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Flashcards in Non-insulin therapy Deck (67):
1

Oral glucose lowering diabetes meds?

- oral glucose lowering: biguanides, sulfonylureas, meglitinieds, TZDs, glucosidase inhibitors, DPP-4 inhibitors, SGLT2 inhibitors

2

Non-insulin injectables?

- GLP-1 receptor agonists
- amylin mimetics

3

types of insulin?

- short
- rapid
- intermediate
- basal

4

Biguanides (metformin) major SE?

- diarrhea
- always start low with med and titrate up

5

MOA of biguanides?

- 2 MOA: inhibits hepatic glucose production (gluconeogenesis and glycogenolysis) and improves insulin sensitivity

- Metformin (Glucophage)
- Metformin/glyburide (Glucovance)
- Metformin/Glipizide (Metaglip)

6

6 reasons why metformin is 1st line therapy?

- glycemic efficacy: decreases A1C by 1.5%
- no wt gain: may lose wt or at least stabilize wt
- no hypoglycemia
- may help improve lipids
- well tolerated
- favorable cost
- pregnancy category: B

7

SEs of metformin?

- GI SEs:
diarrhea, N/V, flatulencee
sxs tend to decrease over time
start with low dose and titrate up
- doesn't usually cause hypoglycemia!!!
- ***can rarely cause lactic acidosis: increased risk if on glucocorticois or with ETOH

8

CIs of metformin?

- alcholics (more likely to have lactic acidosis)
- discontinue temporarily if receiving iodinated contrast
- renal dysfunction
- serum creatinine greater or equal to 1.5 mg/dL in males or greater or equal to 1.4 mg/dL in females
- abnormal creatinine clearance from any cause: including shock, acute MI, or septicemia, acute or chronic metabolic acidosis with or w/o coma (including DKA)

9

Black box warning of metformin?

lactic acidosis is a rare, but potentially severe consequence of therapy with metformin that requires urgent care and hospitalization
- the risk is increased in pts with acute CHF, dehydration, excessive alcohol intake, hepatic or renal impairment, or sepsis
- sxs may be nonspecific ( abdominal distress, malaise, myalgia, respiratory distress, somnolence), low pH, increased anion gap and elevated blood lactate may be observed. D/C immediately if acidosis is suspected
- lactic acidosis should be suspected in any pt with diabetes receiving metformin with evidence of acidosis but w/o evidence of ketoacidosis
- discontinue metformin in pts with conditions associated with dehydration, sepsis, or hypoxemia
- the risk of accumulation and lactic acidosis increases with the degree of impairment of renal function

10

drugs in class of sulfonylureas?

- Glipizide
- Glyburide
- Glimepiride
- main SE: hypoglycemia
- don't use 1st gen b/c of CV SEs

11

MOA of sulfonylureas?

- correct derangements of metabolism of carbs, lipids and proteins
- MOA: bind to beta cell receptors and cause ATP dependent K channels to close
- Ca channels are then opened = increased cytoplasmic Ca++ = increased insulin release from pancreas (why they can cause hypoglycemia)

12

2nd gen agents of sulfonylureas?

- Glimepiride (Amaryl)
- Glipizide (Glucotrol)
- Gluyburide (micronase)

- onset usually within 1-3 hrs and lasts up to 24 hours
- start low, titrate up slow (hypoglycemia)

13

Do sulfonylureas increase insulin sensitivity? hypoglycemia?

- no, doesn't increase insulin sensitivity
- 1/3 of pts with T2DM fail to respond adequately
- major risk of hypoglycemia in following pts: elderly, ETOH abuse, poor nutrition, renal insufficiency
- effectiveness decreases oer time because beta cell function decreases

14

Do sulfonylureas cause wt gain or loss?

- causes wt gain of 2-3 kg ( insulin also causes wt gain)

15

CIs of sulfonylureas?

- sulfa allergy
- high risk for hypoglycemia
- ketoacidosis

16

Who are the ideal pts for sulfonylureas?

