Diabetes- NAPLEX

Diabetes-Specific ASCVD Risk Enhancers

*Presence of one risk factor automatically qualifies diabetic patient for a high-intensity statin* 1. Long duration with diabetes - 10+ years with Type 2 - 20+ years with Type 1 2. Albuminuria - 30mcg+ of albumin per mg of creatinine 3. EGFR <60 (Diagnosis of CKD, essentially) 4. Retinopathy 5. Neuropathy 6. ABI <0.9

Alpha-Glucosidase Inhibitors, Medications, MOA, Glycemic Effect, Weight

- Acarbose (Precose), Miglitol (Glyset) MOA: These medications inhibit alpha-glucosidase, the enzyme in the small intestine responsible for breaking down sucrose into its monosaccharides (glucose and fructose). This causes a decrease in absorption of glucose and fructose, leading to decreased post-prandial BG levels. AGIs do not cause hypoglycemia, and also do not cause any weight changes. However, if hypoglycemia occurs due to another drug and the patient has taken an AGI recently, they CANNOT treat the hypoglycemia with SUCROSE (found in table sugar, fruit juices, etc). They can only treat it with glucose tablets or gels.

Antiplatelet Therapy and Diabetes

- Aspirin 75-162mg daily (usually given as 81mg daily) is recommended for ASCVD *secondary prevention* (e.g. post-MI). - If the patient has an aspirin allergy, use clopidogrel 75mg daily. - Aspirin IS used in pregnancy to decrease the risk of preeclampsia. - Aspirin is NOT recommended for primary prevention (in most patients). The risk of bleeding is equal to the benefit.

Diabetes Medications

- Biguanide - Thiazolidinediones

Bile-Acid Binding Resins, Medications, MOA, Glycemic Effect, Weight

- Colesevelam (Welchol), used in patients with diabetes AND dyslipidemia. MOA: Unknown how it works in diabetes, however it has been shown that Colesevelam can decrease BG levels and lower A1C. Colesevelam is a bile-acid sequestrant, meaning it binds to the secreted bile acids in the gut and prevent their reabsorption, causing the body to produce more bile acids to help facilitate lipid absorption. This causes an increase in cholesterol uptake into bile acids, decreasing cholesterol levels and also LDL levels. Colesevelam does not cause any hypoglycemia or weight changes.

Key Points from Insulin Algorithm ADA Guidelines

- GLP-1 RAs should be started PRIOR to insulin in most patients. An exception to this is when there is very high blood glucose (A1c >10% or BG >300 mg/dL). In this case, insulin is started first. - If the A1c remains above the goal, the next step after GLP-1RA is to add basal or bedtime NPH insulin. Both are started at 10 units daily or at a total daily dose of 0.1 to 0.2 units/kg/day (total body weight). - Titrate the insulin dose until the goal is reached WITHOUT hypoglycemia. Example titration is: increase by 2 units every 3 days until at goal FPG. - If this is not adequate to reach the goal, add prandial insulin, starting with ONE daily dose, before the meal with the highest carbohydrate intake OR before the meal with the highest postprandial blood glucose. - Additional prandial insulin doses can be added, up to 2 to 3 times daily, prior to meals. If this is also insufficient, a full basal-bolus regimen can be used. Another option after adding prandial insulin is using premixed or self-mixed insulin regimens.

Sulfonylureas Medications, MOA, A1C, Weight, Glycemic Effects

- Glipizide (Glucotrol, Glucotrol XL), Glimepiride (Amaryl), Glyburide Micronized (Glynase) MOA: Increases insulin secretion by directly stimulating the prancreatic beta cells via the ATP-sensitive K+ Channels. Depolarization causes an increase in Ca+ in the beta cells, stimulating the release of insulin. Decreases A1C by about 0.8%. These will cause hypoglycemia since they have a direct action on stimulating insulin. The dose should be very carefully titrated, and the patient needs to be aware and not skip meals. Since it stimulates insulin, these will cause weight gain.

Add-on Treatment Considerations

- If ASCVD is the major predominant issue (e.g. has had CAD, MI, or stroke), use an SGLT2i or GLP-1RA with ASCVD benefit. - If HF or CKD is a major issue, use as SGLT2i FIRST if the eGFR is >30. If eGFR is <30, use a GLP-1RA first. - If weight loss is desirable, use an SGLT2i or GLP-1RA. - DO NOT USE a GLP-1RA WITH A DPP4I or a SULFONYLUREA WITH MEGLITINIDE - If the patient is high-risk for hypoglycemia, use a DPP41. GLP-1RA. SGLT2I, or Pioglitazone. - Add-on additional medications according to the algorithm until the patient's A1c is <6.5% (unless the patient's A1c goal is different) - The A1c goal should be reached WITHOUT HYPOGLYCEMIA. HYPOGLYCEMIA IS NEVER ACCEPTABLE.

Basal Insulin with CVD Benefit

- Insulin Glargine U-100 - Insulin Deglutec

DPP4I + SGLT2I

- Linagliptin/Empagliflozin (Glyxambi) - Saxagliptin/Dapagliflozin (Qtern) - Saxagliptin/Dapagliflozin/Metformin (Qternmet XR) - Sitagliptin/Ertugliflozin (Steglujan)

GLP-1 Receptor Agonists, Medications, MOA, A1C, Glycemic Effect, Weight, Big Benefit

- Liraglutide (Victoza, Saxenda [weight loss]), Dulaglutide (Trulicity), Exenatide (Byetta), Exenatide ER (Bydureon, Bydureon BCise), Lixisenatide (Adlyxin), Semaglutide (Ozempic, Rybelsus [oral]) - All are SubQ injections except for oral Semaglutide MOA: GLP-1 mimetics. GLP-1 is an incretin which is typically released when people start eating to stimulate satiety, decrease glucagon, slow gastric emptying, and enhance insulin secretion. All this leads to lower BG. GLP-1RAs should NOT be used with DPP4 Inhibitors, as they have a similar MOA and there is no increased benefit with them together. Lowers A1C about 1%. Will not cause hypoglycemia by themselves, but if used with a medication that can (such as insulin, SUs, Meglitinides), it can worsen the low BG. Big benefit: Other than weight loss, certain GLP-1RAs have an ASCVD benefit (Liraglutide, Dulaglutide, and Semaglutide [inj only]).

