Diabetes

Accumulation

*Once steady state is achieved for a given dose of ultra long acting insulin, ____________ will not occur because the rate of insulin absorption equals the rate of uptake and elimination*

Metformin (Biguanides)

-1% A1C drop as monotherapy -MOA: Inhibits production of glucose, intestinal absorption of glucose, and increases insulin sensitivity in muscle/fat -Adverse Effects: B12 deficiency, GI (nausea, diarrhea, cramping), lactic acidosis (rare) in pts with cardiovascular, renal or hepatic dysfunction -Low risk of hypoglycemia -Weight neutral -First line for most patients -Beneficial for prediabetes -May reduce cardiovascular mortality -Safe in patients with stab;e heart failure and moderate renal impairment

Rapid Acting Insulins

-Aspart (Novolog) -Glulisine (Apidra) -Lispro (Humalog U100/U200) -Inhaled (Afrezza) Onset: 10-30 min. Peak: 30 min-1.5 hours Duration: 3-6 hours

Short Acting Insulins (regular)

-Available OTC (100 units/ml only) -Onset: 30 minutes (<15 for 500U) -Longer time to onset and longer duration than rapid-acting analogues -Lag time between regular insulin administration and meals may not be necessary for all patients with type 2 diabetes -For type 1 diabetes, non-preferred alternative to rapid-acting insulin at each meal with one or two injections of basal insulin -For type 2 diabetes, once daily at largest meal plus basal insulin, or basal-bolus regimen -Clear and colorless

Antidiabetic Drugs

-Biguanides: Metformin -Sulfonylureas: Glyburide, Glipizide, Glimepiride -Meglitinides: Repaglinide, Nateglinide -Alpha-glucosidase Inhibitors: Acarbose, Miglitol -Thiazolidinediones: Pioglitazone, Rosiglitazone -DPP-4 Inhibitors: Alogliptin, Linagliptin, Saxagliptin, Sitagliptin -SGLT-2 Inhibitors: Canagliflozin, Dapagliflozin, Empagliflozin, Ertugliflozin -Bile Acid Sequestrants: Colesevelam -Dopamine-2 Agonists: Bromocriptine -GLP-1 RA: Exenatide, Liraglutide, Lixisenatide, Dulaglutide, Semaglutide -Amylin Mimetics: Pramlintide -Insulins

Hypoglycemia

-Cold sweats, faintness, dizziness -Headache -Tachycardia -Trembling, nervousness -Blurred vision -Hunger -Inability to awaken -Grouchiness -Personality change

Euglycemic DKA

-DKA with normal, or near normal, blood glucose (<250 mg/dL) -Precipitating factors include food restriction, alcohol intake, partial treatment, inhibition of gluconeogenesis -Thought to be rare, but may be the report of under-recognition and under-reporting -Fatal for patients with type 1 diabetes -Check for ketones in the urine

Duration of Action

-Described the duration of fasting blood glucose control and is of importance for deciding the dosing interval (i.e. once or twice daily dosing) -> BASAL -At least 24 hours is required for true once-daily basal insulin dosing

A1C Limitations

-Does NOT provide a measure of glycemic variability or hypoglycemia -For patients prone to glycemic variability, especially patients with T1D or T2D with severe insulin deficiency, glycemia control is best evaluated by combination of results from SMBG or CGM and A1C -May also inform the accuracy of patient's meter (or the patient's reported SMBG results) and the adequacy of the SMBG testing schedule

Insulin Therapy

-Exogenous insulin must mimic physiologic insulin secretion: Continuous low-level secretion between meals/through the night (basal), and incremental, stimulated insulin following meals (prandial/bolus) -Type 2 Diabetes: Needs basal insulin, more severe needs prandial insulin -Type 1 diabetes: Basal-Bolus insulin -GDM/Pregnancy: May require insulin

Glucagon Injection (Gvoke)

-FDA indicated age 2 and above -Auto-injector and pre-filled syringe are for subcutaneous injection only -Dose: Adults and pediatric patients aged 12 and older is 1 mg -Dose: Pediatric patients 2-12 is weight dependent -Weigh less than 45 kg (99 lbs) -- 0.5 mg -Solution should appear clear and colorless to pale yellow and be free of particles -Administer the injection in the lower abdomen, outer thigh, or outer upper arm -Call for emergency assistance immediately -When patient has responded to treatment, give oral carbohydrates -Each device contains single dose of glucagon and cannot be reused -If no response after 15 minutes, administer second dose while waiting for emergency assistance

Glucagon Nasal Powder (Baqsimi)

