Pt Care 5: Module 1 - 2: Diabetes Mellitus and Adrenal, Thyroid and Parathyroid

Module 1: Diabetes Mellitus

Module 1: Diabetes Mellitus

Hemoglobin A1C

Measures glycated RBCs, reflects glucose level over last 2-3 months

Fructosamine

Measures glycated protein, reflects glucose level over last 2-3 weeks

- Used when A1C test is unreliable due to certain disease states like anemia

Hormones Regulating carbohydrate and lipid levels

Pancreas

• Insulin

- Net Effects: Glucose, lipid storage

- Sites of Action: Liver, fat, skeletal muscle

• Glucagon

- Net Effects: glucose production

- Sites of Action: Liver, fat, skeletal muscle

• SST (somatostatin)

- Net Effects: Regulates insulin, glucagon

- Sites of Action: Pancreas

• Amylin

- Net Effects: Inhibits glucagon

- Sites of Action: Brain

Pituitary

• GH (growth hormone)

- Net Effects: Glucose production

- Sites of Action: Liver

Adrenal

• Epinephrine

- Net Effects: Glucose production

- Sites of Action: Liver, fat, skeletal muscle

• Cortisol

- Net Effects: Glucose production

- Sites of Action: Liver, fat, skeletal muscle

GI Tract

• GLP-1, GIP, Gastrin, Secretin, CCK

- Net Effects: Alter insulin secretion

- Sites of Action: Pancreas

What hormone(s) increase glucose production?

Glucagon, EPI, cortisol, Growth hormone

Insulin synthesis

• Formed from a bigger peptide and cleaved into (1) INSULIN & (2) C-PEPTIDE

- Can use C-peptide levels to indirectly figure out insulin levels since they are made in a 1:1 ratio

• Synthesized in the rough ER, transported to golgi and then secreted

• C-peptide does NOT have biological activity

• Secreted insulin composes 2 polypeptide chains (A chain and B chain) linked by disulfide bonds

What level can be used an indirect measure of insulin?

C-peptide levels

Normal Insulin Secretion

• Insulin is always being secreted that breaks down glucose that is constantly being released by liver

• Insulin release after each meal

Physiological Functions of Insulin

• Anabolic effects (BUILDS UP)

➢ Increases glucose uptake in the liver for synthesis of glycogen.

➢ Increases triglyceride storage in adipose tissue.

➢ Stimulates protein synthesis from amino acids in skeletal muscle.

• Secreted together w/ amylin which inhibits glucagon, slows gastric emptying and increases satiety

What is secreted together with insulin?

Amylin

Amylin

• Secreted together with insulin from pancreatic β cells

• Works with insulin to regulate postprandial glucose concentration

• Suppress postprandial glucagon secretion

• Slows gastric emptying, increases satiety, decreases appetite, leading to decreased glucose uptake

• Pramlintide is an analog of human amylin to treat diabetes

Incretin Hormones

GLP-1 (glucagon-like peptide)

★ Cells secreting: Intestinal L cells: Small bowel and colon (stimulators: AA, fiber, sweeteners, sugars > Glucose > FA

★ Effects:

• Stimulates insulin (w/ glucose) - w/o causing hypoglycemia

• Inhibits gastric emptying

• Decreases food intake

• Inhibits glucagon secretion

• Slows glucose production

• Protect β-cells from apoptosis

• Stimulate β-cell proliferation

GIP (gastrin inhibitory peptide OR glucose-dependent insulinotropic peptide)

★ Cells secreting: Intestinal K cells: Duodenum jejunum (stimulators: Fat > Glucose)

★ Effects:

• Stimulates insulin (w/ glucose) - w/o causing hypoglycemia

• Enhances insulin-stimulated incorporation of FA to TG

• Stimulates LPL activity

• Modulates FA synthesis

• Promotes β-cell proliferation and cell survival

GLP-1 (glucagon-like peptide)

★ Cells secreting: Intestinal L cells: Small bowel and colon (stimulators: AA, fiber, sweeteners, sugars > Glucose > FA

★ Effects:

• Stimulates insulin (w/ glucose) - w/o causing hypoglycemia

• Inhibits gastric emptying

• Decreases food intake

• Inhibits glucagon secretion

• Slows glucose production

• Protect β-cells from apoptosis

• Stimulate β-cell proliferation

GIP (gastrin inhibitory peptide OR glucose-dependent insulinotropic peptide)

★ Cells secreting: Intestinal K cells: Duodenum jejunum (stimulators: Fat > Glucose)

★ Effects:

• Stimulates insulin (w/ glucose) - w/o causing hypoglycemia

• Enhances insulin-stimulated incorporation of FA to TG

• Stimulates LPL activity

• Modulates FA synthesis

• Promotes β-cell proliferation and cell survival

GLP-1 is secreted by __ cells and GIP is secreted by __ cells.