GLP-1RA + Basal Insulin

- Liraglutide/Insulin Degludec (Xultophy) - Lixisenatide/Insulin Glargine (Soliqua)

GLP-1 Receptor Agonists Dosing

- Liraglutide: Start 0.6 mg SubQ DAILY for 1 week then increase to 1.2 mg SubQ DAILY afterwards. May increase to 1.8 mg SubQ DAILY if additional A1C lowering is needed. - Dulaglutide: Start 0.75 mg SubQ WEEKLY. Can increase to 1.5 mg SubQ WEEKLY if additional A1C lowering is needed. - Exenatide IR: 5 mcg SubQ TWICE DAILY within 60 minutes of meals - Exenatide ER: 2 mg SubQ once WEEKLY. - Lixisenatide: 10 mcg SubQ once DAILY, within 60 minutes of the first meal of the day for 14 days, increase to 20 mcg SubQ once DAILY on day 15. - Semaglutide (SubQ): 0.25 mg SubQ once WEEKLY for 4 weeks then increase to 0.5 mg SubQ once WEEKLY. May increase to 1 mg once WEEKLY if additional glycemic control is needed after at least 4 weeks on the 0.5 mg dosage. - Semaglutide (Oral): 3 mg once daily for 30 days then increase to 7 mg once daily. May increase to 14 mg once daily if additional glycemic control is needed after at least 30 days on the 7 mg dosage. All GLP-1RAs require a decrease in dose with renal impairment. Exenatide is CI'd with CrCl <30 mL/min, and Lixisenatide is CI'd with CrCl <15 mL/min

Metformin + DPP4I

- Metformin/Alogliptin (Kazano) - Metformin/Linagliptin (Jentadueto, Jentadueto XR) - Metformin/Sitagliptin (Janumet, Janumet XR) - Metformin/Saxagliptin (Kombiglyze XR)

Metformin + SGLT2I

- Metformin/Canagliflozin (Invokamet, Invokamet XR) - Metformin/Dapagliflozin (Xigduo XR) - Metformin/Empagliflozin (Synjardy, Synjardy XR) - Metformin/Ertugliflozin (Segluromet)

Metformin + Sulfonylurea

- Metformin/Glipizide (Metaglip) - Metformin/Glyburide (Glucovence)

Metformin + TZD

- Metformin/Pioglitazone (Actoplus Met)

Metformin + Meglitinide, TZD + Sulfonylurea/DPP4I

- Metformin/Repaglinide (Prandimet) - Glimepiride/Pioglitazone (Duetact) - Alogliptin/Pioglitazone (Oseni)

Risk Factors of Type 2 Diabetes

- Physical inactivity - First-degree relative with diabetes (a sibling or parent) - High-risk race/ethnicity (Black, Asian, Latino/Hispanic, Native American, or Pacific Islander) - Women who deliver a baby >9 lbs or a GDM diagnosis - HDL <35 OR TG >250 - Hypertension (140/90+ OR taking BP medication/s) - A1C 5.7%+ - Conditions that cause insulin resistance (e.g. severe obesity, acanthosis nigricans, polycystic ovary syndrome) - Cardiovascular disease history

Pramlintide, Medication, Indication, MOA, A1C, Glycemic Effects, Weight, Benefits

- Pramlintide (SymlinPen 60, SymlinPen 120) MOA: Pramlintide is a synthetic analog of amylin, which is a peptide hormone that is co-secreted with insulin by the beta cells of the pancreas. Amylin helps to facilitate satiety by slowing gastric emptying, which helps to decrease post-prandial spikes in blood glucose. Pramlintide can be used in BOTH TYPES of diabetes (Type 1 and Type 2). It decreases A1C by about 0.3%. Pramlintide can cause severe hypoglycemia if used with insulin (either with or up to about 3 hours after administration). The meal-time insulin dose MUST be decreased by about 50%. However, this is the ONLY drug besides insulin that is approved to lower BG in patients with T1D. Pramlintide typically causes weight loss due to its MOA (increased satiety). Its big benefit is that it can cause both weight loss and can lower the insulin requirements in people that use insulin (T1D and T2D).

Meglitinides, Medications, MOA, Glycemic Effect, Weight

- Repaglinide (Prandin), Nateglinide (Starlix) MOA: Increases insulin secretion by binding to the ATP-K+ channel in beta cells, causing depolarization. This depolarization increases Ca++ concentration in the beta cells, resulting in insulin secretion. This binding is weaker and disassociates quicker than sulfonylureas, allowing them to be used at mealtimes only. Will cause weight gain, since it stimulates insulin secretion. These will also cause hypoglycemia, especially if a meal is skipped and the patient still takes the dose of medication.

GLP-1RAs with Weight Loss Evidence

- Semaglutide - Liraglutide - Dulaglutide

DPP4 Inhibitors Medications, MOA, Glycemic Effects, A1C, Weight

- Sitagliptin (Januvia), Linagliptin (Tradjenta), Saxagliptin (Onglyza), Alogliptin (Nesina) MOA: Increases Incretin, which is a hormone that enhances insulin, decreases glucagon, facilitates lower blood glucose, and causes satiety. Incretins are metabolized by Dipeptidyl Peptidase-4. A type of incretin is GLP-1, so there is no effect if these are given with a GLP-1RA. Do not use DPP4Is with GLP-1RAs due to the similar MOA. No enhanced effect is seen. Lowers A1C about 1%. DPP4Is do not cause hypoglycemia by themselves, but enhances the effects of insulin. If used in combination with insulin, the dose of insulin may need to be reduced. Does not cause a weight change.