-FDA indicated age 4 and above -Dose is 3 mg administered as one actuation of the intranasal device into one nostril -Administer the dose by inserting tip into one nostril and pressing device plunger until green line is no longer showing (does not need to be inhaled) -Call for emergency assistance immediately -When patient responds give oral carbohydrates -Each device contains one dose of glucagon and cannot be reused -If no response after 15 minutes, as additional 3 mg dose may be administered while waiting for emergency assistance

Intermediate Acting Insulins (NPH)

-Human insulin (rDNA) isophane suspension -Available OTC -For type 1 diabetes, may be used as the basal component of basal-prandial regimens (analogs preferred) -An initial insulin option in type 2 diabetes, often as an add-on to oral agents -As type 2 diabetes progresses, may be used with mealtime rapid- or short-acting insulin with the largest meal -Onset 90 minutes -Administered via subcutaneous injection -Appears cloudy, a suspension; must be GENTLY mixed

Long Acting Insulins (Basal)

-Human insulin analogue (rDNA) -For type 1 diabetes, preferred as the basal component of basal prandial regimens -An initial insulin option in type 2 diabetes, often as an add-on to oral agents -As type 2 diabetes progresses, may be used with mealtime rapid- or short acting insulin with the largest meal (or with a GLP-1 RA) -Administered via subcutaneous injection -Appears clear and colorless

Insulin Mixes

-Human insulin analogue (rDNA) solution and protamine-crystallized human insulin analogue suspension -Others are huamn insulin (rDNA) solution and human insulin isophane suspension -Humulin 70/30 and Novolin 70/30 available OTC -Generally not appropriate for type 1 diabetes due to lack of dose flexibility -Consider for elderly patients with type 2 diabetes due to ease of use -Typically started after failure of basal insulin plus non-insulin -Given before breakfast and supper, or before breakfast, lunch, and supper -Administered via subcutaneous injection -Appears cloudy--GENTLY mix

TIDM

-In general, patients require 50% of their daily insulin as basal and 50% as prandial; treat with MDI (basal/bolus) or insulin pump (prandial insulin--rapid acting analogs perferred) -Total daily insulin requirements can be estimated based on weight, with typical doses ranging from 0.4 to 1.0 units/kg/day -Higher amounts are required during puberty, pregnancy, and medical illness -Typical starting dose of 0.5 units/kg/day in patients who are metabolically stable, with half administered as prandial insulin given to control blood glucose after meals and the other half as basal insulin to control glycemia in the periods between meal absorption -Physiologic insulin secretion varies with glycemia, meal size, and tissue demands for glucose (should be educated to match prandial insulin doses to carbohydrate intake, pre-meal blood glucose levels, and anticipated physical activity)

Insulin Stacking

-Increasing accumulation of insulin that can occur when additional doses of rapid-acting insulin are administered before the previous bolus dose has been completely absorbed -> Increased risk of hypoglycemia -Concern that once-daily administration of basal insulins with half-life >24 hours could contribute -> hypoglycemia

Metformin (Biguanides)

-Intestine: Increased anaerobic glucose metabolism -Liver: Decreased gluconeogenesis, glycogenolysis, FA oxidation -Skeletal Muscle: Increased insulin-mediated glucose uptake and glycogenesis, decreased FA oxidation -Overall, Decreased hyperglycemia -Only medication in this class -Might see shell of ER tabs in stool, concerns patients (warn ahead of time) -Available in combination with SFUs, glitazones, DPP4s, SGLT-2Is Clinical Pearls: -Start low and go slow, with meals to start, increase increments every 5-7 days -Max therapeutic dose is 2000 mg (goal) -Start with ER instead of IR to minimize GI and take once a day

Metformin (Biguanides)

-MOA: Activated AMP-kinase -Primary Action: Decreases hepatic glucose production (gluconeogenesis) and enhances insulin sensitivity in muscle and fat/peripheral tissue, decreases glucose intestinal absorption -First line for all patients -Advantages: Extensive experience, rare hypoglycemia, decreased CVD events, relatively higher A1C efficacy (1-1.5%), cheap, weight loss or weight neutral -Disadvantages: GI SFX, anorexia, metallic taste, abdominal cramps, vitamin B12 deficiency (long-term use, contraindicated GFR <30, acidosis, hypoxia, dehydration, rare lactic acidosis risk

