diabetes exam Flashcards
(275 cards)
1
Q
3 causes of hyperglycemia
A
lack of insulin
- decreased glucose dependent uptake in cells where glucose uptake is insulin-dependent
- decreased glycogen synthesis
- increased conversion of amino acids to glucose
2
Q
cause of hyperlipidemia
A
increased fatty acid mobilization from fat cells
increased fatty acid oxidation (KETOACIDOSIS)
3
Q
cause of ketoacidosis
A
increased fatty acid oxidation
4
Q
complications of diabetes
A
cardiovascular - micro and macro angiopathies
neuropathy - increased BG levels lead to increased utilization of the polyol pathway and increased cytosolic water in neural cells
nephropathy - renal vascular changes and changes in the glomerular basement membrane
ocular - cataracts, retinal microaneurysms and hemorrhage
increased susceptibility to infections
5
Q
role of alpha subunits
A
regulate the insulin receptor
repress the catalytic activity of the beta subunit
repression is relieved by insulin binding
6
Q
insulin effects on liver
A
inhibits glycogenolysis inhibits ketogenesis inhibits gluconeogenesis stimulates glycogen synthesis stimulates triglyceride synthesis
7
Q
insulin effects on skeletal muscle
A
stimulates glucose transport
stimulates AA transport
8
Q
insulin effects of adipose tissue
A
stimulates TG storage
stimulates glucose transport
9
Q
fasting glucose disposal
A
75% non-insulin dependent: liver, GI, brain
25% insulin-dependent: skeletal muscle
glucagon secreted to prevent hypoglycemia
10
Q
fed glucose disposal
A
85% insulin-dependent: skeletal muscle
5% insulin-dependent: adipose tissue
glucagon secretion is inhibited
insulin inhibits release of FFA from adipose tissue
11
Q
GLUT 1
A
Km 1-2 mM - will pull glucose constantly
constitutive
widely expressed
12
Q
GLUT 2
A
Km 15-20 mM - requires higher concentrations of glucose to transport
constitutive
B-cells, liver
13
Q
GLUT 3
A
Km
14
Q
GLUT 4
A
Km 5 mM - because high enough glucose to require insulin
insulin-induced
skeletal muscle, adipose tissue
15
Q
alpha cells produce…
A
glucagon: stimulates glycogen breakdown; increases BG
16
Q
delta cells produce…
A
somatostatin: general inhibitor of secretion of alpha and beta cells
17
Q
beta cells produce…
A
insulin: stimulates uptake and utilization of glucose
amylin: cosecreted with insulin; slows gastric emptying, decreases food intake; inhibits glucagon secretion
18
Q
proinsulin
A
cleaved into A and B chains and C (connecting) peptide
19
Q
ultra rapid/very short action insulin
A
lispro (humalog), aspart (novolog), glulisine (aprida)
20
Q
rapid/short action insulin
A
regluar
21
Q
intermediate insulin
A
NPH
22
Q
long acting insulin
A
glargine (lantus), detemir (levemir) (binds serum albumin extensively)
23
Q
____ leads to covalent modification of proteins
A
hyperglycemia
loss of normal protein function, acceleration of aging process, theorized to account for may long-term complications of diabetes
24
Q
adverse reactions to insluin
A
hypoglycemia
lipodystrophy - lump of fat at over used injection site
lipoatrophy - concavities in SC tissue
insulin resistance - immune response to insulin
25
signs of hypoglycemia
weakness, sweating, hunger, tachycardia, increased irritability, tremor, blurred vision, seizures, coma, increased sympathetic output
26
overview of treatment of T1DM and T2DM
T1 - diet + exercise + insulin
| T2 - diet + exercise; diet + exercise + oral agents; diet + exercise + insulin
27
T2DM most commonly develops in pts who are
obese and over 35
28
insulin receptor binding stimulates
PDK1: activate protein kinase C to increase amount og glucose transporters to membrane = more glucose uptake
PKB: more glucose transporters; upregulate glycolysis to use glucose
MAPK: cause proliferatin and cell growth to store fatty acids with glycerol
29
drugs that increase BG
catecholamines, GCs, OCs, thyroid hormones, somatotropin
30
drugs that increase risk of hypoglycemia
ethanol, somatostatin, beta-blockers
31
sulfonylurea structure
SO2-NH-CO-NH
32
sulfonylurea mechanism
high glucose activates GLUT2 to transport more glucose in = increased ATP = close K+ channel and open Ca+ channel = Ca influx = exocytosis of insulin
low glucose leads to higher ADP:ATP causing K+ channels to remains open and cell remains repolarized
sulfonylureas mimic high ATP:ADP to lead to closed K+ channels and increased insulin released
33
sulfonylurea SE
hypoglycemia (lasting depolarization of B cells and persistent insulin secretion), GI, weight gain, secondary failure of B cells leading to need of insulin
34
GLP-1
released in response to a meal to cause "incretin effect": glucose-mediated insulin released and B-cell proliferation.