DPP4 Inhibitors Dosing, Adverse Effects

- Sitagliptin: 100 mg PO daily. - Linagliptin: 5 mg PO daily. - Saxagliptin: 5 mg PO daily. - Alogliptin: 25 mg PO daily. - All except Linagliptin require dose adjustment with renal impairment Adverse Effects - Generally well-tolerated, but can cause some nasopharyngitis (common cold symptoms), and headache. - Saxagliptin has significantly more ADEs, including edema, UTIs, and hypoglycemia (especially when used with insulin/sulfonylureas)

Titrating Basal/NPH Insulin

- Start with 10 units/day OR 0.1 to 0.2 units/kg/day - Titrate the insulin dose by setting a FPG target, choosing an evidence-based titration algorithm (e.g. increase by 2 units every 3 days) to reach that FPG goal without hypoglycemia. - If hypoglycemia, decrease the dose by 10-20%

Treatment Algorithm for Diabetes

1. *Metformin* is 1st line, with behavioral (lifestyle) changes including weight management and increase in physical activity. 2. After starting metformin, the next step is based on: - HF, CKD, ASCVD/High ASCVD Risk in Everyone (regardless of A1C) - No ASCVD, HF, CKD AND A1C >6.5%

Treatment Goals of Diabetes

1. A1C - Not Pregnant: <7% - Pregnant: <7% - An A1C goal of <6.5% may be acceptable if it can be reached without significant hypoglycemia. An A1C goal of <7 is acceptable for many. A goal of <8 may be appropriate in patients who have severe hypoglycemia, or a limited life expectancy. 2. Fasting Blood Glucose/Preprandial Blood Glucose - Not Pregnant: 80-130 - Pregnant: 95 or less 3. Postprandial Blood Glucose - Not Pregnant: <180 - Pregnant: Measured 1 hour after eating, 140 or less. Measured 2 hours after eating, 120 or less.

Diagnostic Criteria for Diabetes

1. A1C - Prediabetes: 5.7 to 6.4% - Diabetes: 6.5%+ 2. Fasting Plasma Glucose - Prediabetes: 100-125 - Diabetes: 126+ 3. Oral Glucose Tolerance Test (2-Hr PPG) - Prediabetes: 140-199 - Diabetes: 200+ 4. Classic Diabetes Symptoms + Random BG - Prediabetes: 140-199 - Diabetes 200+

Blood Pressure and Kidney Disease in Diabetes

1. ACC/AHA recommend a goal BP of <130/80 in ALL patients. The ADA agrees with the <130/80 if the diabetic has higher ASCVD risk (Clinical ASCVD or 10-year risk score of 15%+). If they do NOT, ADA recommends <140/90. Diabetes with HTN, NO Albuminuria: - Thiazide, CCB, ACEI, or ARB Diabetes with Albuminuria (regardless of HTN): - ACEI or ARB - If needed add a thiazide or a CCB *Do not use an ACEI, ARB or any other RAAS drug if the patient is pregnant!* If they do not have kidney disease, check their urine albumin annually. If they do have kidney disease, urine albumin must be checked twice yearly.

Clinical ASCVD Definition

1. Acute Coronary Syndrome 2. History of MI 3. Stable or Unstable Angina 4. Coronary or other arterial revascularization 5. Stroke 6. Transient Ischemic Attack 7. Peripheral Artery Disease 8. Abdominal Aortic Aneurysm

Macrovascular Complications

1. Atherosclerosis (Atherosclerotic Cardiovascular Disease [ASCVD]) - Coronary artery disease (CAD), including myocardial infarction (MI) - Cerebrovascular disease, including stroke (CVA, TIA) - Peripheral artery disease (PAD), with pain and increased amputation risk

GLP-1 RAs with CVD Benefit

1. Dulaglutide (Trulicity) 2. Liraglutide (Victoza) 3. Semaglutide [SC ONLY] (Ozempic)

SGLT2I with CVD/HF Benefit

1. Empagliflozin (Jardiance) 2. Canagliflozin (Invokana) 3. Dapagliflozin (Farxiga) These are *contraindicated* if the patient's EGFR is <30

Foot Care Counseling in Diabetes

1. Every day: - Examine feet. - Wash and dry feet. 2. Every office visit: - Take off shoes to have feet checked 3. Annually: - Podiatrist for foot exam (for most patients) 4. General Feet Care - Moisturize feet, both top and bottom, but *not* between the toes. - Trim toenails with a nail file. Do NOT leave sharp edges from the clipper. - Wear socks and shoes. - Elevate feet when sitting.

ASCVD Risk Enhancers

1. Family history of premature ASCVD 2. Persistently elevated LDL 160+ 3. Chronic Kidney Disease 4. Metabolic Syndrome 5. Conditions specific to women - Preeclampsia - Premature menopause 6. Inflammatory diseases (especially Rheumatoid Arthritis, psoriasis, and HIV) 7. Ethnicity (All ethnic groups except white, especially South Asian ancestry). 8. Persistently elevated triglycerides 175+ 9. ABI <9 10. hs-CRP 2+ 11. Lp(a) levels >50mg/dl or >125nmol/L 12. ApoB 130+

Insulin Algorithm in T2D

1. First start with behavioral changes (weight management, and increased physical activity) 2. If injectable therapy is needed to reduce A1c, consider a GLP-1RA in most patients FIRST prior to insulin (unless they are already on one, or if a GLP-1RA is not appropriate, or if insulin is preferred over a GLP-1RA). 3. If the patient is on a GLP-1RA, or if a GLP-1RA is not appropriate, or if insulin is preferred and the A1c is above target add basal insulin or bedtime NPH 4. If above A1c target despite adequately titrated basal insulin or bedtime NPH OR basal dose >0.5 units/kg OR FPG at target start Prandial Insulin OR consider twice-daily NPH if on bedtime NPH 5. If still above A1c target after addition of prandial insulin, initiate a stepwise addition of more prandial insulin at the other meals (up until full basal-bolus regimen), consider self-mixed/split insulin regimen, OR consider BID premixed insulin regimen.