GLP1 Receptor Agonists

-MOA: Activates GLP-1 receptors -Primary Action: Increases insulin secretion (glucose dependent), decreases glucagon secretion (glucose dependent), slows gastric emptying, increases satiety -Advantages: Rare hypoglycemia, weight loss, decreased postprandial glucose excursions, decreased CV risk factors, associated with lower CVD event rate and mortality in patients with CVD (liraglutide), A1C 1-1.8% -Disadvantages: GI SFX (NVD), increased HR, acute pancreatitis, C-cell hyperplasia/medullary thyroid tumors in animals (except lixisenatide), *contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2*, Injectable (except sema 9/19), training requirements, expensive -Adverse Effects: GI (diarrhea, nausea), may be associated with pancreatitis (rare)/gallbladder disease, Low risk of hypoglycemia, may lead to retinopathy complications -Weight loss -Injectable -Linked to thyroid cancer in rates -Avoid if GFR <45 (exenatide) -Reduces postprandial glucose -CV benefit Clinical Pearls: -Eat LESS: Minimizes N/V, daily vs. weekly dosing, lumps (Bydureon) -Short Acting: Postprandial lowering > Fasting (exenatide bid and lixisenitide) -Long Acting: Fasting lowering > postprandial -Safe in renal dysfunction (except caution with exenatide 30-50 and CL if <30)

Amylin Analog (Pramlintide)

-MOA: Activates amylin receptors -Primary Action: Decreases glucagon secretion, slows gastric emptying, increases satiety -Advantages: Decreased postprandial glucose excursions, weight loss -Disadvantages: Modest A1C efficacy, GI SFX (N/V), hypoglycemia unless insulin dose is simultaneously reduced, injectable, frequent dosing schedule, training requirements, expensive -Used with insulin

Dopamine 2 Agonists (Bromocriptine)

-MOA: Activates dopaminergic receptors -Primary Action: Modulates hypothalamic regulation of metabolism, increased insulin sensitivity -Quick release -Advantages: Rare hypoglycemia, decreased CVD events -Disadvantages: Modest A1C efficacy, dizziness/syncope, nausea, fatigue, rhinitis, expensive -May (theoretical) centrally reverse many of the metabolic changes that are associated with insulin resistance and obesity -Lowers A1C 0.5-1% -Other Effects: Hypotension, syncope (during dose titration) -Clinical Pearls: Not same as the formulation used for Parkinson's; Third Line -Adverse Effects: Fatigue, dizziness/syncope, nausea, rare hypoglycemia -Weight neutral -CYP 3A4 interactions

Insulins

-MOA: Activates insulin receptors -Primary Action: Increased glucose disposal, decreased hepatic glucose production, suppresses ketogenesis -Advantages: Nearly universal response, theoretically unlimited efficacy, decreased microvascular risk -Disadvantages: Hypoglycemia, weight gain, training requirements, patient and provider reluctance, injectable (except inhaled insulin), pulmonary toxicity (inhaled insulin), expensive -All are made by rRNA (HUMAN)

Thiazolidinediones (TZDs--glitazones)

-MOA: Activates the nuclear transcription factor PPAR-gamma in muscle, liver, and fat leading to changes in gene transcription -Primary Action: Increased insulin sensitivity--Decrease insulin resistance by making muscle and adipose cells more sensitive to insulin; also suppress hepatic glucose production (gluconeogenesis) -Advantages: Rare hypoglycemia, relatively higher A1C efficacy (1-1.5%), durability, decreased triglycerides, decreased CVD events, decreased risk of stroke and MI in patients without diabetes and with insulin resistance and history of recent stroke or TIA, cheap -Disadvantages: Weight gain, edema, black box heart failure (*contraindicated with class III or IV HF*), bone fractures, increased LDL-C, bladder cancer after 1 year -Pioglitazone (Actos), Rosiglitazone (Avandia) -Available in combination with metformin, glimepiride, alogliptin -Clinical Pearls: Start low, go slow; Delayed clinical effect 8-12 weeks; Slows progression of deterioration of β-cell function -Rosiglitazone lost popularity after an inaccurate meta-analysis was published claiming that it caused increase in CVD risk (Debunked -> CVOT) -Adverse Effects: Edema, weight gain, heart failure, increased fracture risk, increased LDL, possible increased risk of bladder cancer -Low risk of hypoglycemia -Glycemic control better sustained over diabetes course than metformin or sulfonylureas -Pioglitazone may improve lipid profile (e.g. Lower triglycerides) -Avoid in patients with symptomatic heart failure -CV benefit (pioglitazone)

Bile Acid Sequestrants (Colesevelam)

-MOA: Binds bile acids in intestinal tract, increasing hepatic bile acid production -Primary Action: Decreased hepatic glucose production, increased incretin levels (Primarily used for cholesterol, found to lower blood sugar), and decreases glucose absorption -Advantages: Rare hypoglycemia, decreased LDL-C, can use in patients in need of LDL lowering meds -Disadvantages: Modest A1C efficacy, constipation, Increased triglycerides, may decrease absorption of other medications (binds to everything--many DDIs), expensive -May reduce hepatic insulin resistance leading to reduction in hepatic glucose production -May effect molecular mediators of glucose metabolism -May reduce intestinal glucose absorption -Lowers A1C 0.5-1% -Lowers LDL up to 20%, increases TG -Clinical Pearls: Monitor for drug interactions (separate by 4 hours); Third line -Adverse Effects: GI (constipation, nausea, bloating), may increase triglycerides, rare hypoglycemia -Lowers LDL cholesterol, may decrease absorption of other meds

