type 2 Diabetes Any adult who is obese or overweight (BMI ≥ 25 or ≥ 23 in

Asian American patients w/ 1 or more of the following risk factors: o First-degree relative with diabeteso High-risk race or ethnicity (African American, Latino,

Native American, Asian American, Pacific Islander o History of CVDo HTN (≥140/90) or therapy for HTNo HDL <35 mg/dl and/or triglyceride level >250 mg/dLo Women with PCOSo Physical inactivityo All patients are screened at age 45 and should be

repeated at a minimum 3-year interval

Diabetes Topic DiscussionNicholas England & Dylan Hotham

October 2, 2018

Goals of Therapy● HbA1c <7%● Fasting plasma glucose <130 mg/dL● 2-hour post-prandial glucose <180 mg/dL● Monitoring for S/S of hypo/hyperglycemia

Lifestyle Modifications● Weight loss

○ Contributes to improvements in blood pressure, cholesterol and blood glucose○ If patients are overweight or obese it is recommended to lose >5% body weight

■ Obesity management can delay progression from prediabetes to type 2 diabetes and may be beneficial in the treatment of type 2 diabetes

○ Reduction of 3500 kcal/week → 1 lb weight loss○ Waist circumference goals

■ Women : <35 inches■ Men: <40 inches

● Nutrition○ No one-size fits all diet ○ Carbs should be from fruits/vegetables, whole grains, legumes, and dairy

■ Caution intake of carbs w/ added fat, sugar, or sodium○ Increase intake of omega-3 fatty acids○ Avoid sugar sweetened beverages○ Reducing sodium intake is important for hypertension control○ Recommend eating something every 3-4 hours to decrease risk of glucose spikes

● Physical Activity○ Reduces risk of hyperglycemia○ Recommended to get up and move every 30 minutes○ 150 minutes of moderate intensity physical activity per week and resistance training twice

weekly○ Older adults may benefit from flexibility and balance training

● Smoking cessation

Type 1 Diabetes Treatment - InsulinBasal vs. Bolus

● Bolus Insulin - Rapid or Short-acting insulin mainly used for two purposes:○ Mealtime blood glucose in fixed doses to prevent elevations from food○ Corrections for short-term elevations in response to self-monitoring of blood glucose

● Basal Insulin - Intermediate or Long-acting insulin that mostly affects fasting blood glucose

Levels of Recommendation● Most individuals with T1DM should use rapid-acting insulin analogs to reduce hypoglycemia risk (A)

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Diabetes Topic DiscussionNicholas England & Dylan Hotham

October 2, 2018● Most people with T1DM should be treated with multiple daily injections of bolus insulin and basal insulin (A)● Consider educating patients with T1DM on matching bolus insulin doses to carbohydrate intake, pre-meal

blood glucose levels, and anticipated physical activity (E)

Types of Insulin

Insulin Typical Administration Notes

BOLUS

INSULIN

Rapid-Acting Insulin

- Aspart (Novolog)- Lispro (Humalog)- Glulisine- Afrezza

Up to 15 minutes prior to meals

Exception: Afrezza - administered immediately before meals

- Afrezza: C/I in COPD, asthma and other chronic lung diseases

- Boxed warning for bronchospasm; med history, physical exam, and FEV1 required prior to initiation

Short-Acting Regular Insulin

- Humulin R, Novolin R- Humulin U-500

30 minutes prior to meals - Used in IV solutions and TPNs

- U-500 recommended for patients requiring >200 units/day

BASAL

INSULIN

Intermediate-Acting Insulin

- NPH (Humulin N, Novolin N)

Give 1-2 times daily - Cloudy appearance

Long-Acting Insulin

- Detemir (Levemir)- Glargine (Lantus,

Toujeo, Basaglar)- Degludec (Tresiba)