L; K

Medications for Type 2 Diabetes

• Biguanides

- Metformin

• Sulfonylureas

- Glimepiride

- Glipizide

- Glyburide

• Thiazolidinediones (TZD)

- Pioglitazone

- Rosiglitazone (not used)

• Dipeptidyl peptidase-4 (DPP4) Inhibitors

- Alogliptin

- Linagliptin

- Saxagliptin

- Sitagliptin

• GLP-1 receptor agonist (oral)

- Semaglutide

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

- Canagliflozin

- Dapagliflozin

- Empagliflozin

- Ertugliflozin

• Meglitinides

- Netaglinide

- Repaglinide

• Alpha-glucosidase inhibitors

- Acarbose

- Miglitol

• Bromocriptine

• Colesevelam

Normal Glucose Homeostasis

(See Image)

Symptoms of diabetes

• Blurred vision

• UTI

• Yeast infections

• Dry, itchy skin

• Numbness/tingling inextremities

• Fatigue

• Polyuria

• Polyphagia

• Polydipsia

• Unexplained weight loss

What are the autoantibodies associated with T1D?

❖ ICA (islet cell autoantibodies) found in 70-85% of patients;

❖ IAA (insulin autoantibodies)

❖ GAD antibodies (glutamic acid decarboxylase)

❖ IA-2 antibodies to protein tyrosinephosphatase

LADA

• Latent Autoimmune Diabetes in Adults

• Responsible for up to 10% of insulin-requiring cases in older patients

• Slow, progressive form of type 1 DM often confused with type 2 DM

• Presentation may include lean body mass, family history of type 1 DM

• C-peptide for insulin production status would be 0 or low since LDA is more related to T1D

• Presence of auto-antibodies (IAA, ICA, GAD, IA-2)

Stages of Type 1 Diabetes

• Stage 1:

- B-cell autoimmunity

- Normoglycemia

- Presymptomatic

• Stage 2:

- B-cell autoimmunity

- Dysglycemia

- Presymptomatic

❖ Can start teplizumab (Tzield) which will delay the onset of stage 3 T1D

• Stage 3:

- B-cell autoimmunity

- Dysglycemia

- Symptomatic (Polydispsia, polyphagia, and polyuria)

Beta cell desensitization in T2D

There is reduced GLUT-2 expression

Risk Factors for T2D

❖ Obesity (80-90%)

❖ Family history of diabetes, first-degree relative with diabetes

❖ History of gestational diabetes

❖ Impaired glucose metabolism, A1C ≥ 5.7%

❖ Physical inactivity

❖ Race/ethnicity

❖ History of CVD

❖ Hypertension (≥140/90 mmHg or on therapy for hypertension)

❖ HDL cholesterol level ≤ 35 mg/dL and/or a triglyceride level ≥ 250 mg/dL

❖ Women with polycystic ovary syndrome (relates to insulin resistance)

There is reduced _________ in skeletal muscle and fat in T2D which decreases glucose uptake in skeletal muscle and fat tissue.

GLUT-4

Type 2 Diabetes Pathophysiology

(See image)

• Beta cell desensitization: reduced GLUT-2 expression

• Reduced GLUT-4 in skeletal muscle, fat.

• Reduced insulin receptor in liver.

• Increased glucagon secretion

Why does the B-cell fail in T2D?

• Glucotoxicity

• Lipotoxicity

• Oversecretion of insulin

There is reduced _____________ receptor in the liver which causes decreased glycogenesis, and increased glycogenolysis and gluconeogenesis?

insulin

β cell Function Loss in Type 2 Diabetes

Gradually lost of β cell function during diabetes development serves as the rational for drug therapy:

• Insulin stimulating/sensitizing drugs at initial stage due to preserved β cell function

• Eventually insulin therapy due to β cell failure

1. Impaired glucose tolerance (IGT)

2. Postprandial hyperlgycemia

3. T2DM diagnosis

4. T2DM Phase II

5. T2DM Phase III

In impaired glucose tolerance (IGT) there is _________ insulin secretion and in T2DM there is ________ insulin secretion due to B-cell damage.

increased; decreased

(IGT progresses into T2DM)

With low A1C you target _______ and with high A1C you target ________.