DPP4 Inhibitors (gliptins)

-MOA: Inhibits DPP4 activity, increasing postprandial incretin concentrations (gastric inhibitory polypeptide and glucagon-like peptide-1 are two primary incretin hormones secreted from intestine on ingestion of glucose or nutrients) -Primary Action: Increases insulin secretion in response to elevated blood glucose, decreases glucagon secretion, increases sense of fullness, and slows gastric emptying -Advantages: Rare hypoglycemia, well tolerated -Disadvantages: Angioedema/urticaria and other immune-mediated dermatological effects, increased acute pancreatitis, increased heart failure hospitalizations (saxa and alo), may cause severe joint pain, expensive, A1C 0.5-0.9% -Adverse Effects: May be associated with pancreatitis, new or worsening heart failure (alo, saxa), may cause severe joint pain -Low risk of hypoglycemia when used as monotherapy -Dosage modifications with renal impairment needed (except lina) -CYP3A4 interactions (saxa, lina) -Reduces postprandial glucose -Weight neutral -Generally well-tolerated

SGLT2 Inhibitors (gliflozins)

-MOA: Inhibits SGLT-2 in the proximal nephron -Primary Action: Blocks glucose reabsorption by the kidney, increasing glucosuria (increased urinary glucose excretion = lower plasma glucose levels) -Blocks 50-80 grams of glucose per day from being reabsorbed -Advantages: Rare hypoglycemia, weight loss, decreased BP, associated with lower CVD event rate and mortality in patients with CVD (MACE-also renal and HF outcomes) -Disadvantages: Genitourinary infections, polyuria, volume depletion/hypotension/dizziness, increased LDL-C, increased Cr (transient), diabetic ketoacidosis (DKA), UTIs -> Urosepsis, pyelonephritis, expensive -Being studied for use without diabetes in patients with renal failure, heart failure, and prevention of MACE -Lowers A1C 0.7-1% -Other Effects: Weight loss, decreased systolic BP, vaginal yeast infections (10%), genital mycotic infections, increased urination, dehydration, hyperkalemia, may increase LDL -Diuretic effect -> Stop/cut in half other diuretics Clinical Pearls: Yeast infections Renal Dosing: -AVOID USE if GFR < 45 (No renal toxicity but NEED renal function for therapeutic effect) -Adverse Effects: Genital fungal (yeast) infections, UTIs, ketoacidosis (rare), increased LDL/urination, Hyperkalemia--especially in patients with renal impairment, fractures, decrease in BMD, risk of bladder cancer/acute pyelonephritis, rare cases of Fournier's gangrene, amputations, -Weight loss -CV benefit (Prevents heart attack, strokes, MI, renal)

Alpha Glucosidase Inhibitors

-MOA: Inhibits intestinal α-glucosidase in the small intestine that hydrolyzes polysaccharides (starches) into simple sugars and therefore delays absorption of dietary CHO -Primary Action: Slows intestinal carbohydrate digestion/absorption -Acarbose (Precose), Miglitol (Glyset) Clinical Pearls: -Can only treat hypo with pure glucose (not table sugar--sucrose, won't be absorbed) -Take with meals that contain CHOs -Advantages: Rare hypoglycemia, decreased postprandial glucose excursions, decreased CVD events in prediabetes (STOP-NIDDM), Nonsystemic -Disadvantages: Generally modest A1C efficacy (0.5-1%), GI SFX (flatulence, bloating, diarrhea), frequent dosing schedule, moderately expensive -Adverse Effects: GI (flatulence, diarrhea), low risk of hypoglycemia when used as monotherapy -Weight neutral -Taken with meals -Reduces postprandial glucose -Requires frequent dosing -Beneficial in treatment of pre-diabetes

Insulins

-MOA: Promotes storage of glucose in muscle and fat tissues, and inhibits production of glucose -Adverse Effects: Hypoglycemia, highest risk of weight gain -Consider initial therapy with metformin if blood glucose is >300 mg/dl or if A1C is >10%

Sulfonylureas (2nd generation)

