DM, Diabetic Ketoacidosis (DKA) & Hyperosmolar Hyperglycemic State (HHS)

nearly 21 million Americans have diabetes (DM), yet only ___ have been diagnosed

2/3

type 1 diabetes (T1DM) acounts for _____ of all cases

5-10%

what was T1DM formerly known as?

insulin dependent mellitus (IDDM) or juvenile onset

when is the typical age of onset for T1DM?

4-6 yrs & 10-14 yrs

- usually symptomatic w/ rapid onset in childhood, but a slower onset can occur in adults

what causes T1DM?

immune mediated destruction of pancreatic B cells

- circulating insulin is either very low or absent

- glycogen is elevated

- disease begins w/ exposure of a genetically susceptible person to a viral infection

what are some sx of T1DM?

- polyuria
- nocturia
- polydipsia (thirst)
- weight loss (from glucosuria, muscle wasting, dehydration)
- polyphagia (hunger)
- often present w/ DKA

in women, what may glucosuria lead to?

vulvovaginitis

how is T1DM treated?

diet, exercise, self-monitoring of BG, & daily insulin injections

type 2 diabetes (T2DM) accounts for ___________ of all cases

> 90%

what was T2DM formerly known as?

non-insulin dependent mellitus (NIDDM) or adult onset

what is the typical age of onset for T2DM?

middle aged to older adults

- often asymptomatic, w/ a slow onset over 5-10 yrs

- becoming more common in children due to obesity & sedentary lifestyle

what are the risk factors for T2DM?

- abdominal visceral obesity
- sedentary lifestyle
- genetic component

what causes T2DM?

insulin resistance in muscle & liver, w/ subsequent defect in pancreatic insulin secretion
- pancreatic B cells are functioning to some degree thus there is enough circulating insulin present to prevent DKA

how is T2DM treated?

diet, exercise, oral meds, sometimes insulin (usually basal)

gestational diabetes mellitus (GDM)

glucose intolerance that appears during pregnancy

- occurs in 7% of pregnancies

- most common in 3rd trimester

- often assoc. w/ large birth weight babies (>9lbs)

- caused by placenta producing hormones that block the actions of insulin; cortisol levels increase

- tx: diet, self-monitoring of BG & sometimes insulin

what is insulin resistance syndrome/metabolic syndrome/syndrome X?

the co-occurrence of metabolic risk factors for both T2DM & CV disease

chronic hyperinsulinemia leads to..

increased VLDL & TG, along w/ atherosclerosis

diabetics have..

- high TG (typically 300-400)
- low HDL (typically < 30)
- structurally altered LDL which is even more atherogenic than normal LDL

what does high TG lead to?

sodium retention & HTN

reduction of risk factors for CVD includes:

- adequate HTN tx
- smoking cessation
- glycemic control
- cholesterol mgmt

what accounts for 90% of DM-related deaths?

hyperglycemia

what are the macrovascular complications of hyperglycemia?

cardiovascular, cerebrovascular, &/or peripheral vascular related
- HTN
- ASCVD
- hypercholesterolemia

what are the microvascular complications of hyperglycemia?

- retinopathy
- nephropathy (proteinuria, reduced GFR)
- neuropathy (nerve damage)
- poor peripheral circulation
- difficult to treat infections
- amputations
- impotence
- gastroparesis

hypoglycemia =

BG < 70 mg/dL w/ or w/o sx

sx of hypoglycemia:

- tachycardia
- palpitations
- sweating
- anxiety
- tremor
- nervousness
- HA
- confusion
- drowsiness
- fatigue
- if severe: seizures, coma, & death

what should be prescribed to insulin users?

glucagon

which is more urgent: hyper or hypoglycemia?

hypoglycemia

how is hypoglycemia treated?