PPG (postprandial glucose): FPG (fasting plasma glucose)

What hormone is unusually high in those with T2DM postprandially?

Glucagon

Women who have had gestational diabetes have a...

... 20-50% chance of developing diabetes in the next 5 - 10 years.

Drug induced hyperglycemia:

◦ Atypical Antipsychotics - Alter receptor binding characteristics, leading to increased insulin resistance.

◦ Beta-blockers - Inhibit insulin secretion.

◦ Calcium Channel Blockers - Inhibits secretion of insulin by interfering with calcium release.

◦ Corticosteroids - Cause peripheral insulin resistance and gluconeogenesis.

◦ Niacin - Increased insulin resistance due to increased free fatty acid mobilization.

◦ Protease Inhibitors - Inhibit the conversion of pro-insulin to insulin.

◦ Thiazide Diuretics - Inhibit insulin secretion due to hypokalemia, also cause increased insulin resistance due to increased free fatty acid mobilization

Chronic Complications of Diabetes

Microvascular abnormalities:

• Diabetic retinopathy leading to blindness

• Diabetic nephropathy leading to chronic kidney disease (leading cause of end stage renal disease in US)

Macrovascular abnormalities: accelerated atherosclerosis (↑ LDL)

• Increased incidence of cerebrovascular disease (stroke)

• Increased risk of coronary artery disease (myocardial infarction)

• Increase in peripheral vascular atherosclerosis

Neuropathic abnormalities, diabetic neuropathy

• Involve the ANS and PNS: both motor and sensory

• Pain, numbness or impaired sensory/motor function

• Can be progressive

• Ulceration and gangrene in extremities (esp feet) can occur due to infection + poor perfusion + neuropathy

Med Chem: Biguanides

• True mechanism unclear but some ideas...

– AMPK activator which causes a cascade of events that leads to....inhibition of hepatic gluconeogenesis and improving insulin sensitivity

• Chemical structure consists of 2 guanides

Med Chem: SGLT2i's

• -gliflozin

• Blocks the reabsorption of glucose and sodium

• Structure Activity relationship:

- Has a sugar moiety and an aglycone

- The o-glycoside is replaced by a c-glycoside to increase selectivity and stability

- Has a methylene linker (a 1 carbon linker between two rings) which is optimal

- Has a lipophilic substituent (methyl, chlorine, fluorine, etc.) in the 4 position (PARA) of BOTH rings is essential for SGLT2 inhibition

• (Least Potent) Canagliflozin < Dapagliflozin < Empagliflozin (most potent)

Para, meta and ortho subsitution

Lipophilic substituent in the 4 position (PARA) is most optimal for SGLT2i's

Med Chem: GLP-1A

• Gut hormone secreted by L-cell in the gut

• Susceptible to cleavage at the Ala amino acid by DPP4

• How to prevent quick excretion or metabolism?

– Conjugate to albumin which rarely leaves the bloodstream, usually done by conjugating a fatty acid which likes to bind to albumin

➢ Semaglutide (FA conjugation)

➢ Liraglutide (FA conjugation)

➢ Albiglutide (albumin conjugation)

– Ala substitution to prevent recognition by DPP-4

➢ Exenatide (Gly) - including extended-release formulation

➢ Semaglutide (Aib) - including oral formulation

➢ Lixisenatide (Gly)

➢ Albiglutide (Gly)

➢ Dulaglutide (Gly)

– Antibody conjugation

➢ Dulaglutide (dual bound to IgG4 Fc)

Med Chem: Exenatide

• Has an alanine substitution (with glycine)

Med Chem: Semaglutide

• Has a alanine substitution (with Aib, an unnatural AA)

• Has a fatty acid conjugation which binds to albumin to prevent excretion

Med Chem: Liraglutide

• Has a fatty acid conjugation which binds to albumin to prevent excretion

Med Chem: Lixisenatide

• Has an alanine substitution (with glycine)

• Has a polylysine tail (x number of lysine in name)

Med Chem: Albiglutide

• Has an alanine substitution (with glycine)

• Directly conjugated to albumin

Med Chem: Oral semaglutide

• Has a alanine substitution (with Aib, an unnatural AA)

• Has a fatty acid conjugation which binds to albumin to prevent excretion

• Co-formulated with SNAC

Med Chem: ER-Exenatide

• Has an alanine substitution (with glycine)