-MOA: Stimulates pancreatic insulin secretion -Adverse Effects: Hypoglycemia especially with renal dysfunction, weight gain -Avoid in elderly -Discontinue when more complex insulin regimens are started (basal plus prandial insulins) -Relatively short-lived efficacy -Start with low doses and titrate up for elderly and those with hepatic or renal dysfunction -Advantages: Extensive experiences, decreased microvascular risk, relatively higher A1C (1-1.5%) efficacy, cheap -Disadvantages: Hypoglycemia, increased weight, reduced efficacy over time Clinical Pearls: -Not preferred by ADA or AACE, esp elderly/renal impairment -Dose adjustment in renal dysfunction/hepatic impairment -Highest hypoglycemia with glyburide (longest T 1/2 and active metabolite), taken with food to minimize hypoglycemia -Cheap

CVOT

-Multiple large RCTs reporting statistically significant reduction in CV events in patients with TIIDM with SGLT-2 (Empagliflozin, Canagliflozin, Dapagliflozin) or GLP-1RAs (Liraglutide, Semaglutide, Dulaglutide) -These drugs all had beneficial effects on indices of CKD -The subjects enrolled using Empagliflozin, Canagliflozin, Liraglutide, Semaglutide had A1C >6.5% and >70% were taking Metformin at baseline; thus practical extension of these results to clinical practice is to use these drugs preferentially -For these patients, incorporating one of the SGLT2 inhibitors or GLP-1 RAs that have been demonstrated to have CVD benefit is recommended

Onset of Action

-Not of high importance when considering prescribing newer long-acting basal insulins because the duration of action of newer basal insulins covers or exceeds 24 hours, and are dosed at steady state

Rapid Acting Insulins

-Onset 10-30 minutes (Fiasp faster) (Prandial insulin) -For type 1 diabetes, recommended at each meal (three or more injections daily) with one or two injections of basal insulin -For type 2 diabetes, once daily at largest meal plus basal insulin, or basal-bolus regimen (two/three times daily with meals plus basal insulin) -All are given via subcutaneous injection except Afrezza (inhaled) -All are clear and colorless

TIIDM

-Preferred to start GLP-1RA over insulin--if already using GLP-1RA or a GLP-1RA not appropriate OR insulin is preferred: -Add basal analog or bedtime NPH: Initiate 10 units a day or 0.1-0.2 units/kg/day; titrate 2 units every 3 days tor each a fasting target without hypoglycemia (U100) (titrate every 3-5 days for ultralong acting Degludec/U300 glargine); For hypoglycemia, determine cause, of no reason lower dose by 10-20%; Evaluate for overbasalization (>0.5 U/kg) -If A1C above goal: Add GLP-1RA if not already taking (lower basal dose) or Add prandial insulin, one dose with largest meal (start with 4U or 10% of basal dose and if A1C is lower than 8% consider lowering the basal dose by the same amount; titrate by 1-2 U or 10-15% twice weekly; for hypoglycemia with unknown cause lower by 10-20%); If on NPH at bedtime, consider converting to twice a day (ex. take 80% current dose and give 2/3 in the AM and 1/3 at bedtime) -If above A1C target: Stepwise approach (2 then 3 injections--meal time); go to full basal bolus; consider NPH bid and rapid acting/short acting with 2 meals; consider Premixed insulin regimen

Meglitinides (glinides)

-Repaglinide (Prandin) with meals -Nateglinide (Starlix) -Start low, go slow

Meglitinides (glinides)

-Similar MOA and ADRs to SFUs -MOA: 'Squeezes' pancreas to release insulin -Primary Action: Increased insulin secretion -Advantages: Decreased postprandial glucose excursions, dosing flexibility (short-acting) -Disadvantages: Hypoglycemia, weight gain, (both less than SFUs), frequent dosing schedule, A1C 0.5-1% -Reduces postprandial glucose -Provides flexible dosing (e.g. can hold dose if skipping meal) -Consider over sulfonylureas (less hypoglycemia, better postprandial control)

Insulin Concentration

-U100 = 100 units/ml (most insulins) -U500 = 500 units/ml (regular insulin): Different kinetics than regular U100 insulin--mimics NPH kinetically, smaller volume (1/5) -Lispro U200 = 200 units /ml (Rapid acting insulin): Identical PK to lispro U100, smaller volume (1/2) -Glargine U300 = 300 units/ml (Basal insulin): Longer DOA than glargine U100, different PK, smaller volume (1/3) -Degludec U200 = 200 units/ml (basal insulin): Identical PK to degludec U100, smaller volume (1/2)

Premixed Insulins

70/30 N/R and 50/50 N/R NPL/Lispro 75/25, 50/50 Aspart protamine/Aspart 70/30

Amylin

A hormone co-secreted with insulin by pancreatic β-cells at meal time, that decreases glucagon secretion, slows gastric emptying, and increases satiety