35
GLP-1 MOA
stimulates insulin secretion, suppression of glucagon secretion, slows gastic emptying, but only in glucose-dependent manner
36
GLP-1 SE
N/V, pancreatitis, risk of thyroid tumors (liraglutide), abiglutide is DPP-IV resistant (longer half-life)
37
DPP-IV
degrades GLP-1; inhibitors are orally active
38
DPP-IV inhibitors
sitagliptin, saxagliptin, linagliptin, alogliptin; enhance GLP-1 action
39
DPP-IV inhibitors AE
N/V, constipation, HA, severe skin rxn, reduced white blood cell count, risk of cancer
low risk of hypoglycemia, may facilitate weight loss (feeling full)
40
amylin analog
pramlintide; slows gastric emptying, decreases food intake, inhibits glucagon secretion; can be used in T1 and T2; used in conjunction with insulin
41
alpha-glucosidase inhibitors
decrease absorption of carbohydrates from intestine via inhibition of gut glucosidases; acarbose and miglitol AE: GI, diarrhea, nausea, flatulence
42
SGLT2 MOA
increase amount of glucose excreted by blocking transporter that reabsorbs glucose back into blood
43
canagliflozin AE
increased risk of UTI, increased urine flow/volume depletion, increased risk of hypoglycemia, CI in renal failure
44
dapagliflozin AE
increase risk of hypoglycemia especially in use w SU and insulin
45
Empagliflozin AE
increased risk of UTI, increased urine flow/volume depletion, increased risk of hypoglycemia, CI in renal failure
46
insulin resistance
decreased responsiveness to insulin - less glucose uptake
caused by obesity (abdominal cavity) or inactivity
occurs in skeletal muscle (less uptake), adipose tissue (less uptake, less lipolysis to mobilize FA) and liver (less inhibition of gluconeogensis and glycogenolysis)
47
insulin resistance mechanism
excess nutrients activate mTOR pathway to phosphorylate serine residue on insulin receptor substrate (IRS) = inhibition of PI3 kinase = no GLUT 4 brought to membrane
cytokines can induce serine phyosphorylation as well
48
metformin advantages
rarely causes hypoglycemia or weight gain
49
metformin works by...
increasing sensitivity to insulin in the liver, fat, and muscle cells by decreasing hepatic gluconeogensis and increasing glucose uptake and glycolysis in muscle and fat cells
50
metformin mechanism in liver
stimulates organic cation transporter (OCT1) to suppress formation of ATP and increase concentration of AMP
- activation of AMPK that blocks lipid and cholesterol synthesis
- [blocks glucagon action of increasing cAMP and PKA = prevents gluconeogenesis
51
metformin mechanism in skeletal muscle
activation of AMPK stimulates translocation of GLUT4 to membrane to increase glucose uptake
52
thiazolidinediones (TZDs)
decrease insulin resistance or improve target cell response to insulin
activators of PPARgamma (transcription factor)
53
main target of TZDs
adipocytes: enhance differentiation, enhance FFA uptake into SC fat, reduce serum FFA, shift lipids into fat cells from non-fat cells
- live to enhance glucose uptake, reduce gluconeogenesis
- skeletal muscle: enhance glucose uptake
54
Rosiglitazone
restricted due to cardiovascular toxicity, CI in CHF
55
Pioglitazone
some hepatotoxity, does not cause hypoglycemia, CI in CHF
56
factors regulated by activation of PPARgamma
resistin, adiponectin, TNFa, leptin, angiotensinogen, plaminogen activator inhibitor 1
57
resistin
elevated in T2DM, TZDs decrease level
58
adiponectin
decreased in T2DM; generally reduces BG and insulin resistance; TZDs increase level
59
TNFa
increased in T2DM; stimulates lipolysis and insulin resistance; TZDs decrease levels