Give 1-2 times daily at the same time each day

- If Levemir is given daily: give with evening meal or at bedtime

- Tresiba can be given at any time of the day

Premixed Insulin- Novolog mix 70/30- Humalog mix 70/25- Humalog mix 50/50- Novolin 70/30

Typically twice daily dosing -Named by the % of each component basal/bolus

Adverse Effects - Hypoglycemia, hypokalemia, weight gain, lipodystrophy

Drug Interactions - Other medications that increase hypoglycemia● Do not use with sulfonylureas or meglitinides● May require dose decrease in combo w/ TZDs, SGLT2 inhibitors, DPP-4 inhibitors, GLP-1 agonists and

pramlintide

Dosing

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Diabetes Topic DiscussionNicholas England & Dylan Hotham

October 2, 2018● Type 1

○ Starting insulin dose is based on total body weight○ Should be initiated at a starting daily dose of 0.6 units/kg/day, divided between bolus and basal

insulins○ Basal-bolus strategy should be used for patients beginning on insulin therapy

■ Ex: T1DM patient, weighing 80 kg, starting on Lantus and Humalog■ Calculate the total daily dose of insulin:

● (0.6 units/kg/day) x (80 kg) = 48 units■ Divide the total daily insulin dose into 50% basal and 50% bolus insulin

● 24 units Lantus and 24 units Humalog■ Divide bolus insulin into 3 divided doses → 8 units Humalog TID with meals■ Final dose: Inject 24 units Lantus once daily in PM; Inject 8 units Humalog TID with

meals○ However, not every person responds to insulin with the same sensitivity, leading to adjustments

of bolus insulin. These can be adjusted based on the amount of carbohydrates the patient is consuming during a meal

■ Rule of 500 (bolus insulins)● (500 / total daily dose of insulin) = Number of grams of carbohydrates covered

by 1 unit of bolus insulin● Ex: (500 / 48 units of insulin) = ~10.4 grams of carbs covered by 1 unit of bolus

insulin■ Rule of 450 (regular insulin)

● (450 / total daily dose of insulin) = Number of grams of carbohydrates covered by 1 unit of regular insulin

○ All diabetic patients taking insulin should know how to correctly calculate their correction dose, which is the amount of insulin added to the amount a patient would normally take for a meal

■ Correction Factor (CF)● 1,800 Rule (for bolus insulin)

○ (1,800 / total daily dose of insulin) = CF for 1 unit of bolus insulin○ Ex: (1,800 / 48 units of insulin) = 37.5

● 1,500 Rule (for regular insulin)○ (1,500 / total daily dose of insulin) = CF for 1 unit of regular insulin

■ Correction Dose● ((blood glucose now - target blood glucose) / (CF)) = Correction Dose● ((Ex: 200 mg/dL - 125 mg/dL) / (37.5)) = 2 units of bolus insulin

● Type 2○ Not all Type 2 diabetics use insulin, but basal insulin may be initiated in patients who are not

meeting goal with the use of multiple oral medications.○ Basal Insulin Starting Doses

■ 0.1-0.2 units/kg/day (TBW) OR 10 units/day■ Dose is titrated by 10-15% or 2-4 units once or twice a week to reach fasting blood

glucose goal

Oral Medications for Type 2 Diabetes

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Diabetes Topic DiscussionNicholas England & Dylan Hotham

October 2, 2018Metformin: First line treatment for type 2 diabetes and can be used for prediabetes. ↓ hepatic glucose production, ↓ intestinal absorption of glucose and ↑ insulin sensitivity.