E

A patient with uncontrolled T2DM without ASCVD or CKD/HF needs another agent added to their regimen. They are concerned about weight gain. According to the ADA 2021 guidelines which of the following agents should be added after Metformin in patients who need to minimize/avoid weight gain? A. Sulfonylurea only B. Glitazone only C. SGLT-2 inhibitor only D. GLP-1 Receptor Agonist only E. Either a SGLT-2I or GLP-1RA

Steady State

A state in which rate of absorption equals the rate of elimination, so that the system is not changing over time -Typically obtained within 4-5 half-lives -Important for chronically administered drug products, like LA basal insulin analogs (*U300 glargine, U100/U200 degludec only*) -Insulin levels are not expected to further increase unless the dose or dosing interval is changed -Attempts to mimic the physiological profile of endogenous basal insulin secretion by providing constant plasma insulin profile -Basal insulins with longer half-lives will take longer to reach than shorter acting basal insulin -When dose adjustments of long-acting basal insulin is needed, *daily dose changes are NOT recommended* because the effect will only become apparent after a couple of days

PPG (Prostaprandial Plasma Glucose)

A1C < 8.4%: _______ contributes 50% or more to hyperglycemia

FPG (Fasting Plasma Glucose)

A1C > 8.4%: _________ contributes 50% or more to hyperglycemia

Linagliptin

All DPP-4 Inhibitors must be renal dosed EXCEPT for _____________

DPP4 Inhibitors (gliptins)

Alogliptin (Nesina) Linagliptin (Tradjenta) Saxagliptin (Onglyza) Sitagliptin (Januvia)

Acarbose, Miglitol (Precose, Glyset)

Alpha Glucosidase Inhibitors

Pramlintide

Amylin analog

Glargine

Basal insulin with same dosing but U300 and U100 have different pharmacokinetics, the U300 has longer duration of action -U300 forms a precipitate (compact depot) from which small amounts of insulin are slowly released, smaller volume -U300 1/3 the injection volume as U100

Colesevelam

Bile acid sequestrant

A1C

Blood test that measures glycosylated hemoglobin (HbA1c) to assess glucose control; estimates average glucose

Dopamine 2 Agonist

Bromocriptine

SGLT2 Inhibitors (gliflozins)

Canagliflozin (Invokana) Dapagliflozin (Farxiga) Empagliflozin (Jardiance) Ertugliflozin (Steglatro)

SGLT2 Inhibitors (gliflozins)

Class of anti-diabetic drug specified in the diabetic guidelines to be prescribed in patients with heart failure

SGLT2

Co-transporter found in PCT responsible for reabsorbing 90% of glucose back into pulmonary circulation

Bile Acid Sequestrants

Colesevelam

Alogliptin, Linagliptin, Saxagliptin, Sitagliptin

DPP-4 Inhibitors

Bromocriptine

Dopamine 2 Agonist

GLP1 Receptor Agonists

Dosing Information: -Lixisenitide: Give up to 60 minutes before first main meal of the day -Exenatide bid: Give up to 60 minutes before the 2 main meals of the day -Liraglutide: Give once a day, regardless of meal, about the same time daily -Semaglutide (PO): Give on an empty stomach with no more that 4 ounces of water, nothing else for at least 30 minutes -Weekly injectables--give once a week same day

GLP1 Receptor Agonists

Drug class injected subcutaneously (first oral just came out) that mimics GLP-1 and is resistant to DPP-4 degradation, prolonging effects

GLP1

Endogenous peptide hormone that is secreted in response to food and functions to: -Decrease appetite in the brain -Slow gastric emptying of the stomach -Stimulate insulin secretion and suppress glucagon secretion in the pancreas 1-2 minute half-life; broken down by DPP-4

DPP4

Enzyme that breaks down GLP-1

GLP1 Receptor Agonists

Exenatide Liraglutide Lixisenatide Dulaglutide Semaglutide

Metformin (Biguanides)

FDA Dosing Recommendations: -Patients with GFR >60 ml/min require no dose adjustments and are able to safely use with annual monitoring -Patients with GFR between 45-60 ml/min may continue treatment but require more frequent renal function monitoring every 3-6 months -Do NOT initiate in patients with moderate chronic kidney disease (GFR 30-45 ml/min); consider 50% dose reduction in patients already taking medication -Contraindicated in advanced kidney disease (GFR <30 ml/min) -Discontinue at time of or before an iodinated contrast imaging (radiocontrast media) procedure in patients with GFR between 30-60 ml/min; in patients with Hx of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast -Re-evaluate GFR 48 hours after the imaging procedure; restart medication if renal function is stable

Liraglutide

GLP1 Receptor Agonist shown to have mortality benefits in patients with CVD

Exenatide, Liraglutide, Lixisenatide, Dulaglutide, Semaglutide

GLP1 Receptor Agonists

Long Acting Insulins

Glargine (Lantus U100, Basaglar) Detemir (Levemir) Glargine (Toujeo U300) -Onset 6 hours Degludec (Tresiba U100 & U200) Duration 42 hours Onset: 1-2 hours Peak: None Duration: ~24 hours