• Polymers are bound to several sites

Med Chem: Dulaglutide

• Has an alanine substitution (with glycine)

• Dual bound to 2-antibodies that are similar to albumin

Med Chem: DPP4 inhibitors

• Agents: -gliptans

➢ Saxagliptan

• α/β-hydrolase is the main catalytic region of DPP4

• DPP4 is a serine exo-peptidase (cleaves at the ends of the protein) that inactivates incretins

• The mechanism is catalyzed by a catalytic triad

1. Serine = nucleophile

2. Histidine = acts as base/acid

3. Aspartic acid = stabilizes histadine

• Saxagliptin undergoes a pinner reaction since it has a pyrrolidine group which is bound to a nitrile group (CN - triple bond)

• If you have a pyrrolidine molecule aka saxagliptin (dark blue nitrogenous ring in saxagliptan), it binds to S1, S2 and S2 extensive

• Trifluorophenyl moieties or analogs = sitagliptin it binds to S1, S2 and S2 extensive

• Pyrimidine-2,4-dione or analogs = linagliptin it binds to S1, S2, S1' and S2'

Groups of -gliptans (DPP4 inhibitors)

• Pyrrolidine molecule = saxagliptin

➢ Binds to S1, S2 and S2 extensive

➢ Undergoes pinner reaction

• Trifluorophenyl moieties = sitagliptin

➢ Binds to S1, S2 and S2 extensive

• Pyrimidine-2,4-dione = linagliptin

➢ Binds to S1, S2, S1' and S2'

Pyrrolidine molecule = saxagliptin

➢ Binds to S1, S2 and S2 extensive

➢ Undergoes pinner reaction

Trifluorophenyl moieties = sitagliptin

➢ Binds to S1, S2 and S2 extensive

Pyrimidine-2,4-dione = linagliptin

➢ Binds to S1, S2, S1' and S2'

Pinner Reaction

• Saxagliptin undergoes a pinner reaction since it has a pyrrolidine group which is bound to a nitrile group (C≡N)

• The Pinner reaction is a chemical reaction where nitriles react with alcohols in the presence of an acid catalyst to form imino ethers (also known as Pinner salts), which can then be further reacted to produce various products like amidines, esters, or orthoesters.

Med Chem: Thiazolidinediones (TZDs)

• glitazone drugs

• Thiazolidinedione scaffold

• Binds to ppar-gamma (transcription factor) to induce gene transcription

• Binds to omega pocket and Tyrosine 473

Med Chem: Sulfonylureas

• Lower blood sugar by stimulating the release of insulin from pancreatic beta cells, primarily by binding to and closing ATP-sensitive potassium (KATP) which has a sulfonylurea receptor 1 (an octameric complex that contains a sulfonylurea binding site and a benzamido binding site) channels, which leads to cell depolarization, calcium influx, and ultimately, insulin secretion

• Contains a sulfonyl group (O=S=O) and urea (ketone with two nitrogens connected to it) connected to a phenyl with an x-substituent in the para-position

➢ 1st Gen: X = CH3, Cl or NH2

➢ 2nd Gen: X = ethyl connected to an amide

• 1st Gen = Tolbutamide

➢ Binds to ONLY SU binding site

• 2nd Gen = Glyburide, Glipizide, Glimepiride

➢ Binds to BOTH SU binding site and benz/carbox-amido-binding site

Tolbutamide (1st Gen sulfonylurea) vs 2nd Gen Sulfonylureas

• 1st Gen = Tolbutamide

➢ Binds to ONLY SU binding site

• 2nd Gen = Glyburide, Glipizide, Glimepiride

➢ Binds to BOTH SU binding site and benz/carbox-amido-binding site

Med Chem: Meglitinides

• Repaglinide and meglitinide binds to Benz/carboxy-amido-binding site

• Nateglinide binds to SU binding site (like tolbutamide)

Med Chem: Alpha-glucosidase inhibitors

• Drugs

– Acarbose, Miglitol

• Looks like a sugar and the nitrogen is hard to break through, so it stays stuck to the alpha-glucosidase enzyme and occupies it

• How does it work?