Need for Weight Loss, Diabetes Algorithm

1. If the patient has a compelling need for weight loss, then first we start with a GLP-1 that has the best evidence for weight loss or an SGLT2i: 2. If A1c still >6.5, initiate the other weight loss class of medication (either SGLT2I or GLP-1RA). 3. If A1c still >6.5, and triple therapy is required AND/OR an SGLT2i or GLP-1RA are contraindicated, use a DPP-4i IF NOT ON A GLP-1RA - If DPP4I not tolerated, contraindicated or the patient is already on a GLP-1RA, CAUTIOUSLY ADD: = Pioglitazone = Basal Insulin = Sulfonylurea

ASCVD Risk Factors

1. LDL 100+ 2. Hypertension 3. Current Smoker 4. Chronic Kidney Disease 5. Albuminuria 6. Family History of Premature ASCVD (ASCVD event in men <55 and in women <65)

Combination Products in T2DM Medications

1. Metformin + Sulfonylurea 2. Metformin + TZD 3. Metformin + DPP4I 4. Metformin + SGLT2I 5. Metformin + Meglitinide 6. Sulfonylurea + TZD 7. DPP4I + TZD 8. DPP4I + SGLT2I 9. GLP-1RA + Basal Insulin

Microvascular Complications

1. Retinopathy - Mild to complete vision loss 2. Nephropathy - Kidney impairment/failure 3. Neuropathy - Pain, loss of feeling with decreased blood circulation - Leads to amputations 4. Autonomic Neuropathy - Erectile Dysfunction - Gastroparesis, with nausea, erratic blood glucose control - Loss of bladder control, UTIs

Need to Minimize Hypoglycemia Diabetes Algorithm

1. Start with options that have little to no risk of hypoglycemia - DPP4i - GLP-1RA - SGLT2i - TZD 2. If A1c is still >6.5 after starting one of the medications above: - Add a different class from above BUT NOT DPP4i and GLP-1RA TOGETHER. 3. If A1c is still >6.5, add another one of the medications above, BUT NOT DPP4I AND GLP-1RA TOGETHER.

Candidates for Metformin in Pre-Diabetes

1. Younger (<60 years of age) 2. BMI >35 3. History of Gestational Diabetes 4. Progressive Hyperglycemia (hyperglycemia getting worse despite lifestyle changes) Only need one characteristic to be a candidate for metformin, but the more the patient has, the better the candidate and the more it will help.

Diagnostic Test Results for Diabetes

A positive result with the A1C (6.5%+) OR a FPG of 126+ must be confirmed by retesting with the same or a different blood sample, or with another diagnostic test. If an OGTT is done and is positive, the test does not need to be confirmed, as it is a highly sensitive test.

Diabetes and Psychosocial Assessment

A psychosocial assessment should be used to determine if a mood or anxiety disorder is present that could interfere with being able to eat well, be active, take medication, and keep appointments. When mental health is questionable, cognitive function should be tested.

Biguanide, Medications, MOA, A1C Effect, Weight, Benefits

AKA Metformin (Glucophage, Glucophage XR, Fortamet, Glumetza, Riomet) MOA: Decreases hepatic gluconeogenesis (mostly), increases insulin sensitivity and decreases intestinal glucose absorption. Decreases A1C 1-1.5% with monotherapy. No hypoglycemia, no weight gain (possibly weight loss, mostly neutral weight changes) BIG BENEFIT: Well-tolerated, with the GI effects usually transitory, no weight gain, good decrease in A1C, and a possible CVD benefit.

Thiazolidinediones Medications, MOA, A1C Effect, Weight

AKA TZDs - Pioglitazone (Actos), Rosiglitazone (Avandia) MOA: Increases muscle cell sensitivitiy to insulin, increasing blood glucose entry. Peroxisome Proliferator Activated-Receptor- Gamma agonists (PPAR-Gamma). Decreases A1C about 1%. Will not cause hypoglycemia by itself, but enhances the effects of insulin, so if used in combination or insulin, the insulin dose may need to be reduced. Weight GAIN.

Hyperglycemia

Abnormally high blood glucose. This is the central problem in all types of diabetes, Type 1, Type 2, and Pre-Diabetes. Chronically high blood glucose can cause diabetes.

Presentation of T1DM

About 25% of the children with T1DM initially present with DKA once insulin production is very low or absent. In adults, T1DM presents more gradually, and actually can be mistaken for T2DM. A peptide called C-Peptide is used to test if T1DM is present.

High Risk of ASCVD Definition

According to the ADA guidelines, High Risk of ASCVD in this context is considered age 55+ with coronary, carotid, or lower extremity artery stenosis >50% OR Left Ventricular Hypertrophy.

GLP-1 Receptor Agonists Adverse Effects, Warnings

Adverse Effects - Nausea/Vomiting, Diarrhea - Decreased appetite, weight loss - Dyspepsia - Injection site reactions BOXED WARNINGS - ALL GLP-1RAs (except Byetta and Adlyxin): DO NOT USE if there is a personal/family history of medullary thyroid cancer (MTC) - ALL GLP-1RAs (except Byetta and Adlyxin): DO NOT USE if there is history of multiple endocrine neoplasia (MEN2) Warnings - Pancreatitis: Monitor for symptoms of severe abdominal pain/nausea - AKI/CKD (kidney damage) from fluid loss/dehydration due to potential vomiting/diarrhea - Hypersensitivity, including anaphylaxis, and angioedema - Gallbladder disease - GI symptoms are common with GLP-1RAs. Titrate dose slowly. Discontinue if the patient has fluid depletion (e.g. lots of nausea). Do not use if the patient has gastroparesis. - Bydureon specifically: Serious injection-site reactions such as abscess or skin nodules are possible. - Ozempic specifically: Diabetic retinopathy

HF, CKD, ASCVD/High ASCVD Risk Treatment Algorithm for Diabetes

After patients have started metformin first-line, the algorithm splits based on whether the patient has HF, CKD, ASCVD or is high risk for ASCVD. If they are one of these things, then REGARDLESS of A1C, the patient is started on another diabetes medication based on the predominant condition: 1. ASCVD Major Issue: - Use a GLP-1 RA with CVD Benefit OR an SGLT2I if their EGFR is adequate (CI'd if EGFR <30) 2. HF or CKD Major Issue - Use SGLT2I FIRST that reduces HF and/or CKD progression if EGFR is adequate (CI'd if EGFR <30) - If the patient cannot use an SGLT2I, use a GLP-1 RA with CVD benefit Next step in the algorithm is now based on their A1C. If their A1C is still >6.5%, start the other class that has CVD benefit. There are various options at this step, and others can be added based on their A1c.