Long Acting Insulins (Basal)

Glargine (Lantus, Basaglar): 100 U/ml -Duration: 10.8-<24 hours Glargine (Toujeo): 300 U/ml -Duration: <36 hours Degludec (Tresiba): 100, 200 U/ml -Duration: <42 hourterm-119s Detemer (Levemir): 100 U/ml -Duration 5.7-<24 hours

Sulfonylureas (2nd generation)

Glyburide, Glipizide, Glimepiride

Glucagon

Hormone used to increase blood glucose level during hypoglycemic episode -For decades only available as injection that needs to be mixed -Two formulations approved in 2019: Auto-injector & prefilled syringe (Gvoke) and dry nasal powder (Baqsimi)

Short Acting Insulins (regular)

Humulin R (100U) -Duration: 4-12 hours Humulin R (500U) -Duration: ~21 hours Novolin R -Duration: 8 hours -Frequency: 1-3X, inject 30 minutes before meal

Intermediate Acting (NPH) Insulins

Humulin-N Novolin-N Onset: 1-2 hours Peak: 3-13 hours Duration: Up to 24 hours

Short Acting (R) Insulins

Humulin-R Novolin-R Onset: ~30m Peak: 1-3 hours Duration: ~8 hours

Less Stringent (<8%)

Individualization of Glycemic Targets for Adults with Diabetes: Lowering A1C below or around 7.0% shown to reduce microvascular complications and macrovascular disease -Severe hypoglycemia history -Limited life expectancy -Advanced microvascular/ macrovascular complications -Extensive comorbidities -Long-term diabetes in whom general A1C target difficult to attain

More Stringent (<6.5%)

Individualization of Glycemic Targets for Adults with Diabetes: Lowering A1C below or around 7.0% shown to reduce microvascular complications and macrovascular disease -Short diabetes duration -Long life expectancy -No significant CVD/vascular complications

Rapid Acting Insulins

Insulin lispro (Admelog, Humalog) Insulin Aspart (Novolog) Insulin Glulisine (Apidra) Insulin Aspart (Fiasp) -> IV (not pump reservoir) -Onset: 10-30 minutes -Duration: 3-5 hours -Frequency: 1-3 times daily before/immediately after a meal

Pump Reservoir

Insulin lispro (Admelog, Humalog), insulin aspart (Novolog), Insulin glulisine (Apidra)

Humulin, Novolin (N)

Intermediate acting insulins

E

JM is a 59 y/o male with diabetes, hypertension, hyperlipidemia. He had a MI 3 years ago. According to the ADA 2021 guidelines which of the following agents should be added after Metformin in patients with established/predominant ASCVD? A. Sulfonylurea B. Glitazone C. SGLT-2 Inhibitor D. GLP-1 Receptor Agonist E. Either an SGLT-2I or GLP-1RA

SGLT2 Inhibitors (gliflozins)

Key Points: -Inhibits SGLT2 in proximal nephron blocking the reabsorption of glucose leading to glucose urea -Positive CV outcomes/renal outcomes -Yeast infections, UTIs, DKA, Fourniers, amputations -Lowers BP--Stop/lower thiazides/other diuretics

D

LG is a 55 year old female with diabetes, hypertension and a recent diagnosis of heart failure. According to the ADA 2021 guidelines which of the following agents should be added after Metformin in patients with established/predominant heart failure? A. Basal insulin B. Sulfonylurea C. GLP-1 Receptor Agonist D. SGLT-2 Inhibitor E. Either a SGLT-2i or GLP-1RA

D

MT is a 66 y/o male with diabetes, hypertension, hyperlipidemia, COPD, and Chronic Kidney Disease with albuminuria (DKD). According to the ADA 2021 guidelines which of the following agents should be added after Metformin in patients with established/predominant CKD and albuminuria? A. Basal insulin B. Sulfonylurea C. GLP-1 Receptor Agonist D. SGLT-2 Inhibitor E. Either a SGLT-2i or GLP-1RA

Repaglinide, Nateglinide (Prandin, Starlix)

Meglitinides

Basal-Bolus Insulin

Mimics Physiology -In healthy individual, pancreas releases background insulin (basal) 24 hours a day at a fairly constant, low rate, post-meal insulin spikes (bolus) in response

Intermediate Acting Insulins (NPH)

Novolin N Humulin N -Duration: Up to 24 hours -Frequency: Once/twice daily -Subcutaneous injection