Agents Dosing Contraindications Warnings Other Notes

Metformin (Glucophage, Fortamet, Glumetza, Riomet)

IR tabs, ER tabs

Initially: - IR: 500 mg BID

or 850 mg daily- ER: 500-1000 mg

QD with dinner

Titrate by 500 mg weekly or 850 mg every 2 weeks

GFR <30, acute or chronic metabolic acidosis (including DKA) with or w/o coma

Boxed warning for lactic acidosis

Not recommended to initiate if GFR 30-45; assess risk vs benefit if already taking and GFR falls <45

-Max: 2000-2550 mg/day

-Give w/ a meal to prevent GI upset

-↓A1C by 1-2%

● Adverse Effects: N/V/D, flatulence, abdominal cramping● Monitoring: renal function, vitamin B12● Drug Interactions: ↑ risk of lactic acidosis with

○ Alcohol use○ Iodinated contrast dye

■ Hold metformin at time of and before imaging procedure and for 48h in select patients● GFR between 30-45● History of hepatic disease, alcoholism or heart failure

Sulfonylureas: Insulin secretagogues that work by stimulating insulin secretion from the pancreatic β-cells to decrease postprandial blood glucose.

Agents Dosing Contraindications Warnings Other Notes

Glipizide (Glucotrol, Glucotrol XL)

Glucotrol: 5 mg/day, increase by 2.5-5mg every couple of days. Daily doses >15mg should be divided to BID. MAX = 40 mg/day

Glucotrol XL: 5 mg daily. Titrate to a MAX of 20 mg/day

*Listed Below* *Listed Below* Glucotrol: Taken 30 minutes before a meal; may need to hold dose is patient is NPO

Glucotrol XL: Osmotic Release Oral System (OROS) formulation and may leave a ghost tablet in stool

Glimepiride (Amaryl) 1-2 mg/day. Increase by 1-2mg q1-2wks to a MAX of 8 mg/day

Hypersensitivity Reactions

Glyburide (Glynase, Micronase, Diabeta)

Glyburide: 2.5-5 mg/day. Increase by 2.5mg weekly to a MAX dose of 20 mg/day

Use with Bosentan *Listed Below* - Micronized glyburide = Glynase- Weak active metabolite that’s renally cleared → not

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Diabetes Topic DiscussionNicholas England & Dylan Hotham

October 2, 2018

Glynase: 1.5-3 mg/day. Increase by 1.5mg weekly to a MAX of 12 mg/day

preferred in patients with renal insufficiency - Tablets can’t be used interchangeably with the micronized form (Glynase)

● Contraindications: T1DM, Diabetic Ketoacidosis, Sulfa Allergy (although not likely to cross-react)● Warnings: Hypoglycemia, G6PD Deficiency● Monitoring: Blood glucose, HbA1c● Other Notes: Decreases HbA1c by 1-2%, Decreased efficacy after long-term use due to declining

pancreatic β-cell function● Drug Interactions:

○ Insulin, Meglitinides, and Sulfonylureas should never be used in combination due to the increased risk for hypoglycemia

○ If starting a patient on a TZD, GLP-1 Agonist, DPP-4 Inhibitor, or SGLT2 Inhibitor, a reduction in the Sulfonylurea dose may be required to lower the risk of hypoglycemia

○ Use these agents with caution in patients taking CYP2C9 inducers or inhibitors○ Alcohol can increase the risk for hypoglycemia when taking these agents

Meglitinides: Decrease postprandial glucose by stimulating insulin secretion from the pancreatic β-cells

Agents Dosing Contraindications Warnings Other Notes

Repaglinide (Prandin)

0.5-2 mg TID AC(15-30 min prior to meals)

-Type 1 DM, DKA-Use w/ gemfibrozil

Hypoglycemia, headache, URTIs

-↓A1C by 0.5-1.5%

Nateglinide (Starlix)

60-120 mg TID AC Type 1 DM, DKA

● Adverse Effects: weight gain, headache, URTIs● Drug Interactions:

○ Other medications that contribute to hypoglycemia○ Repaglinide metabolism inhibited by clopidogrel and gemfibrozil

Thiazolidinediones (Nick): PPARγ agonists that cause increased peripheral insulin sensitivity.