– Blocks the breakdown of sugar oligomers into monomers by competitive inhibition of alpha-glucosidase

• For alpha-glucosidase, Asp is the nucleophile, and the acid/base

Med Chem: Pramlintide (amylin analog)

• Amylin co-secreted with insulin

• Amylin binding to amylin receptors:

– Promote satiety

– Slows gastric emptying

– Inhibits postprandial glucagon secretion

• Amylin prone to aggregating

– Introduce proline mutations

• Need to decrease aggregation potential but maintain biological activity

• Increase water solubility

Med Chem: Insulin

• Has a histidine which binds to zinc to facilitate storage by becoming a hexamer - mutations are made to reduce insulin's ability to form hexamer which allows a quick onset

1. Glulisidine

▪ Aspergine (Asn3) → Lysine (in β chain)

▪ Lysine (Lys29) → Glutamine (in β chain)

2. Glargine

▪ Aspergine (Asn21) → Lysine (in α chain)

▪ Two Argines (arg) are added to the β chain)

▪ These mutations shift peptide's isoelectric point to make it less soluble at physiological pH = precipitation of the insulin in the tissue = slow release of insulin over time

3. Lispro

▪ Lys29 and Pro28 are switched (now Lys28 and Pro29)

▪ There is less hexamer formation as a result and more readily available insulin units

4. Aspart

▪ Pro28 → Aspartic acid (in β chain)

▪ Disrupts hexamer formation = more rapid absorption and quick onset

5. Degludec

▪ Deletion of 30th position in β chain

▪ Addition of hexadecanedioic acid at Lys29 which is similar to a fatty acid and binds to albumin = prolonged stay in serum

6. Detemir

▪ Deletion of 30th position in β chain

▪ Addition of myristic acid at Lys29 which is similar to a fatty acid and binds to albumin = prolonged stay in serum

Degludec has a conjugation of ____________ acid whereas detemir has a conjugation of ______ acid at Lys29 to prolong half-life.

Hexadecanedioic; myristic

How many mLs in an insulin vial?

10 mL

Types of Insulin Products

• Rapid-acting

– Insulin aspart (Novolog, Fiasp)

– Insulin lispro (Humalog, Admelog, Lyumjev)

• Insulin lispro U-200 (Humalog U-200)

– Insulin glulisine (Apidra)

– Inhaled Insulin (Afrezza)

• Short-acting

– Regular Insulin (Humulin R, Novolin R, Myxredlin)

• Intermediate-acting

– Insulin NPH (Humulin N, Novolin N)

– Regular insulin U-500

• Long-acting insulin

– Insulin glargine (Lantus)

– Insulin glargine U-300 (Toujeo)

– Insulin glargine (Basaglar)

– Insulin glargine (Semglee)

– Insulin glargine (Rezvoglar)

– Insulin detemir (Levemir)

– Insulin degludec (Tresiba)

– Insulin degludec U-200 (Tresiba U-200)• Mixed insulins

Mixed Insulin

• Novolog Mix and Humalog Mix contain NPH (intermediate) with rapid-acting insulin

★ Deliver 15 minutes before meal

• Novolin and Humulin contain NPH with regular insulin (short-acting)

★ Deliver 30 minutes before meal

• Ryzodeg (70% degludec/30% aspart)

★ Deliver 15 minutes before meal

Insulin Dose Timing

• Rapid-acting

– 15 min prior to meals or with elevated BG (correctional dosing)

• Can administer up to 20 min following a meal

– Skip if not eating a meal

• Regular insulin/Short-acting

– 30 min prior to meals or with elevated BG (correctional dosing)

– Skip if not eating a meal

• Intermediate-acting insulin (NPH) and mixed insulin

– Once or twice daily (breakfast and dinner OR bedtime)

• Long-acting insulin

– Once daily (sometimes twice daily)

– Consistent times of day are important (Tresiba can be administered any time of the day and can be dosed within 8 hours of normal scheduled time due to long half life)

(True/False) Long-acting insulins don't have a peak.

True.

What regular insulin is intermediate acting and NOT short-acting?

U-500

Insulin

• MOA

– Administered to replace absent insulin secretion in T1D or supplement insufficient insulin secretion in T2DM

• ADME

– Produced by recombinant DNA technology using strains of E. coli

– Polypeptide primarily delivered by subcutaneous injection

• Alternative routes – IV (regular insulin), inhaled insulin (Afrezza), use of continuous subcutaneous insulin infusion (insulin pump)

• Onset and duration can be affected by:

– Dose, injection site, blood supply, temperature, and physical activity

• Metabolism/Excretion

– Metabolized in liver and excreted in kidney

– Insulin sensitivity may increase in severe renal impairment due to fact it is excreted by kidney

• Adverse effects

– Hypoglycemia

– Weight gain

– Skin reactions

• Rotate injection sites to avoid lipohypertrophy and lipoatrophy

• Drug interactions

– Other antidiabetic agents - ↑ hypoglycemia

– Beta-blockers

• Mask symptoms (e.g. tachycardia)

– Thiazide diuretics - ↑ glucose

– Corticosteroids - ↑ glucose

Insulin Mixing

– Regular (Short-acting)/rapid-acting + NPH = ok to mix

– Long-acting insulin = do NOT mix with other products in the same syringe

What insulin cannot be mixed together?