- duration of disease of less than 5 years
- no hx of prior insulin therapy, or good control on less than 40 U of insulin per day
- close to normal body weight (b/c of wt gain) - higher BMI = more insulin resistance
- fasting glucose of less than 180 (shows that there is adequate B cell function)
- No hx of sulfa allergy
- avoid in persons (like the elderly) who are at high risk for hypoglycemia

17

Difference in sulfonylurea drugs?

- Glipizide (glucotrol):
14-16 hr duration, less incidence of hypoglycemia comparted to longer action meds
- Glyburide (Diabeta): 20-24+ hr
- Glimepiride (Amaryl)

18

Thiazolidendiones (TZDs) drugs?

- Rosiglitazone (Avandia)
- Pioglitazone (Actos)

19

MOA of thiazolidinediones?

- increase insulin sensitivity in skeletal msucle and fat by binding to nuclear steroid hormone receptor PPAR-gamma thereby decreasing peripheral insulin resistance
- may decrease hepatic glucose production at higher doses
- improvement of endothelial function and decreases albumin excretion
- can have positive effect on lipid profile

20

When are TZDs usually used?

- used as an add-on therapy down the line in pts who have failed or are unable to tolerate other therapies

21

Precautions with TZDs?

- won't cause hypoglycemia if used by itself, just increases sensitivity, not increasing insulin secretion
- if used with insulin or sulfonylureas: yes it could occur with improvement of insulin sensitivity in pts on supplemental insulin or SUs

22

Major adverse effects of Thiazolidinediones?

- wt gain
- fluid retention
- hepatotoxicity: acquire baseline liver functions, every 2 months for first 12 months, then periodicially therafter
- increasing evidence of causing decreased bone density
- cardiovascular effects: think Rosiglitazone: elevates LDL and HDL, may increase risk of cardiovascular events and heart failure

23

TZDs black box warning?

- CHF:
TZDs including rosiglitazone, cause or exacerbate CHF in some pts. After intitiation of rosiglitazone and after dose increases, observe pts carefully for signs and sxs of heart failure (including excessive, rapid wt gain, dyspnea, and/or edema). If these signs and sxs develop, manage the HF according to current stds of care/ Furthermore consider d/c or dose reduction of rosiglitazone.

- Rosiglizatone: not recommended inpts with sx heart failure, initiation of rosiglizatone in pts with est. New York Heart assocn class III or IV HF is CI

24

Rosiglitazone BBW?

- MI: showed that rosiglitazone to be assoc. with a stat. sig. increased risk of MI.

25

Thiazolidinediones - how were they perceived initially comparted to now?

- - first came out everybody thought they were great and tehn the data about SEs started popping up
- now this is a med typically reserved for use down the line after metformin, sulfonylureas, and some experts would say insulin therapy

26

What are the drugs of the alpha-glucosidase inhibitors?

- acarbose (precose)
- miglitol (glyset)

27

MOA of alpha-glucosidase inhibitors?

- slows the absorption of carbs from intestines by interfering with alpha-glucosidase, an enzyme found on the brush border of the intestine necessary for the absorption of starch and disaccharides

28

Therapeutic uses of alpha-glucosidase inhibitors?

- most useful in pts with postprandial hyperglycemia and pts with high A1C levels and poor dietary adherence

29

Major adverse effects of alpha-glucosidase inhibitors?

- GI effects including increased intestinal gas, flatulence, diarrhea, and abdominal distension

30

CIs of alpha-glucosidase inhibitors?

- pts with GI motility (SE of diabetes) disorders, cirrhosis, and diseases of the bowel ( IBD, absorptive disorders)

31

are alpha-glucosidase inhibitors used very often?

- no, has a place but generally not used that much

32

How do you use alpha-glucosidase drugs?