Insulin Mixes

Novolog Mix 70/30 (Insulin aspart protamine suspension/insulin aspart solution) Humalog Mix 75/25 (insulin lispro protamine suspension/insulin lispro solution) Humalog Mix 50/50 (Insulin lispro protamine suspension/insulin lispro solution) Humulin 70/30 (NPH/rgular) Novolin 70/30 (NPH, regular) -Duration: Up to 24 hours -Frequency: 15 minutes before breakfast/dinner, or breakfast/lunch/dinner -Subcutaneous injection

TIIDM

Pharmacologic Therapy: -Metformin is the preferred initial pharmacologic agent -Once initiated, Metformin should be continued as long as it is tolerated and not contraindicated; other agents, including insulin should be added to Metformin -Early combination therapy can be considered in some patients at treatment initiation to extend the time to treatment failure -The early introduction of insulin should be considered if there is evidence of ongoing catabolism (weight loss), if symptoms of hyperglycemia are present, or when A1C levels (>10%) or blood glucose levels (>300 mg/dL) are very high -A patient-centered approach should be used to guide the choice of pharmacologic agents; considerations include effect on CV and renal comorbidities, efficacy, hypoglycemia risk, impact on weight, cost, risk for side effects, and patient preferences -Among patients with ___ who have established atherosclerotic CVD or indicators of high glucose cotransporter 2 inhibitor or glucagon-like peptide 1 receptor agonist with demonstrated cardiovascular disease benefit is recommended as part of the glucose-lowering regimen independent of A1C and in consideration of patient-specific factors -In pts with ___, a glucagon-like peptide 1 receptor agonist is preferred to insulin when possible -Recommendation for treatment intensification for patients not meeting goals should not be delayed -The medication regimen and medication-taking behavior should be reevaluated at regular intervals (every 3-6 months) and adjusted as needed to incorporate specific factors that impact choice of treatment -Clinicians should be aware of the potential for overbasalization with insulin therapy; clinical signals include basal dose more than ~0/5 IU/kg, high bedtime-morning or post-preprandial glucose differential, hypoglycemia (aware or unaware), and high variability; indication of overbasalization should prompt reevaluation to further individualize therapy

TIDM

Pharmacologic Therapy: -Most people should be treated with multiple daily injections of prandial and basal insulin OR continuous subcutaneous infusion (insulin pump) -Most individuals should use rapid-acting insulin analogs to reduce hypoglycemia risk -Patients should be trained to match prandial insulin doses to carbohydrate intake, premeal blood glucose, and anticipated physical activity

Amylin Analog

Pramlintide

TIIDM

Progressive disease involving multiple metabolic abnormalities -Pancreas β-cells: Decreased insulin secretion -Fat: Increased free FA (lypolysis) -Brain: Neurotransmitter dysfunction -Intestine: Decreased Incretin effect -Kidney: Increased glucose reabsorption -Pancreas α-cells: Increased glucagon secretion -Liver: Increased endogenous glucose production -Muscle: Reduced glucose uptake

A

RG is a 42 y/o female taking Metformin. She needs additional therapy. She had a hypoglycemic reaction in the past and doesn't remember which drug it was but she stopped taking it. According to the ADA 2021 guidelines which of the following agents should be AVOIDED in patients who want to avoid hypoglycemia? A. Sulfonylurea B. GLP-1 Receptor Agonist C. Glitazone D. SGLT-2 Inhibitor E. Avoid either a SGLT-2i or GLP-1RA

Aspart, Glulisine, Lispro, Afrezza (inhaled)

Rapid Acting insulins

Canagliflozin, Dapagliflozin, Empagliflozin, Ertugliflozin

SGLT2 Inhibitors

Humulin, Novolin (R)

Short acting insulins

TIIDM

Some Considerations: -GLP-1RA is first for MOST -Consider insulin as first injectable if catabolism, symptoms of hyperglycemia, A1C >10% or BG are very high (>300) or suspected TIDM (early insulin use!) -Select GLP-1RA based on patient preference, A1C lowering, weight lowering, frequency of injection or if ASCVD--choose with proven benefit -For patients on both GLP-1RA and basal insulin consider a fixed ratio combination (iDegLira or iGarLixi) -Progressive nature of diabetes -> Most will eventually require insulin (NEVER use as a threat!)

Glyburide, Glipizide, Glimepiride

Sulfonylureas 2nd generation

Pioglitazone, Rosiglitazone (Actos, Avandia)

Thiazolidinediones

Glargine (Toujeo U300), Degludec (Tresiba U100 & U200)

Ultra-long acting basal insulins >24 hrs and 42 hrs hours respectively

Humulin R U500

Used when -TDD >200 units -Requires much smaller volume -Can reduce number of daily injections -SAME DOSE AS U100, smaller amount (volume wise)