LONG-ACTING insulin

What type of insulins are cloudy?

NPH and NPH-containing products

When can you skip a dose of RA or SA insulin?

If you skip a meal

Inhaled Technosphere® Insulin (Afrezza)

• Rapid-acting

• Dry powder formulation

• Common side effects

– Cough (25.6% to 31.6%)

– Hypoglycemia

• Monitoring

– Spirometry at baseline, 6 months and annually

Pramlinitide (Symlin)

• Amylin (Islet amyloid polypeptide) is a peptide produced in pancreatic β-cell and secreted with insulin

• Binds to amylin receptor:

– Inhibits glucagon release

– Delays gastric emptying

– Improves satiety

• Pramlintide (Symlin) is a synthetic analog of amylin that has several amino acids altered to improve bioavailability

• Therapeutic use

– An adjunct therapy to those who take mealtime insulin

• T1DM – reduce A1c by 0.3 to 0.5%, weight loss of 1 to 2 kg, insulin sparing

• T2DM – reduce A1c by 0.5%, lowers insulin requirements, weight loss of 1 to 2.5 kg over 3 to 6 months

• ADME

– t ½ = 50 minutes, duration about 3 hrs

– Metabolism and clearance by the kidney

• No substantial accumulation noted in those with moderateor severe renal impairment (CrCl 21 – 50 ml/min)

• T1DM – 15 mcg subcutaneously prior to each main meal

– Meal should be at least 250 kcal or 30 g of carbs

– Titrate to target dose of 60 mcg with each meal

– BBW: Reduce mealtime insulin dose by 50% when initiating

• T2DM – 60 mcg subcutaneously prior to each meal

– Meal should be at least 250 kcal or 30 g of carbs

– Titrate to target dose of 120 mcg with each meal

– BBW: Reduce mealtime insulin dose by 50% when initiating

• Common adverse effects

– Hypoglycemia

– Nausea and vomiting

• Do not titrate more often than every 3 to 7 days

• May need to reduce dose if N/V occurs

• Precaution/contraindications

– Gastroparesis or other disorders that slows GI motility

• Drug interactions

– Use caution with other agents that may decrease GI motility

• CANNOT be mixed with insulin in the same syringe

GLP-1 RA

• Short-acting agents

– Exenatide BID (Byetta)

– Liraglutide daily (Victoza)

– Lixisenatide daily (Adlyxin)

• Long-acting agents (administered weekly)

– Exenatide (Bydureon)

– Dulaglutide (Trulicity)

– Semaglutide (Ozempic and Rybelsus oral)

– Tirzepatide (Mounjaro)

• Efficacy

– A1c lowering of ~1 to 2.4%

• Therapeutic uses

- Initial agent for ASCVD/CKD

• Beneficial adverse effects

– Weight loss– variable by agent

– Semaglutide, Liraglutide and Tirzepatide with FDA indication

• Common or notable adverse effects

– Nausea and vomiting

– Injection site reactions

– Pancreatitis and pancreatic cancer

– Thyroid C-cell tumors (animal study) - BLACK BOX WARNING

• General rules

– Exenatide BID – should be dosed within 60 min of AM and PM meal

– Other agents can be dosed regardless of mealtime

– Consistent time each day/week

– Injection/administration sites are similar to insulin injection sites

Unique Features of GLP-1 RA

• CV benefits:

– LEADER (liraglutide) – significant reduction in composite CVD outcome (non fatal MI, non fatal stroke, CV death)

– SUSTANE 6 (semaglutide) – significant lower in non-fatal stroke

– REWIND (dulaglutide) – significant reduction in composite CVD outcome (non fatal stroke, CV death)

• NO CV benefits:

– ELIXA (lixisenatide) – no difference vs. placebo

– EXSCEL (extended-release exenatide) – no difference vs. placebo

• Dosing in renal impairment

– <30 ml/min = exenatide not recommended

– Other agents no dose adjustment, although experience limited

• Fasting and PPG Glucose Regulation

– Long-acting – better FPG reduction

– Short-acting – better PPG reduction

• Use with Basal Insulin (combination product)

– Soliqua (Lixisenatide + Insulin glargine)

– Xultophy (Liraglutide + Insulin degludec)

– Dose adjustment is based on insulin, not GLP-1 RA

What GLP-1 agonists demonstrated CV benefits?