No ASCVD, HF, or CKD AND A1c is >6.5%, Diabetes Algorithm

After starting metformin and intensive lifestyle modification, if A1c is >6.5 and the patient does NOT have ASCVD, HF, CKD or HIGH RISK for ASCVD will be started based on their: 1. Need to minimize hypoglycemia 2. Need for weight loss

SGLT2 Inhibitors, Warnings and Contraindications

BOXED WARNING - Canagliflozin: Amputation risk, avoid in patients if they have foot problems/peripheral neuropathy Warnings - Increased LDL-C - Hyperkalemia - Fluid loss, hypotension - KETOACIDOSIS, even with BG <250 mg/dL - SEVERE UTIs, genital fungal infections - Risk of Fournier's gangrene (rare ADE) - Canagliflozin has increased risk of bone fractures, avoid in patients with fracture risk.

Pramlintide Warnings, Contraindications

BOXED WARNING - SEVERE HYPOGLYCEMIA with Pramlintide is used with insulin or about 3 hours after administration. The meal-time insulin dose MUST be decreased by 50% when starting Pramlintide. Contraindications - Gastroparesis - Hypoglycemia unawareness

Thiazolidinediones Warnings and Contraindications

BOXED WARNINGS - DO NOT USE WITH NYHA CLASS III/IV HEART FAILURE Warnings - Hepatic failure - Edema, including macular edema - Can cause or worsen HF - Fractures (especially in females) - Can stimulate ovulation, may need contraception if the patient is premenopausal - Pioglitazone specifically has been linked to bladder cancer, avoid if the patient has history

Biguanide Warnings, Contraindications

BOXED WARNINGS - Lactic Acidosis: Increased risk in patients with renal disease, alcoholism, hypoxia Warnings - Do no start in patients with an eGFR of 30-45 mL/min/1.73m2 - May cause vitamin B12 deficiency - STOP metformin prior to iodinated contrast media (for most patients) Contraindications - eGFR <30 mL/min/m2

Risks of Gestational Diabetes

Blood glucose during pregnancy should be close to normal (Preprandial 95mg/dL or less, 1-Hr Postprandial 140 or less and 2-hr postprandial 120 or less). Babies born to mothers who had hyperglycemia during the pregnancy are larger than normal (termed fetal macrosomia) and are at a higher risk for developing obesity and diabetes later in life.

C-Peptide

C-Peptide is a protein that is released by the pancreas ONLY when insulin is released. T1DM is diagnosed when there is very low or absent (undetectable) C-Peptide level.

SGLT2 Inhibitors Medications, MOA, A1C, Glycemic effects, Weight, Big Benefit

Canagliflozin (Invokana), Empagliflozin (Jardiance), Dapagliflozin (Farxiga), Ertugliflozin (Steglatro) MOA: Increase blood glucose renal excretion by inhibiting the Sodium-Glucose Co-Transporter 2 channels. Decreases A1C about 0.7 to 1% Will not cause hypoglycemia by itself, but it will enhance the effects of insulin. If used in combination with insulin, the insulin dose may need to be decreased. Can cause weight loss. Has a big benefit in heart failure and in CKD if Canagliflozin or Empagliflozin is used. Dapagliflozin has shown to decrease HF hospitalizations.

SGLT2 Inhibitors, Dosing, Adverse Effects

DOSING - Canagliflozin: Start 100 mg PO every morning before the first meal, max of 300 mg per day. - Empagliflozin: Start 10 mg PO daily every morning, max of 25 mg daily. - Dapagliflozin: Start 5 mg PO every morning, max of 10 mg daily. - Ertugliflozin: Start 5 mg PO every morning, max of 15 mg daily. - ALL SGLT2Is must have dose decreased with renal impairment ADVERSE EFFECTS - UTIs, genital fungal infections, weight loss, - Increased urination, increased thirst - Ketoacidosis if oral intake is impaired, discontinue Ertugliflozin 4 days prior to surgery and discontinue the others 3 days prior to surgery. Restart SGLT2Is when normal oral intake is resumed.

Overall Treatment of Diabetes

Diabetes care must be COMPREHENSIVE, as in it must contain all elements needed to keep healthy. Everyone, with any risk, including simply getting older, should quit smoking and get moving. Minimum exercise goal of 150 minutes a week, spread over at least 3 days, with aerobic and resistance exercise (e.g. with weights). Other aspects of diabetes care includes: - Antiplatelet therapy - Cholesterol control - Neuropathy - Foot care - Weight control - Diabetic retinopathy - Blood pressure control and kidney disease - Psychosocial assessment - Vaccinations

Neuropathy and Diabetes

Diabetics typically develop Peripheral Neuropathy, which is a loss of sensation, often in the feet. This leads to foot injuries/ulcers, and infections, which can lead to amputations. Annually, diabetics should get a 10-g Monofilament Test and 1 other test (such as Pinprick, Temperature, or Vibration test) to assess sensation (feeling). Diabetics should get a comprehensive foot exam, and if high-risk, refer them to a podiatrist. Treatment options for neuropathy includes pregabalin, duloxetine, and gabapentin.

Bile-Acid Binding Resins Dosing, Adverse Effects, Notes, Contraindications

Dosing - 3.75 grams/day divided into 1 to 2 divided doses (large tablets) Adverse Effects - Constipation, increased TGs - Decreased absorption of fat soluble vitamins (ADEK), counsel on taking a multivitamin with these vitamins at a different time. Notes - MANY drug-drug interactions. Monitor closely. Contraindications - TG levels >500 mg/dL - History of hypertriglyceridemia-induced pancreatitis - Bowel obstruction

Alpha-Glucosidase Inhibitors Dosing, Adverse Effects

Dosing - Both can be started at 25 mg PO 3 times daily with the FIRST BITE of each meal. - It can be started at only one meal to decrease potential GI ADEs. - These do not need to be taken if skipping a meal. Adverse Effects - GI side effects are very common, such as flatulence, diarrhea, and abdominal pain (inhibiting breakdown and absorption of complex carbohydrates).