oral glucagon, or dextrose

explain the oral tx of hypoglycemia:

consume 15-20 g of carbohydrate
- 8 oz skim milk, small box raisins, or 4 oz orange juice, or 3-6 glucose tabs
- repeat BG measurement in 15 mins
- if < 70 mg/dL, repeat
- once BG normalizes, eat meal/snack

if the hypoglycemic pt is unconscious, unable or unwilling to eat, what can be done?

administer glucagon emergency kit IM or Baqsimi intranasal

what is glucagon?

a hormone that promotes glycogen breakdown & increases blood glucose levels

after administering glucagon, it is important to..

roll patient on side bc vomiting is likely following administration

if hospitalized pt w/ IV access is hypoglycemic, what can be done?

administer 50% dextrose IV
- 50 ml for adults

describe the process for glucagon administration for severe hypoglycemia:

1. inject the liquid into the vial of glucagon powder
2. gently shake the mixture until the powder dissolves & the solution becomes clear
3. for adults & children over ~45 lbs, withdraw all the solution (1 mg)
4. for children <45 lbs, withdraw half of the solution (0.5 mg)
5. inject into the arm, thigh, or buttock. turn the person on his/her side in case of vomiting
6. the person may eat when conscious. this may take ~15 mins.

what are the benefits of tight blood glucose control (A1C <7%)?

* reduced:
- risk of microvascular complications (retinopathy, nephropathy, neuropathy, poor peripheral circulation, difficult to treat infections, amputations, impotence, gastroparesis)
- long-term health care costs

to effectively reduce risk of macrovascular complications (HTN, ASCVD, hypercholesterolemia), what should be targeted?

HTN & lipids

drawbacks of tight glucose control

* higher doses/combo of oral meds may be needed
* more frequent injections of insulin
* increased:
- risk of hypoglycemic episodes
- monitoring
- cost of meds
* compliance may be harder

beneficial meds in diabetics:

- antiplatelet therapy (if indicated)
- antihypertensive therapy
- ACE/ARB (especially if urinary albumin > 30 mg/g)
- statin therapy
- adult vaccines (PPV, influenza, hepatitis B)

problematic meds in diabetics:

- corticosteroids
- oral decongestants (ex: pseudoephedrine; increase BG)
- antipsychotics
- some herbals
- BBs (mask s/s of hypoglycemia)

ADA guidelines suggest A1C goal of ____ for most patients

<7%
- ACE suggests <6.5%

american geriatric society (AGS) suggests A1C goal <7% for most patients; however, for frail, older adults, persons w/ life expectancy <5 yrs, or where risks of intensive glycemic control outweight the benefits, a goal of ____ is appropriate.

<8%

what does ADA suggests for glycemic self-monitoring blood glucose (SMBG) goals?

- preprandial (fasting): 80-130 mg/dL
- postprandial: <180 mg/dL

check A1C __ months if at goal or __ months if over goal

q6 ; q3

how many times daily is SMBG done if multiple daily insulin injections are used?

3

is SMBG necessary for a patient on oral meds that do not cause hypoglycemia & who is meeting A1C goals?

may not be necessary

what is the BP goal for most diabetic patients?

< 130/80

what are the treatment goals for a diabetic pediatric patient?

- ADA suggests A1C goal of </= 7% for most
- </= 7.5% may be appropriate if unable to articulate sx of hypoglycemia
- </= 6.5% may be acceptable if can be achieved w/o significant hypoglycemia or undue burden

what are the treatment goals for gestational diabetes?
*not tested

- prevent complications to mother (HTN, preeclampsia, T2DM after pregnancy) and child (macrosomia, hypoglycemia at birth, jaundice, respiratory distress)
- more stringent glycemic goals:
*preprandial (fasting) <95 mg/dL
*1 hr postprandial <140 mg/dL
*2 hrs postprandial <120 mg/dL

what drug class does metformin fall in?

biguanides

what are the brand names of metformin?