Liraglutide, semaglutide, and dulaglutide (NOT lixisenatide or exenatide)

Diagnosis of Diabetes

• A1c ≥6.5%*†

• Fasting Plasma Glucose (FPG)*– ≥ 126 mg/dL, no caloric intake for at least 8 hrs

• 2-hr Plasma Glucose during Oral Glucose Tolerance Test (OGTT)*– ≥ 200 mg/dL, no caloric intake for at least 8 hrs, then administer 75 g anhydrous glucose dissolved in water

• Symptoms of hyperglycemia or hyperglycemic crisis AND random plasma glucose ≥ 200 mg/dL

†Should NOT use point-of-care testing devices for diagnosis at sites approved to use only low-complexity tests.

*Repeat testing needed to confirm results in absence of “unequivocal hyperglycemia”.

Diagnosis of Pre-diabetes

• A1c 5.7-6.4%

– As A1c rises, DM2 risk rises disproportionately

• Fasting Plasma Glucose (FPG)– 100-125 mg/dL

• 2-hr Plasma Glucose during OGTT– 140-199 mg/dL

Who should T1DM be screened in?

• Consider screening first-degree relatives of people with T1DM due to the development of Teplizumab

• Tests include autoantibodies for:

– GAD

– IA-2

– ZnT8

– Insulin

Screening for Diabetes - T2DM

• BMI >25; Asian-Americans BMI >23 + at least 1 risk factor

• Pre-diabetes – test annually

• Women with h/o Gestational DM – test at least every 3 years

• Age ≥35 years – test at least every 1-3 years

• HIV (before starting antiretroviral therapy; at time of change in therapy; 3-6 month after start/change in therapy; annually)

Screening for Diabetes -Children and Adolescents

– Weight > 85th percentile for age and sex

– AND at least 1 risk factor

• Maternal history of gestational DM during the child’s gestation• Family history of type 2 DM (1st or 2nd degree relatives)

• African American, Latino, Native American, Asian American, Pacific Islander

• Signs of insulin resistance (acanthosis nigricans ,hypertension, dyslipidemia, PCOS, large or small for gestational age birthweight)

- Start screening at age of 10 or onset of puberty (whichever comes first)

- Test at least every 3 years

- More frequent if BMI increasing

Gestational Diabetes

DM onset during 2nd or 3rd trimester of pregnancy that was NOT pre-existing

What is the most common A1C goal?

< 7%

Glycemic Treatment Targets - Adults

• A1c: < 7%

• Preprandial plasma glucose : 80 - 130 mg/dL

• Postprandial Plasma goal: < 180 mg/dL

• CGM

Time IN range of 70 - 180: ≥70%

Time BELOW range: < 4%

Time < 54 mg/dL: <1%

• A1c Testing Frequency:

- A1c above goal: every 3 months

- A1c below goal: every 6 months

Glycemic Treatment Targets – Older Adults

Healthy – few coexisting chronic illnesses, intact cognitive and functional status

Complex – multiple co-existing chronic illnesses or 2+ instrumental ADL impairments or mild-to-moderate cognitive impairment

Very complex – LTC or end-stage chronic illnesses or moderate-to-severe cognitive impairment or 2+ ADL dependencies

.*Focus on avoiding hypoglycemia and symptomatic hyperglycemia

Glycemic Treatment Targets -Children

• A1c: < 7%

• Preprandial plasma glucose: 90 - 130 mg/dL

• Bedtime or overnight glucose: 90 - 150 mg/dL

• Before physical activity: 126 - 180 mg/dL

*A1c goal of <7.5% is reasonable if not able to identify hypoglycemia (cannot articulate symptoms or have unawareness); lack access to insulin analogs or advanced insulin delivery technology/continuous glucose monitoring; cannot check blood glucose regularly.

Adolescents and young adults may follow adult treatment targets if no developmental or psychological issues are present AND without excessive hypoglycemia.

Glycemic Treatment Targets - Pregnant Women

Time in range = the percentage of time the BG is 63 - 140 mg/dL

How long does the CGM need to be active for to get an accurate interpretation of the results?