Sulfonylureas Dosing, Adverse Effects

Dosing - Glipizide: start 5 mg PO daily, max of 40 mg daily. - Glimepiride: start 1 to 2 mg PO daily, max of 8 mg daily. - Glyburide: start 2.5 to 5 mg PO daily, max of 20 mg daily. - Glipizide IR should be given 30 minutes PO before breakfast. All others are given *with breakfast.* Adverse Effects - These are generally well-tolerated, but can cause hypoglycemia and weight gain. - Glucotrol XL is an OROS (Osmotic controlled-release Oral Delivery System), meaning as the tablet passes through the GI tract osmotic pressure from water entering the tablet pushes the active drug out of the tablet to be absorbed. Because of this, a ghost tablet (empty shell) will be seen in the stool. - ALL sulfonylureas will see decreased efficacy after long-term use as beta cell function declines.

Biguanide Dosing, Adverse Effects

Dosing - IR: start 500mg PO daily or 500mg PO BID - ER: start 500mg PO daily *with dinner* - IR/ER: titrate dose to a max of 2,000 mg daily (or 2,550 mg daily if taking 850 mg TID). Adverse Effects - Generally well-tolerated but can cause diarrhea, nausea, flatulence, and dyspepsia - Give with a meal to decrease nausea. The ER formulation must be swallowed whole and taken with dinner. - ER formulations leave ghost tablets in stool.

Thiazolidinediones Dosing, Adverse Effects

Dosing - Pioglitazone: Start 15-30 mg PO daily, max dose of 45 mg daily. - Rosiglitazone: Start 4-8 mg PO daily, max dose of 8 mg daily. - NO dose adjustments for renal impairment, but generally not used due to fluid retention. Adverse Effects - Edemia, weight gain, bone fractures, upper respiratory tract infections - Rosiglitazone can increase LDL, HDL, Total Cholesterol, and BP

Meglitinides Dosing, Adverse Effects, Warnings, Contraindications

Dosing - Repaglinide: Start 0.5 to 1 mg PO TID, 15 to 30 minutes BEFORE MEALS. Start at 0.5 mg if patient is close to their A1C goal. - Nateglinide: Start 60 to 120 mg PO TID, 15 to 30 minutes BEFORE MEALS. Start at 60 mg if the patient is close to their A1C goal. Adverse Effects - Generally well-tolerated, but can cause hypoglycemia and weight gain. - Skip the dose if a meal is skipped to avoid hypoglycemia. Warnings - Hypoglycemia - DO NOT USE with insulin or sulfonylureas (same MOA)

Pramlintide Dosing, Adverse Effects, Notes

Dosing - T1D: Start at 15 mcg SubQ with meals and increase as needed in 15 mcg increments to up to 60 mcg/dose (if no significant nausea for at least 3 days). - T2D: Start at 60 mcg SubQ with meals and increase to the maintenance dose of 120 mcg/dose (if no significant nausea for at least 3 days). Adverse Effects - Nausea/Vomiting - Anorexia - Headache - Weight loss Notes - SKIP if <30 grams of carbohydrates are consumed at the meal. - Pramlintide is injected at meal-times, and SHOULD NOT be mixed with insulin.

Weight Control and Diabetes

If overweight, encourage a 5%+ weight loss. A dietician should be used to develop an Individualized Medical Nutrition Therapy (what works best for each patient). Insulin resistance increases with stomach weight (termed Central Adiposity, essentially having a "gut"). - A healthy waist circumference is key to reducing insulin resistance (<35 inches in females, <40 inches in males).

Twice-Daily NPH

If the patient is on bedtime NPH and their A1c is above target despite it being adequately titrated OR the dose is >0.5 units/kg OR their FPG is at target, consider switching to a twice-daily NPH regimen. Conversion to this is based on individual needs and current glycemic control. Example: - Total dose of twice-daily NPH is 80% of the current bedtime NPH dose. - Give 2/3rds of that in the morning and 1/3 of that at bedtime. - Titrate based on individual needs. If twice-daily NPH is not resulting in the target A1c, move onto adding prandial insulin.

After Prandial Insulin

If the patient is still above target A1c despite addition of prandial insulin to the largest meal or the meal with the greatest PPG excursion, and it is adequately titrated, there are three potential options: 1. Stepwise additional injections of prandial insulin (two, then three additional injections) until the patient is on full basal-bolus regimen (basal insulin + prandial insulin with every meal) 2. Consider self-mixed/split insulin regimen 3. Consider twice daily premixed insulin regimen

HF, CKD, ASCVD/High ASCVD Risk Treatment Algorithm for Diabetes Final Options

If the patient's A1c is still >6.5% after starting a medication with ASCVD benefit, it is possible to: 1. Add the other class (SGLT2i or GLP-1RA) using the drugs with CVD benefit. 2. If not on a GLP-1RA (cannot tolerate or some other reason), add a DPP-4I. However, do not use a GLP-1RA and a DPP4I together, they have similar mechanisms of action and can be harmful. 3. Add basal insulin with CVD benefit. 4. Pioglitazone (NOT with heart failure). 5. Sulfonylurea

Pre-Diabetes

In Pre-Diabetes, the blood glucose is higher than normal, but it is NOT high enough for a diabetes diagnosis. The primary goal in Pre-Diabetes is to make healthy changes (specifically weight-management and regular physical activity) that can avert, or at least delay, T2DM. Pre-Diabetes can be reversed with a healthier lifestyle. Blood glucose should be checked annually to see if the condition has progressed to T2DM or has improved. If it has progressed, treatment is required. Metformin can be used to delay T2DM if the patient is younger (<60 years old), is at a higher risk, minimally moderate obesity (BMI >35) and/or a history of a diabetes diagnosis during pregnancy (gestational diabetes, or GDM).

Diabetic Retinopathy

In T2DM, patients should get an initial eye exam with DIAGNOSED, and should include dilation of the eye. If retinopathy is diagnosed, the patient should then get an eye exam annually. If there is no retinopathy, repeat an eye exam every 1 to 2 years. To decrease the risk/slow the progression: - STOP SMOKING - Control Blood Glucose, Blood Pressure, and Cholesterol Diabetic Retinopathy is the TOP cause of blindness.