- dose with first bite of the meal (TID)
- start at lowest dose and titrate up every 1-2 months as needed
- 1 hr post prandial glucose measurement will help assess the response during titration of drug
- monitoring: LFTs q 3 momths the first yr of therapy
* not very effective

33

What are the meglitinides?

- nateglinide (starlix)
- repaglinide (prandin)

34

What are meglitinides similar to?

- sulfonylureas
- cause hypoglycemia
- used as alt for pts with sulfa allergies

35

MOA of meglitinides?

- similar to sufonylureas, increase insulin secretion from the pancreas
- lowers post prandial glucose levels but doesn't change fasting plasma glucose levels (not that effective)

36

When are meglitinides used?

- alt for pts who are candidates for SUs but have sulfa allergy
- possibly less risk of hypoglycemia (can consider this an alternative if hypoglycemia on SUs)
- good for pts with erratic eating schedules (take with meals) - dose up to 4x a day and only take if they eat
- for pts with acceptable fasting plasma glucose levels and elevated post prandial levels

37

Meglitinides and renal insufficiency?

- Nateglinide: may cause severe hypoglycemia in pts with renal insufficiency
- Repaglinide: no dose adjustments needed with renal insufficiency
- wt gain can be an issue
- drug interactions with drugs metabolized through the CYP450 3A4 pathway (used in renal failure (repaglinide))

38

What are the DPP-4 inhibitors?

- Sitagliptin (Januvia)
- Saxtagliptin (Onglyza)
- Linagliptin (Tradjenta)
- Alogliptin (Nesina)

39

Major side effect of DPP-4?

- head ache

40

MOA of DPP-4 inhibitors?

- inhibits the enzyme that breaks down endogenous GLP-1 thereby allowing increased amounts
- GLP: decreases gluconeogenesis, increases insulin and decreases glucagon secretion
- prolongs time that endogenous GLP is active by inhibiting DPP4 breakdwon of GLP, done in small intestine

41

Dosing for DPP-4 inhibitors?

- once daily oral dosing
- generally well tolerated
- no hypoglycemia unless combined with SU

42

CIs/interactions of DPP-4 inhibitors?

- caution with renal impairment
- sitaliptin CI with hx of pancreatitis
- drug interactions: saxtagliptin is potent CYP3A4/5 inhibitor avoid with ketoconazole, diltiazem, and erythromycin

43

Major side effects of DPP-4 inhibitors?

- URIs, UTIs, and HA
- hypoglycemia when used with SU
- hypersensitivity rxns: angioedema
- pancreatitis

44

What are the SGLT2 inhibitors?

- Canagliflozin (Invokana)
- Dapagliflozin (Farxiga)
- Empagliflozin (Jardiance)

45

MOA of SGLT2 inhibitors?

- inhibits SGLT2 in proximal nephron
- SGLT2 is transporter in renal tubule where 90% of glucose resoprtion occurs
- T2DM pts have upregulation of SGLT2 and have increased renal glucose reabsorption
- these meds work by blocking these SGLT2 sites which decreases glucose reabsorption in the kidney therefore causing glucosuria
- GFR needs to be at least 45 mL/min -have to have some kidney function
- may be 2nd line therapy for some pts

46

Benefits of SGLT2 inhibitor therapy?

- no hypoglycemia
- promotes wt loss (peeing out sugar, getting rid of excess calories)
- effective at all stages of DM
- can take with other DM therapies and may have a role in T1DM
- targets the kidney so minimal risk for off target adverse effects (still have to have some kidney fxn)

47

SEs of SGLT2 inhibitors?

- GU infections
- polyuria
- dehydration, dizziness, low BP
- increased LDL (5-7%)
- transient increase in creatinine
- caution for hypoglycemia if used with insulin or SUs
- usually very well tolerated
- expensive though: $400/month for Invokana

48

What are the GLP-1 receptor agonists?

- Exenatide (Byetta)
- Liraglutide (Victoza)
- Albiglutide (Tanzeum)
- Dulaglutide (Trulicity)

49

MOA of GLP-1 receptor agonists?