Agents Dosing Contraindication Warnings Other Notes

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Diabetes Topic DiscussionNicholas England & Dylan Hotham

October 2, 2018

Pioglitazone (Actos) 15-30 mg/day

NYHA Class I/II patients: start with 15 mg/day

MAX dose = 45 mg/day

NYHA Class III/IV Heart Failure

- Increased risk of urinary bladder tumors

- Do not use in patients with active bladder cancer

- Contraception in female premenopausal women is recommended

- Take without regards to meals

- Decreases HbA1c by 0.5-1.4%

Rosiglitazone (Avandia)

4-8 mg/dayMAX dose = 8 mg/day

Boxed Warning: Increased risk of MI

● Boxed Warnings: Can cause or exacerbate heart failure● Warnings: Hepatic failure, Risk of fractures, Edema, Unintended pregnancy in premenopausal women

(which can lead to unplanned pregnancy)● Monitoring: LFT’s, HbA1c, blood glucose, S/S of heart failure● Drug Interactions: Major substrates of CYP2C8. Use caution with inducers (i.e., rifampin) or inhibitors (i.e.,

gemfibrozil)

SGLT2 Inhibitors (Dylan): Inhibits the sodium glucose co-transporter to decrease glucose reabsorption → ↑glucose excretion in the urine and ↓ glucose in the blood.

Agents Dosing Renal Dose Adjustments Warnings

Canagliflozin (Invokana)

100 mg QAM(max 300 mg)

eGFR 45-59: Max 100 mgeGFR 30-44: not recommendedeGFR <30: contraindicated

Boxed Warning: ↑risk of leg and foot amputations-hyperkalemia, inc risk of fractures

Dapagliflozin (Farxiga)

5 mg QAM(max 10 mg)

eGFR 30-59: not recommendedeGFR <30: contraindicated

-risk of bladder cancer

Empagliflozin (Jardiance)

10 mg QAM(max 25 mg)

eGFR 30-44: not recommendedeGFR <30: contraindicated

Ertugliflozin (Steglatro)

5 mg QAM(max 25 mg)

eGFR 30-59: not recommendedeGFR <30: contraindicated

● Administration: In the morning, before breakfast● Contraindications: eGFR <30, ESRD, on dialysis● Warnings: ketoacidosis, genital mycotic infections, urosepsis, and pyelonephritis, AKI, hypotension● Adverse Effects: weight loss, hypoglycemia, ↑urination,↑ thirst

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Diabetes Topic DiscussionNicholas England & Dylan Hotham

October 2, 2018● Monitoring: renal function, volume status, LDL● Drug Interactions:

○ Closely monitor kidney function when used in combination with meds contributing to AKI - diuretics, RAAS inhibitors, NSAIDs

○ UGT inducers ↑concentration of canagliflozin- may require dose decrease■ Rifampin, phenytoin, phenobarbital

DPP-4 Inhibitors (Nick): Prevent DPP-4 from breaking down incretin hormones, GLP-1 and GIP. These hormones help to regulate blood glucose levels by increasing insulin release from the pancreatic β-cells and decreasing glucagon secretion from the pancreatic α-cells.

Agents Dosing Renal Dose Adjustments Warnings Other Notes

Sitagliptin (Januvia) 100 mg/day CrCl 30-49 mL/min: 50 mg/day

CrCl <30 mL/min: 25 mg/day

*Listed below* - Decreases HbA1c by 0.5-0.8%

- Decreases postprandial blood glucose

Saxagliptin (Onglyza) 2.5-5 mg/day eGFR <45 mL/min/1.73m2: 2.5 mg/day

Risk of heart failure (esp. in patients with history of heart failure or renal impairment)

Linagliptin (Tradjenta) 5 mg/day No renal dose adjustment *Listed below*

Alogliptin (Nesina) 25 mg/day CrCl 30-59 mL/min: 12.5 mg/day

CrCl <30 mL/min: 6.25 mg/day

- Risk of heart failure (esp. in patients with history of heart failure or renal impairment)