Glucophage
Glucophage XL

what is the MOA of metformin?

decreases glucose production by interfering w/ lactate oxidation, & enhances insulin sensitivity in hepatic & peripheral (muscle tissues)

what is the drug of choice for initial therapy in most patients w/ diabetes?

metformin

benefits of metformin:

- good efficacy
- reductions in CV-related M/M
- low cost (<$10/mo)
- lack of weight gain & hypoglycemia
- very good A1C reductions
- modest weight loss 2-3 kg
- may decrease plasma TG & LDL-C
- may increase HDL

metformin reduces fasting & postprandial BG. does it reduce one more than the other?

yes, fasting > postprandial

metformin may decrease plasma TG & LDL-C by _______, and increase HDL-C by ___

8-15% ; 2%

when should metformin be given?

w/ largest meal of the day
- to reduce GI ADRs

what dose of metformin should you start with?

500 mg once daily
- increase by 500 mg q 1-2 wks
- can titrate faster if tolerating GI side effects

what is the goal dose of metformin?

2,000 mg/day (2g/day)
- 1,000 bid wm

which formulation of metformin may be better tolerated (less GI ADRs), has a longer duration of action, & can result in ghost tablets in the stool?

extended release (ER)

what is the most common ADR of metformin?

diarrhea
- along w/ other GI effects (decreased appetite, metallic taste, N/V, abdominal cramping, flatulence)

metformin ADRs:

- diarrhea (+ other GI effects)
- Vit B12 & folic acid deficiency (reduces oral absorption of Vit B12; may rarely induce anemia)
- hypoglycemia (very low risk)
- lactic acidosis (very rare = 0.003%, but potentially life threatening)

of those on metformin, asymptomatic Vit B12 deficiency occurs in ___.

~7%

how often should someone on metformin be evaluated for Vit B12/folic acid deficiency?

annually

metformin contraindications/precautions (all due to risk of lactic acidosis):

- renal restrictions ( do not use if GFR <30)
- persons @ high risk of acute renal failure, CV event, &/or hypoxic states
- excessive alcohol consumption
- severe liver dysfunction

why is metformin contraindicated in renal failure?

bc it can accumulate & increase risk of lactic acidosis

DO NOT START METFORMIN IF eGFR __________

<45 ml/min

DISCONTINUE METFORMIN IF eGFR ___________

<30 ml/min

metformin should be stopped before administration of iodinated radiocontrast dye. when can it be reinitiated?

48 hrs after dye administration

sodium-glucose co-transporter 2 (SGLT2) inhibitors

- GLIFLOZIN

canagliflozin (Invokana)

empagliflozin (Jardiance)

dapagliflozin (Farxiga)

ertugliflozin (Steglartro)

SGLT2 inhibitor MOA

blocks glucose reabsorption in the proximal tubule & increases glucosuria
- decreases glomerular filtration pressure & albuminuria
- provides diuresis, naturiuresis, & decreases BP

what are the renal benefits of SGLT2 inhibitors?

decreases glomerular filtration pressure & albuminuria

what are the cardiac benefits of SGLT2 inhibitors?

diuresis, natriuresis, & decreased BP

what are the compelling indications for use of an SGLT2 inhibitor?

renal (CKD, ARF, etc) or CHF

SGLT2 inhibitor for T2DM:

- mild A1C reductions
- reductions in CV related M/M
- lack of weight gain & hypoglycemia
- reduces both fasting & postprandial BG
- drawback: EXPENSIVE

what is considered 1st line for T2DM w/ CKD?

same for:

what is considered 2nd line for T2DM w/ high ASCVD risk or established CVD?

what is considered 2nd line for T2DM if overweight/obese?

SGLT2 inhibitor + metformin
- improves renal & CV related M/M
- modest weight loss 2-3 kg

how are SGLT2 inhibitors administered?