75%

Hypoglycemia

• BG ≤ 70 mg/dL

• Mild: shaking, sweating, dizziness, anxious, tachycardia, hunger

• Moderate: blurred vision, personality change, irritability, weakness, fatigue

• Severe: loss of consciousness, seizure

• Level 1: ≥ 54 mg/dL to < 70 mg/dL (requires 15 grams of carbs)

• Level 2: < 54 mg/dL (requires 30 grams of carbs)

• Level 3: Altered mental or physical status that requires assistance for treatment of hypoglycemia

• Treatment: 15 grams of pure glucose followed by a protein/carbohydrate-based snack or meal

ABCDEF-HMV of Diabetes

• A = A1c

• B = Blood Pressure/Blood glucose

• C = Cholesterol/ASCVD risk

• D = Diet/weight

• E = Exercise

• F = Family/friends; social support; Feet

• H = Hypoglycemia

• M = Medication adherence/side effects; Mood

• V = Vaccines (Influenza, Pneumococcal conjugate [PCV13], Pneumococcal polysaccharide [PPSV23], SARS-CoV-2, Hepatitis B, HPV, Tdap, Zoster, RSV

Annual Diabetes Assessment:

- Comprehensive foot exam (visual inspection, pedal pulses, sensory exam)

- Dental exam

- Dilated retinal exam

- Screening for albuminuria

- Serum creatinine/eGFR

- Screen for BP at least every 6 months

Annual Diabetes Assessment:

- Comprehensive foot exam (visual inspection, pedal pulses, sensory exam)

- Dental exam

- Dilated retinal exam

- Screening for albuminuria

- Serum creatinine/eGFR

T1DM: Intensive Insulin Therapy - LA + RA

• Long-acting insulin is given HS or at breakfast

• Bolus given before mealtime

T1DM: Intensive Insulin Therapy - IA (NPH) + RA/SA (regular)

• Intermediate acting/NPH is BID at breakfast and at supper/dinner NOT lunchtime since you take advantage of the NPH peak at lunch

- Give lower dose at supper to prevent hypoglycemia

• Bolus given before breakfast and supper

T1DM: Continuous Insulin Infusion

• ONLY use rapid-acting insulin

• During the meal, the # of carbs are inputted by the patient

Insulin Injection Technique

• Clean injection site and hands

• “Pinch an inch”

– Children < 6 years

– Adults with BMI 19-25

• Location: abdomen, thigh, upper arm

– MUST be subcutaneous tissue, not muscle

• Recommend short needles

– 4 mm; 5/32”

– 5 mm; 3/16”

• Rotate injection sites to avoid lipohypertrophy and lipoatrophy

• Insert needle perpendicular to the skin

• Pens: Count to 10 after dose administered before removing needle

• Needles should be used ONCE, then discarded

– Do not leave needles on pen devices for storage

Initial Insulin Dosing T1DM

• Starting dose:

– 0.5 units/kg daily (Typical dose range needed for goal glycemic control: 0.4-1 unit/kg/day)

• 50% of dose = basal

• 50% of dose = bolus

– Divided between meals (eg, 20% breakfast, 15% lunch, 15% dinner)

• Some patients require up to 1 unit/kg/day (higher doses needed during puberty and pregnancy)

– Adjustments can be made to dose or timing of bolus dose

– Bolus dosing adjusted based on carbohydrate intake, pre-prandial BG, and anticipated exercise in next 3-4 hrs

Insulin to Carb Ratio

= 500 / Total daily insulin dose (TDID)

• Calculation to identify how many grams of carbohydrate will be “covered” by 1 unit of bolus insulin

• I:C calculation assumes insulin sensitivity remains constant throughout the day...but that’s not what happens all the time.

• Use this as a starting point, the ADJUST based on the patient’s response!

Correction Factor (CF) aka: Insulin Sensitivity Factor (ISF)

- CF = 1500 ÷ TDID (for regular/SA insulin)

– CF = 1800 ÷ TDID (for insulin analogs/RA insulin – lispro, aspart, glulisine)

– The result is in blood glucose in mg/dL that will be lowered by 1 unit of bolus insulin

Why should SGLT-2i be avoided in T1DM?

Since it increases the risk of euglycemic DKA

What is the duration of the most effective DSME/DSMS (Diabetes Self-management Education/support)?

Total duration ≥10 hrs (over 6-12 months) and space education sessions