- Hepatotoxicity

● Warnings: Acute pancreatitis, Severe & disabling joint pain, Hypersensitivity reactions● Monitoring: Blood glucose, HbA1c, Renal function● Drug Interactions:

○ Saxagliptin is a major CYP3A4 and P-gp substrate. Limit dose to 2.5 mg/day with strong CYP3A4 inhibitors (i.e., clarithromycin, ketoconazole)

○ Linagliptin is a major CYP3A4 and P-gp substrate. Levels of this agent are decreased by strong CYP3A4 inducers (i.e., St. John’s wort, carbamazepine)

Others:● Alpha-glucosidase Inhibitors (acarbose, miglitol)

○ Delay glucose absorption via inhibition of the metabolism of intestinal sucrose○ GI side effects ○ Doses must be taken with first bite of meals ○ If hypoglycemia occurs - must use oral tablets or gels

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Diabetes Topic DiscussionNicholas England & Dylan Hotham

October 2, 2018● Colesevelam (Welchol)

○ Bile acid sequestrant ○ Constipation○ Prone to drug interactions

Injectable Medications GLP-1 Agonists: Analogs of GLP-1, which increases glucose-dependent insulin secretion, decreases glucagon secretion, slows gastric emptying, and can result in weight loss. Approved for T2DM patients.

Agents Dosing Side Effects Warnings Other Notes

Exenatide (Byetta)

Exenatide ER (Bydureon)

Byetta: 5μg SC BID x 1 month; Can increase to 10μg SC BID

Bydureon: 2mg SC once weekly

*Listed below* Bydureon: Risk of thyroid C-cell carcinoma (Boxed Warning); Serious injection site reactions

- Byetta: Give dose 60 minutes prior to meals. Needles are not provided with Byetta- Bydureon: Can be given without regards to meals- CrCl <30 mL/min: NOT Recommended

Liraglutide (Victoza) 0.6mg SC daily x 1 week, then 1.2mg SC daily; Can increase to 1.8mg SC daily

*Listed below* - Pen needles are not provided with Victoza- Approved to reduce risk of CV events in patients with T2DM & ASCVD- Saxenda: Agent used for weight loss

Dulaglutide (Trulicity) 0.75mg SC once weekly; Can increase to 1.5mg SC once weekly

CV effects (i.e., Tachycardia)

*Listed below*

Lixisenatide (Adlyxin) 10μg SC daily x 14 days, then increase to 20μg SC daily

*Listed below* - eGFR <15: NOT recommended- Give dose 60 minutes prior to meals- Pen needles are not provided with Adlyxin

Semaglutide (Ozempic) 0.25mg SC once weekly x 4 weeks, then increase to 0.5mg SC once weekly; Can increase to 1mg SC once weekly

*Listed below* Increased complications with diabetic retinopathy

*Listed below*

● Contraindications (All agents except Byetta & Adlyxin): Personal or family history of medullary thyroid carcinoma or patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)

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Diabetes Topic DiscussionNicholas England & Dylan Hotham

October 2, 2018● Warnings: Pancreatitis, NOT recommended for patients with severe GI disease● Monitoring: Blood glucose, HbA1c, Renal function● Other Notes: Decreases HbA1c by 0.5-1.5%, Decreases postprandial blood glucose, Pen injection needles

should NEVER be shared with others● Drug Interactions:

○ Slows gastric emptying and can reduce the rate of absorption of PO administered drugs○ Take PO contraceptives at least 1 hour before exenatide or Adlyxin, and at least 11 hours after

Adlyxin○ Can increase the INR in patients taking warfarin

Pramlintide (SymlinPen): A synthetic analog of amylin. Amylin slows gastric emptying which suppresses glucagon secretion following meals.