PO once daily in the morning w/ or w/o food

SGLT2 inhibitor AEs:

- increased risk of hypoglycemia if taken w/ insulin or sulfonylureas

- genital fungal infections

- UTIs

- increased urination, dehydration, hypotension, & LDL

- rare: decreased BMD (fractures), ARF, ketoacidosis, bladder cancer, pancreatitis

all SGLT2 inhibitors have limited efficacy when eGFR is ______________________

< 45 mL/min/1.73m2
- less for canagliflozin & empagliflozin

canagliflozin & empagliflozin have limited efficacy when eGFR is _________________________

< 30 mL/min/1.73m2

SGLT2 inhibitors can be used down to an eGFR of _____________ for CKD, CHF & CV benefits

20 mL/min/1.73m2

GLP-1 receptor agonists (GLP-1 RA)

- TIDE (all given SubCut)

albiglutide (Tanzeum weekly)

exenatide (Byetta BID weekly, Bydureon weekly)

dulaglutide (Trulicity weekly)

liraglutide (daily Victoza for DM or Saxenda for BMI)

semaglutide (weekly Ozempic for DM or Wegovy for BMI)

which GLP-1 RAs have proven CV benefit?

Don't Like STEMIs

- dulaglutide

- liraglutide

- semaglutide

which GLP-1 RAs have proven BMI benefit?

weigh less

- liraglutide

- semaglutide

which medication is a GLP-1 RA & GIP RA?

tirzepatide (SubCut; Mounjaro weekly)

- BMI benefits

GLP-1 RAs MOA:

synthetic versions of exendin
- stimulate GLP-1 receptors which stimulates glucose-dependent insulin secretion
- inhibits release of glucagon after meals
- slows rate of stomach emptying
- reduce appetite

GLP-1 RAs are synthetic versions of exendin. where is this substance found?

gila monster saliva

what are the compelling indications for use a GLP-1 RA?

obesity/elevated BMI or high ASCVD risk/established CVD

GLP-1 RAs for T2DM

- good efficacy
- reductions in CV related M/M
- reduces postprandial > fasting BG
- drawbacks: EXPENSIVE & REQUIRES INJECTIONS

do GLP-1 RAs decrease postprandial or fasting BG more?

postprandial

what is considered 1st line for T2DM w/ high ASCVD or established CVD?

GLP-1 RA (specifically: dulaglutide, liraglutide, semaglutide) + metformin

what is considered 2nd line for T2DM w/ CKD?

GLP-1 RA + metformin

why are GLP-1 RAs (specifially: liraglutide, semaglutide) + metformin 1st line for someone w/ elevated BMI?

bc they reduce hunger, increase satiety & cause weight loss w/ or w/o DM

tirzepatide has _________ weight loss as compared to GLP-1 RAs, but ________ CVD evidence

improved ; less

how much weight loss can be expected w/ a GLP-1 RA?

varies, but in general:
- 1st 24 wks: 8 lbs
- after 6 months: plateaus
- can be used for up to 2 yrs to maintain

GLP-1 RAs AEs

- nausea (40-50%)

- loss of appetite

- weight loss

- diarrhea (13%)

- hypoglycemia when added to a sulfonylurea

- small, temporary lumps @ injection site (normal)

- rare: pancreatitis, gall bladder disease, ARF, bowel obstruction

why should you consider reducing the dose of a sulfonylurea when adding a GLP-1 RA?

due to risk of hypoglycemia

once weekly GLP-1 RA injections may cause small, temporary lumps at the injection site. is this normal?

yes

exenatide has a renal contraindication w/ eGFR _________________, but other GLP-1 RAs can be used until eGFR _________________

< 30 ml/min/1.73m2 ; < 10-15 ml/min/1.73m2

GLP-1 RA contraindications:

- hx of pancreatitis
- personal or fam hx of medullary thyroid cancer

dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors)

- GLIPTINS (all oral)

alogliptin (Nesina)
saxagliptin (Onglyza)
linagliptin (Tragenta)
sitagliptin (Januvia)