Vaccinations and Diabetes

In addition to all childhood vaccines diabetics should receive: - Hepatitis B Vaccine (HBV) - Influenza, annually - BOTH pneumococcal vaccines (Prevnar 13, Pneumovax 23).

Interpreting the A1C

It is not easily apparent how an A1C value correlates with the values measured on a glucose meter, which can make the A1C hard to understand. It is important that patients understand long-term blood glucose control, as long-term control leads to less micro- and macrovascular damage. The Estimated Average Glucose (eAG) is an interpretation of the A1C value that makes it appear similar to a glucose meter value.

Complications from Hyperglycemia

Left untreated, diabetes damages nearly ALL parts of the body. The primary cause of death in diabetes is the same as the general population (some type of cardiovascular disease), but at a 2 to 4 times higher incidence. Other complications include: - Lower-extremity amputations (diabetes is top cause) - Kidney Failure - Blindness - Depression (associated with diabetes, makes self-management very challenging) - DKA and HHS (Acutely, very high blood glucose only) The complications of diabetes categorized as Microvascular (small vessel complications), or Macrovascular (large vessel complications).

Consequences of Hyperglycemia

Long-term hyperglycemia can cause damage throughout the body to small vessels (known as Microvascular Damage) and the large vessels (known as Macrovascular Damage). Acutely, very high blood glucose can be fatal.

Symptoms of Diabetes

Overall, symptoms of diabetes are based on the 3 P's: - Polyuria (Increased urination) - Polydipsia (Increased thirst) - Polyphagia (Increased hunger) These three symptoms are common among both T1DM and T2DM, but T1DM symptoms happen fast and usually lead to a quick diagnosis. In T2DM, these symptoms are milder and can go unnoticed for years, all the while causing the micro- and macrovascular damage. Other symptoms include (with these being typically only present in T2DM): - Fatigue - Blurry vision - Erectile Dysfunction - Vaginal fungal infections

Cholesterol Control and Diabetes

Patients should get an annual lipid panel and most will need statins. Add a statin and recheck in 4 to 12 weeks after starting or increasing the dose. 1. *Diabetes + ASCVD* (e.g. post-MI, Peripheral Artery Disease), OR aged 50-75 with MULTIPLE ASCVD risk factors: - High-Intensity statin 2. Diabetes without ASCVD but older (40-75 years) - Moderate-Intensity statin 3. Diabetes without ASCVD and younger (<40 years): - If no ASCVD risk factors, no statin - If they do have risk factors, start a moderate intensity statin Can add ezetimibe to a maximally-tolerated statin if the ASCVD 10-yr risk score is >20%. If LDL is controlled, but TGs are 135 to 499, preferentially add icosapent ethyl (Vascepa) to decrease CVD risk. *The ADA guidelines state the risk for diabetes with statins is low, so statins should be used when indicated.*

Natural Products Used in Diabetes

Patients with T2DM commonly use natural products, although this is low to minimal efficacy. Products used that lower blood glucose include: - Cassia cinnamon - Alpha Lipoic Acid - Chromium - Magnesium - Panax/American Ginseng Most patients with diabetes will still require prescription medications.

Adding Prandial insulin

Prandial (Bolus) insulin should be added only if the patient is above their A1c target despite: - Adequately titrated basal/bedtime NPH insulin OR - Basal dose >0.5 units/kg OR - FPG at target Usually when adding prandial insulin it is added as one dose at the largest meal or the meal with the greatest PPG excursion. Prandial insulin is started at 4 units/day or 10% of the basal insulin dose. If the patient's A1c is <8%, consider decreasing the basal dose by 4 units per day or 10% of the basal dose Prandial Insulin is titrated by increasing the dose by 1-2 units or 10-15% twice weekly. If the patient experiences hypoglycemia, decrease the dose by 10-20%.

Twice-Daily Premixed Insulin Regimen

Started usually unit per unit at the same total insulin dose, but may require adjustments to individual needs. This is titrated based on individual needs.

Screening and Testing for Diabetes

Symptoms can clearly indicate that testing is needed (e.g. polyuria or polydipsia), but other symptoms may not be so apparent. Diabetes is important to screen for risk factors that will ID people at risk for diabetes, who can be diagnosed either early or before they develop diabetes. Risk for diabetes increases with age. Therefore, EVERYONE, even those with NO RISK FACTORS, should be tested beginning at age 45. If the patient is overweight (BMI 25+ or 23+ in Asians) and asymptomatic and has at LEAST ONE MORE RISK FACTOR (e.g. obesity, not just overweight), they should be tested for diabetes. If the result is normal, testing should be repeated every 3 years (minimally). This applies to all asymptomatic children, adolescents, and adults.

Key Points from the ADA Drug Treatment Algorithm

T2D treatment is based on the drug treatment algorithm and the insulin algorithm. With both algorithms, proceed to the next step is A1c remains above goal. METFORMIN IS FIRST-LINE. Given alone or started in combination when A1c >1.5% above goal (or if patient has ASCVD, CKD, HF, or high risk for ASCVD, then A1c does not matter). - If eGFR is <30, DO NOT START METFORMIN. Insulin can be used initially if hyperglycemia is severe (typically when A1c is >10% or BG >300 mg/dL) and especially if there is catabolic presentation (weight loss or ketosis). After metformin, select add-on treatment based on individual patient needs.

Measuring the A1C

The A1C is a very important measure that can indicate long-term blood glucose control. It typically is measured quarterly (every 3 months) if the patient is "not yet at goal*. If the patient is at goal, then it is measured every 6 months. Typically the A1C is measured using a blood sample that is sent to the lab, however there is now Point-of-Care A1C test kits that provide the result right away and can be used by both prescribers and patients. The A1C is the primary test used to assess BG control on a continuous basis. The goal for most is <6.5 or <7.

eAG

The estimated average glucose. This is a value that correlates to the A1C, and helps people understand what blood glucose level corresponds to what A1C level. An A1C of 6% is equivalent to an eAG of 126mg/dL. Each additional 1% increases the eAG by about 28mg/dL. Example: An A1C of 7% is 126 + 28 = 154.