● Type 1 Dosing: Start at 15 mcg/dose and increase by 15 mcg every 3 days as tolerated○ Max 60 mcg/dose

● Type 2 Dosing: Start at 60 mcg/dose and increase to 120 mcg/dose after 3 days as tolerated● Boxed Warning: Severe hypoglycemia when used with insulin

○ Reduce mealtime insulin by 50% when starting● Contraindications: gastroparesis, hypoglycemia unawareness● Adverse Effects: N/V, anorexia, headache, weight loss

Comparison of Mechanism of Action

↑ or replace insulin

↓ hepatic glucose output

↓glucagon, which ↓ glucose production

Slow gastric emptying

↑glucose excretion

↑ insulin sensitivity

InsulinSulfonylureasMeglitinides

Metformin GLP-1 agonistsDPP-4 inhibitorsPramlintide

GLP-1 agonistsPramlintide

SGLT2 inhibitors TZD’sMetformin

Adverse Effect Overview

Agents Effect on Blood Sugar

Effect on Weight

GI Side Effects Infections Other Side Effects

Insulin Hypoglycemia Gain - Hypokalemia- Lipodystrophy

Metformin - N/V/D

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Diabetes Topic DiscussionNicholas England & Dylan Hotham

October 2, 2018

- Flatulence- Abdominal Cramping

Sulfonylureas Hypoglycemia Gain Nausea

Meglitinides Hypoglycemia Gain URTI’s Headache

TZD’s Gain URTI’s - Peripheral Edema- Myalgia- Heart Failure

SGLT2 Inhibitors

Hypoglycemia Loss Genital Infections (↑urination)

↑thirst

DPP-4 Inhibitors

- URTI’s- UTI’s- Nasopharyngitis

- Peripheral Edema- Rash- Acute Pancreatitis

GLP-1 Agonists Hypoglycemia Loss N/V/D/C Injection Site Reactions

Pancreatitis

Pramlintide Hypoglycemia Loss N/V - Headache- Anorexia

Choosing a Medication for Type 2 Diabetes

Biggest Decrease in A1C Insulin, metformin, sulfonylureas, TZDs, GLP-1 agonist

Greatest risk of Hypoglycemia Insulin, sulfonylureas, meglitinides, pramlintide (w/ insulin)

Most likely to cause weight gain Insulin, sulfonylureas, meglitinides, TZDs

Most likely to cause weight loss SGLT2 inhibitors, GLP-1 agonists, pramlintide

Cardiac benefits Empagliflozin, liraglutide, canagliflozin

Cheapest Metformin, sulfonylureas, TZDs

HyperglycemiaWhich drugs can cause hyperglycemia?

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Diabetes Topic DiscussionNicholas England & Dylan Hotham

October 2, 2018

β-Blockers* Diuretics (Thiazides/Loops)

Immunosuppressants (i.e., cyclosporine, tacrolimus)

Niacin Fluoroquinolones*

Atypical Antipsychotics (i.e., clozapine, olanzapine, quetiapine)

Statins Systemic Steroids Protease Inhibitors

Posaconazole

Cough Syrups Octreotide* * = May also cause hypoglycemia

Hyperglycemic Crises● Diabetic Ketoacidosis (DKA): A hyperglycemic crisis that most commonly presents in patients with T1DM,

but can also present in patients with T2DM○ Occurs due to insulin non-compliance, a condition that can cause hyperglycemia (i.e., infection,

MI, or stress), and sub-therapeutic insulin dosing○ Recognizing DKA:

■ Blood glucose >250 mg/dL■ Ketones in the urine &/or serum (these patients will have a fruity breath)■ Anion gap metabolic acidosis (pH <7.35, anion gap >12)

● Hyperosmolar Hyperglycemic State (HHS): A hyperglycemic crisis that most often occurs in T2DM due to some type of severe stress (i.e., severe infection, high blood glucose levels)