- exendin-4 also naturally occurring component of Gila monster saliva, and shares 53% sequence identity with GLP-1. Key: it is resistant to DPP-IV degradation and therefore exhibits a prolonged half life
(Exenatide is essentially a synthetic Exendin-4)

50

Incretin Mimetics (GLP-1 analog) dosage? Advantages?

-requires 2 subq injections daily prior to meals
- common SE is Nausea (but mild to moderate intensity and wanes over time)
- glucose dependent effects on insulin and therefore no hypoglycemia
- reduces A1C
- promotes wt loss
- cost is about $450/mo for Byetta

51

SEs of Exanitide (Byetta)

- not approved for use with insulin
- delays gastric emptying: helps with satiety but don't use in pts with gastroparesis (acid reflux)
- SEs: GI related - N/V/diarrhea, dyspepsia
- hypoglycemia if given with SU

52

What is the amylinomimetic drug?

- Pramlintide acetate (Symlin)

53

What is Pramlintide acetate used for?

- used for both type 1 and 2
- synthetic analog of human amylin cosecreted with insulin by pancreatic beta cells
- high risk for hypoglycemia when given with insulin
- add on therapy to insulin or SU or combo of both when failure to achieve A1C goals

54

MOA of Pramlintide acetate?

- reduces postprandial glucose increases via the following mechanisms:
1) prolongation of gastric emptying time
2) reduction of postprandial glucagon secretion
3) reduction of caloric intake through centrally-mediated appetite suppresion

55

SEs of pramlintide?

- N/V
- hypogylcemia unless insulin dose is simultaneously reduced

56

CIs of pramlintide?

- gastroparesis
- hypoglycemia unawareness
- poor compliance
- concomitant therapy with drugs that stimulate gastric motility
- A1C > 9
- don't use with alpha-glucosidase inhibitors
- fair number of drug interactions result in hypoglycemia

57

What meds should you not use in renal disease or at least use caution with renal disease?

- metformin: CI
- sitagliptin, saxagliptin(DPP-4 inhibitors): caution
- exenitide, liraglutide (GLP-1 receptor agonists): severe renal disease
- Canaglifozin, empagliflozin (SGLT2 inhibitors) : CI GFR

58

What kind of A1C drop should you expect with each new calss of noninsulin agent added to initial therapy?

- A1C lowering of 0.9-1.1%

59

What are the glycemic targets in diabetes therapy?

- HbA1C: less than 7% (mean PG - 150-160 mg/dL)
- pre-prandial PG less than 130
post prandial PG less than 180
- individualization is key:
tighter targets (6-6.5%) - younger healthier, looser targets (7.5-8%)- older, comorbidities, hypoglycemia prone
- avoidance of hypoglycemia

60

More commonly used oral agents and non-insulin injectables?

- metformin
- sulfonylureas
- thiazolidinediones
- DPP-4 inhibitors
- SGLT-2 inhibitors
- GLP-1 receptor agonists

61

Initial therapy of diabetes?

- fist educate pt on healthy eating, wt control, increased physical activity, and diabetes education
- metformin - number 1 go to!

62

Dual therapies? (add on to metformin)

- + sulfonylureas
- + thiazolidine
- + DPP-4 inhibitor
- + SGLT2 inhibitor
- +GLP-1 receptor agonsit
- + insulin (basal)

63

If pt comes in as uncontrolled diabetic what you do?

- don't use 2nd line drugs just go right to metformin + insulin
(metformin won't get you to A1C goal if greater than 10)

64

What drugs cause hypoglycemia?

- sulfonylureas
- insulin

65

What drugs cause wt gain?

- SUs
- Thiazolidines
- insulin

66

When should you adjust pt's therapy if not to A1C goal?

- every 3 months

67

At what fasting BG level should you start insulin therapy and why at this level?

- at 180-200 or A1C is greater than 9% - likely no beta cell function and need insulin