T2DM Causes and Diagnosis

The major contributors that cause this overabundance of insulin are a low level of physical activity and being overweight or obese. Lifestyle, genetics, and other risk factors increase the likelihood of insulin resistance, and eventually T2DM. Most T2DM is diagnosed after years of poor lifestyle, between the ages of 45 and 64. However, while the incidence of T2D increases with age, the incidence in children has become prevalent as weight has increased and physical activity has decreased.

Albuminuria

The presence of protein in the urine. Albuminuria is diagnosed if there is a urine albumin of 30mg+/24 hours OR a urine-to-creatinine ratio (UACR) of 30mg+/g.

Selecting Medications for T2DM

There are 2 big similarities with the top 3 treatments in the ADA algorithm: - Metformin, GLP-1RAs, and SGLT2I all cause weight loss and NO hypoglycemia (metformin is technically weight-neutral, but has great A1c reduction, easy to tolerate, very low cost, and may have a CVD benefit). The algorithm says: 1. Metformin FIRST (unless insulin is needed). 2. GLP-1RA or SGLT2I based on comorbid conditions (if HF or CKD #1 issue, add SGLT2I first, then GLP-1RA if additional therapy is needed). 3. Add the other class if needed. 4. Then a variety of options are available depending on the need to keep weight gain minimal, avoid hypoglycemia, and when to use insulin. Insulin is only in the 2nd algorithm. Remember to make sure if the specific drug has benefit in the patient's primary area of concern. Not all GLP-1RAs/SGLT2Is have benefit in ASCVD. Remember to make sure the drug can be used safely! Some medications require renal dose adjustment, especially the SGLT2Is, but also GLP-1RAs. - Dulaglutide can be used in severe renal insufficiency, whereas exenatide cannot. - Make sure to check for allergies.

Diagnostic Tests for Diabetes

There are three types of tests used to identify if prediabetes or diabetes is present. 1. Hemoglobin A1C - Indicates the average blood glucose over the past approximately 3 months 2. Fasting Plasma Glucose - Gives blood glucose at that moment, and is taken after an 8+ hour fast 3. The Oral Glucose Tolerance Test (OGTT) - Measures how well a very sugary drink is tolerated by measuring postprandial glucose levels.

Gestational Diabetes

This is diabetes when the patient is pregnant. There are two ways diabetes can be present during pregnancy: - Diabetes was present prior to becoming pregnant, or - Diabetes developed during pregnancy (GDM) Most women are tested for GDM at 24-28 weeks. High risk women are tested earlier. The Oral Glucose Tolerance Test (OGTT) is highly sensitive and is preferred in pregnancy. If the women is diagnosed with GDM, lifestyle modifications with diet and exercise should be tried first. If medications are needed for tight control, insulin is preferred. Metformin and glyburide are sometimes used.

Self-Mixed/Split Insulin Regimen

This is typically the strategy if the patient is on NPH and prandial insulin. This strategy can be flexible because it allows the clinician to adjust the NPH and prandial insulin separately. Example: - Total new NPH dose: 80% of current NPH dose, with 2/3rds given before breakfast and 1/3rd given before dinner - Add 4 units of prandial insulin to each injection, or 10% of this new reduced NPH dose - Titrate each component of the regimen based on individualized needs

GLP-1 Receptor Agonists Other Considerations

Trulicity, Bydureon, Bydureon BCise, and Ozempic are all dosed once weekly. Victoza, and Adlyxin are dosed once daily. Byetta is dosed twice daily. Pen needles are provided with weekly injections ONLY. The others do not come with pen needles and must be dispensed to the patient separately (either with Rx or OTC if allowed).

Type 1 Diabetes

Type 1 Diabetes is an autoimmune disorder where the patient's own antibodies attack and destroy the beta cells (AKA the Islet Cells) in the pancreas, which are the cells responsible for making insulin. Most T1DM is diagnosed in children, but it can develop at any age. EVERYONE with T1DM REQUIRES INSULIN. They require insulin because insulin is required for glucose to enter the muscle cells, and when the muscle cells are starved of glucose the body enters starvation mode, shifting to metabolize fat into ketones to use as an alternative energy source. Ketones are very acidic and very high ketone levels can cause Diabetic Ketoacidosis (DKA), which is a medical emergency.

Hyperglycemia in the Types of Diabetes

Type 1: - In type 1, the patient has no insulin whatsoever (due to a variety of factors, but mostly because of autoantibodies). Without insulin, glucose cannot enter the muscle cells, leading to chronically high blood glucose. Type 2/Pre-Diabetes - In these types, the body becomes resistant to insulin, and requires more and more insulin to cause glucose to enter the muscle cells. In both scenarios, glucose builds up in the blood, causing hyperglycemia, while at the same time the cells are starved for energy.

Type 2 Diabetes

Type 2 Diabetes is primarily due to a loss of insulin sensitivity over time due to an overabundance of insulin. The muscle cells require more insulin to transport the same amount of glucose, so the net effect is a decrease in glucose uptake by the cells. Over time, the pancreas will attempt to overcome insulin resistance by producing more insulin. Eventually, the beta cells become dysfunctional, and insulin production decreases, causing BG to elevate. Insulin resistance plus less insulin production is a double whammy for causing hyperglycemia.

Sulfonylureas Warnings and Contraindications

Warnings - Hypoglycemia - Beers Criteria: Do not use in the elderly due to the risk of hypoglycemia, especially those with the highest risk (glyburide and 1st generation SUs such as chlorpropamide and others). Contraindications - SULFA ALLERGY: Sulfonylureas contain a sulfa moiety, however there is not likely to be cross-reactivity. We should still use cautiously in patients with sulfa allergies, especially severe sulfa allergies.

DPP4 Inhibitors Warnings and Contraindications

Warnings: - Pancreatitis - Severe arthralgias (joint pain) - Acute renal failure - Alogliptin associated with hepatotoxicity - Alogliptin and Saxagliptin: DO NOT USE IN HEART FAILURE