○ Recognizing HHS:■ Blood glucose >600 mg/dL■ Extreme dehydration■ Altered consciousness (i.e., dizziness, confusion, seizures)■ High serum osmolality >320 mOsm/L■ pH >7.3 and bicarbonate >15 mEq/L

● Treatment○ Fluids

■ Begin with NS■ When blood glucose is 250 mg/dL, switch to D5W½NS

○ Regular insulin infusion■ Insulin of choice for IV solutions■ 0.15 units/kg bolus, then a continuous infusion is started at a rate of 0.1 units/kg/hr

○ Prevent hypokalemia■ Insulin shifts K+ into cells■ Monitor K+ and keep serum level between 4-5 mEq/L

○ Treat acidosis■ Only if pH <7.0■ Give NaHCO3 PRN

Hypoglycemia ● Defined as blood glucose <70 mg/dL● Symptoms: dizziness, headache, anxiety, irritability, shakiness, sweating, hunger, confusion, lack of

coordination, blurred vision, tremors, increased heart rate. ○ Severe - seizures, coma, death

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Diabetes Topic DiscussionNicholas England & Dylan Hotham

October 2, 2018● The activities of insulin, sulfonylureas, meglitinides and pramlintide are

insulin dependent, so they should be administered with food to decrease risk of hypoglycemia.

● GLP-1 agonists, DPP-4 inhibitors, TZDs, and SGLT2 inhibitors have a low risk of causing hypoglycemia alone, but when used in combination with a medication that causes hypoglycemia the risk can increase.

● Beta-blockers can mask all symptoms of hypoglycemia except sweating and hunger

● Rule of 15○ Take 15 grams of glucose of simple carbs (3-4 glucose tablets, glucose gel, 4 oz non-diet soda, 8

oz juice)○ Recheck blood glucose after 15 minutes○ Repeat step 1 if hypoglycemia continues ○ Eat a small snack to prevent re-occurrence

● Glucagon (GlucaGen)○ For high risk hypoglycemia patients. Only used if patient is unconscious or not conscious enough

to self-treat. Can teach caregivers or family how to administer. ○ Patient lays on side while administered ○ 1 mg SC, IV, or IM

Comprehensive Care Antiplatelet

● Recommendations○ Aspirin (75-162 mg/day) as a secondary prevention strategy in patients with diabetes and a

history of ASCVD (A)○ Patients with ASCVD and a documented aspirin allergy, clopidogrel (75 mg/day) should be used (B)○ Dual antiplatelet therapy (low-dose aspirin and a P2Y12 inhibitor) is reasonable for one year after

an ACS (A) and may have benefits beyond use of one year (B) ● Aspirin (75-162 mg/day) should be considered for primary ASCVD prevention in diabetic patients who are

not at an increased risk of bleeding○ Includes most diabetic patients >50 yoa and have >1 additional ASCVD risk factor

● Low-dose aspirin should be used in pregnant patients with T1DM or T2DM to reduce the risk of pre-eclampsia

○ Pre-eclampsia: High BP in pregnancy with signs of damage to another organ system (i.e., liver, kidneys, etc.)

○ Should be started in the 1st trimester and continued until the baby is born

Cholesterol ● Statin therapy is indicated for most patients with diabetes

○ Patients w/ clinical ASCVD → high intensity statin○ Patients w/o ASCVD and <40

■ No ASCVD risk factors - no statin ■ ASCVD risk factors - moderate intensity statin

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Medications that Cause Hypoglycemia Insulin Sulfonylureas Meglitinides Pramlintide Linezolid Belviq Beta blockers Quinolones

Diabetes Topic DiscussionNicholas England & Dylan Hotham

October 2, 2018○ Patients w/o ASCVD and ≥ 40 → moderate intensity statin

● Obtain lipid panel at diagnosis and at least every 5 years thereafter○ If on a statin - annually and more frequently during initiation and dose changes

Blood Pressure Control● The ADA guidelines recommend a BP goal of <140/90 mm Hg in most patients with diabetes

