Exam 3: Diabetes Pt 3: Non-insulin tx

Question 1

Ideal treatment functions with oral agents

Answer 1

Ideal treatments would preserve B cell function, prevent weight gain, prevent hypoglycemia, and improve/not worsen concomitant disease states

Question 2

Metformin (Glucophage, Fortamet, Glumetza): MOA

Answer 2

Decreases hepatic production of glucose

Increases intestinal glucose utilization and decreases glucose uptake into circulation

Can increase GLP-1 secretion

Modest effect on increasing tissue uptake and utilization of glucose by muscle
-Mostly helps w/insulin sensitivity - helps the insulin you have work better

Question 3

Metformin Clinical Applications

Answer 3

As an adjunct in T2DM patients that are uncontrolled

In combination w/insulin and other non-insulin agents in T2DM

ADA recommendations: Consider for use in all T2DM pts if tolerated and not contraindicated
-Shown to reduce risk of mortality and CGV death
-efficacious with minimal hypoglycemia
-Widely available and inexpensive

Off-label:
-Being used in T1DM pts who are overweight and have a low risk of ketoacidosis
-PCOS - lowers androgen, increases ovulation

Question 4

Metformin Efficacy

Answer 4

Lowers A1C 1.50-2%
Lowers FBG 60-80 mg/dL
Weight: No weight gain and often weight loss (2-3 kg)
Insulin is still the best - however metformin does a great job

Question 5

Pharmacokinetics

Answer 5

Excreted unchanged in the urine
-Renal function dosing comes into play

Question 6

Metformin advantages

Answer 6

Less risk of hypoglycemia due to no insulin release

Benefit on lipids: lower TG and LDL by 8-15%

Weight loss or at least weight neutral

Cost-effective

Increased fibrinolysis = CV protection
-Breaking up any fibrin clots

Has been shown to lower macrovascular complications and the risk of total mortality in clinical trials

Decrease risk of stroke and all-cause mortality when compared to insulin and sulfonylureas

Decreased diabetes-related death and MI vs conventional treatment

Question 7

Metformin disadvantages

Answer 7

May cause lactic acidosis (rare)
-Weak causal relationship between metformin and lactic acidosis

Question 8

Metformin cautions for use and contraindications

Answer 8

-Renal dysfunction
determined by eGFR

-Acute decompensated hospitalized HF pts
unstable HD pts, or HF coupled with sever renal/hepatic disease = avoid (HF)

-Alcoholics
Watch excessive intake and avoid in heavy intake
Overall increased risk of LA in these patients

-Avoid use in any pt at risk for lactic acidosis
Post MI
Hepatic failure
COPD
Shock
Surgery/radiologic procedure with contrast dye (hold met 1-2 days before and then ~2 days after depending upon patient status)

GI effects (30-50%)
-Take with largest meal
-Titrate dose

Vitamin B12 malabsorption/and or deficiency (15%)
-Can worsen neuropathy
-Monitor annually and provide supplementation if needed

Dementia risk
-Controversial
-some studies have shown met to lower risk of Alzheimer’s, other show it increases

Question 9

Initial metformin dose

Answer 9

Initial dose is 500 mg po BID or 850 mg po daily, with meals to decrease side effects; titrate dose weekly or bi-monthly and increase by 250-500 mg/day

Question 10

Maximum dose of metformin

Answer 10

Clinical: 2 grams
Package insert: 2.50

Question 11

Dosing in renal insufficiency

Answer 11

eGFR:
≥ 60:
-No renal contraindication to metformin
-Monitor SCr annually

<60 and ≥ 45
-Safe to start therapy
-Continue to use if already taking
-Monitor SCr every 3-6 months

<45 and ≥ 30:
Starting met. not recommended
-Reduce met dose by 50% if already taking
-Monitor SCr every 3 months

<30:
-Do not start met
-Stop met if currently taking

Question 12

SGLT2 inhibitors

Answer 12

Canagliflozin - Invokana

Dapagliflozin - Farxiga

Empagliflozin - Jardiance

Ertugliflozin - Steglatro

Question 13

SGLT2 inhibitors MOA

Answer 13

SGLT2 is the major transporter of renal glucose to assist in glucose reabsorption

Inhibition of SGLT2 leads to renal glucose excretion (up to 60-90 gm/day)

Question 14

Clinical application of SGLT2 inhibitors

Answer 14

Adjunct to diet and exercise in T2DM pts - First line
-Recommended w/orw/o met as an appropriate INITIAL therapy for T2DM and
-Those with ASCVD
-Those at high risk for atherosclerotic CVD (>55 YOA + 2 risk factors [HTN, HLD, obesity, smoking, or albuminuria])
-Those w/ HF
-Those with CKD

Question 15

Efficacy of SGLT2 inhibitors

Answer 15

Lowers A1C 0.5-1%
Lowers FBG 25-35 mg/dL
Lowers PPG by 40-60 mg/dL
Lowers weight 1-5 kg
Lowers SBP 3-6 mmHg and DBP 2-3 mmHg

Question 16

Pharmacokinetics of SGLT2 inhibitors

Answer 16

Undergoes glucuronidation by UGT1A9 and UGT2B4 to inactive metabolites
-UGT = UDP-glucuronosyl transferase
-CYP3A4 metabolism is minimal
-Excreted mostly in feces, but 1/3 in urine

Question 17

Adverse effects of SGLT2 inhibitors

Answer 17

Most common: UTIs, female/male genital mycotic infections increased urination

Patients with recurrent UTIs should be evaluated for underlying risk factors
May consider SGLT2i use if pt remains UTI - free for past year

Genital Mycotic infections (GMIs)
81% increased risk of vulvovaginal infections among pts with T2DM vs w/o DM - whether on SGLT2 or not

Higher risk than UTIs
-pts with a hx of uncomplicated GMI should not be considered a contraindication
-Pts w/a hx of complicated GMI whose underlying risk factors are rectified, should be considered for SGLT2I
-Counsel on S/s
-D/C might be warranted in the setting of life threatening infections
Increased urination
AM dosing

Question 18

FDA warning for serious genital infections (SGLT2i)

Answer 18

Fournier’s Gangrene
-Necrotizing fasciitis of the perineum
-Urologic emergency and requires tx with broad spectrum antibiotics and immediate surgical intervention
-Pts should be counseled to seek medical attention with any s/s tenderness, redness or swelling of the genitals or area from the genitals to back of rectum; also fever, fatigue, and malaise

Question 19

Other adverse effects of SGLT2i

Answer 19

Hypotension - Due to osmotic diuretics effects
-More prevalent with low baseline BP or decreased eGFR
-Concomitant diuretic use may increase the risk of orthostatic hypotension
-The diuretic dose may need to be adjusted

Hyperkalemia

Raised cholesterol

Question 20

Other FDA warnings with SGLT2i: DKA

Answer 20

DKA
-Risk 6 cases per 1,000 person years
-Most pts were T2 patients with mildly elevated BG
Factors that may have triggered the euglycemic acidosis: illness, decreased food/water intake, decreased insulin dose, and h/o alcohol consumption

New recommendations by FDA for use of SGLT2 around surgery
-Hold Three days before surgery (four if ertugliflozin)
-May restart therapy once oral intake is back to baseline and other risk factors for ketoacidosis have resolved

An occurrence of euglycemic DKA is not an absolute contraindication for restarting SGLT2i

Question 21

Canagliflozin FDA warnings

Answer 21

Bone fractures and decreased bone marrow density

AKI for Canagliflozin and dapagliflozin

Increased risk of leg and foot amputations