○ A lower target (<130/80 mm Hg) is appropriate for specific patients at risk of CVD○ 1st-line treatment includes a medication from one of the following drug classes:

■ Thiazide Diuretics (i.e., chlorthalidone, hydrochlorothiazide)■ Calcium Channel Blockers (CCB’s) (i.e., amlodipine)■ ACE Inhibitors (i.e., lisinopril, ramipril)■ ARB’s (i.e., losartan, candesartan)

● In patients with albuminuria, an ACE inhibitor or ARB should be used first to delay the progression of diabetic kidney disease

● If baseline BP is >160/100 mm Hg, patients with diabetes often require 2 drugs (ACE Inhibitor/ARB, Thiazide Diuretic, or CCB)

○ The ACC/AHA and ADA guidelines recommend one of these medications be taken at bedtime

Diabetic Kidney Disease● One of the leading causes of ESRD is diabetic kidney disease ● Annual urine test to measure microalbumin excretion

○ Regardless of HTN presence, all non-pregnant patients presenting with urinary albumin excretion ≥30 should be on either an ACE inhibitor or an ARB

Neuropathy and Foot Care● Neuropathy

○ All patients should be assessed at least annually for diabetic neuropathy using the 10-gram monofilament and at least one additional test (these include temperature, pinprick, or vibration sensation)

○ Optimizing a patient’s blood glucose helps avoid and delay the progression of neuropathy○ FDA-approved medications: duloxetine (Cymbalta), pregabalin (Lyrica), and tapentadol (Nucynta)

■ The ADA guidelines recommend duloxetine and pregabalin as 1st-line agents, where tapentadol is not recommended due to being less effective and for the concern of addiction

■ Other agents that can be considered: TCA’s, gabapentin (Neurontin), venlafaxine (Effexor), carbamazepine (Tegretol), tramadol (Ultram), and topical capsaicin

● Foot Care○ Diabetic patients are at increased risk for foot ulcers and amputations due to the loss of

sensation that occurs with peripheral neuropathy○ All adults with diabetes should have a foot exam, at least once per year○ Patients without feeling in their feet, foot deformities and ulcers should have their feet inspected

at every visit with their PCP○ All diabetic patients should inspect their feet daily○ Counseling:

■ Check feet every day for any changes. Call your PCP if any breaks into the skin, signs of infection, or ingrown toenails are noted

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Diabetes Topic DiscussionNicholas England & Dylan Hotham

October 2, 2018■ Wash feet every day and dry them completely, especially in between the toes■ Avoid walking barefoot. Wear socks at all times, and shoes when needed■ Wear properly fitted shoes■ Keep blood flowing to the feet■ Protect feet from both cold and heat

Diabetic Retinopathy● Leading cause of blindness ● Diabetic eye exam recommended at diagnosis of Type 2 diabetics and within 5 years of Type 1 diagnosis● Annual examination recommended ● Smoking cessation, and optimization of blood glucose, blood pressure and cholesterol control can slow

progression of retinopathy

Vaccinations ● Patients with diabetes should receive all age-appropriate vaccines, as well as the following:

○ Annual influenza vaccine○ Both pneumococcal vaccines

■ >65 yoa: 1 dose of PCV13 (if not received previously) and 1 dose of PPSV23● Give PCV13 now, then PPSV23 >1 year later

○ Hepatitis B vaccine■ Age 19-50 yoa (or at age >60 yo per PCP discretion)

References:1. American Diabetes Association (ADA). Standards of Medical Care in Diabetes - 2018. Diabetes Care.

2018;41(1):1-1502. 2017 ACC/AHA guideline for the prevention, detection, evaluation, and management of high blood

pressure: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:e13-e115

3. American Diabetes Association (ADA). Hyperglycemic Crises in Adult Patients with Diabetes. Diabetes Care. 2009;32(7):1335-1343

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