60
leptin
increased in T2DM and obesity, signal satiety
61
angiotensinogen
elevated in obesity; excess leads to HTN
62
plaminogen activator inhibitor 1
elevated in obesity; increase of blood clots with obesity
63
glucose uptake by brain is
insulin independent
64
glucose uptake by tissues other than brain is
insulin dependent
65
s/sx of diabetes
polyuria, polydipsia, polyphagia, weight loss, fatigue, UTI, URI, ketoacidosis (T1), blurred vision
66
drugs that decrease insulin secretion
phenytoin - inhibit insulin secretion, more profound in patients with pre-existing hyperglycemia
B-blockers - decrease insulin release in response to hyperglycemia
CCB - decrease insulin release in response to hyperglycemia and can increase proteinuria
67
drugs that increase hepatic glucose output
GC, sympathomimetics
68
beta blockers in diabetics
CAN USE THEM
issue: may blunt s/sx of hypoglycemia, less likely w cardio selective agents, caution w use in brittle diabetics (esp w ultra short acting agents), always consider indication
69
drugs that increase insulin resistance
thiazide diuretics - not an issue until > 50 mg/day
niacin - w higher doses
GC
70
drugs that are toxic to beta cells
pentamidine - prevents insulin secretion
71
diagnostic criteria
```
2 positive:
FBG >126
AIC > 6.5%
random glucose > 200 with sx of DM
2 hr PPG > 200 during an OGTT (75gm glucose)
```
72
"normal" values
FBG 100-126
| A1C
73
microvascular complications
- Cataracts, retinopathy (yearly eye exams)
- Nephropathy = decrease GFR
- Neuropathy: peripheral, gastroparesis (slow transit), urinary retention, postural hypotension, impotence
74
macrovascular complications
-Coronary Heart Disease – leading cause of death in T2DM
+BP Goal 7.5%
-Stroke: keep BP under control
-Peripheral vascular disease: leading cause of non-traumatic amputations; causing leg pain, cold feet, and absent pulses
-Periodontal disease: requires dentist visits every 6 months
-Antiplatelets: consider aspirin for primary prevention in patients with high CVD risk
75
SMBG goals
ADA:
FBG 80-130mg/dL
PPG (2 hours after eating)
76
A1C goals
ADA
77
statin use in pts
ADA:
no risk = none
CVD risk = mod-high
overt CVD = high
78
statin use in pts 40-75
```
ADA:
no risk = mod
CVD risk = high
overt CVD = high
ACC/AHA:
mod
high for pts w 10y ASCVD > 7.5%
```
79
statin use in pts >75
ADA:
no risk = mod
CVD risk = mod-high
Overt CVD = high
80
every 1% drop in A1C results in
18% reduction in risk of CVD events
81
A1C
short duration of DM, no CVD, long life expectancy
82
4 "m" components of therapy
meals movement monitoring medications
83
goal carb intake
women 45 gm/meal
| men 60 gm/meal
84
medical nutrition therapy components
moderate caloric restriction, modest weight loss, monitor carb intake, limit sugar-sweetened beverages, sat fat
85
insulin used as IV
regular
86
insulin that can't be used IV
NPH (suspension)
87
insulin that precipitates at physiologic pH
glargine (Lantus and Toujeo)
88
insulin that binds albumin
detemir
89
insulin uses
T1DM and T2DM
-fasting glucose >280-300
-ketoacidosis
-gestational diabetes
-when deemed appropriate by clinician and patient
hyperkalemia (even w no DM)
T2DM in combination with various oral agents
90
ultra short acting insulin examples
aspart, lispro, glulisine
91
ultra short insulin onset
15-30 min
skip meal = skip dose
inject when food is in front of you
92
ultra short peak
1-2 hours
93
ultra short duration
3-4(5) hours
94
ultra short compatibly mixed w
NPH (and degludec?)
95
short acting insulin examples
regular (U-100 and U-500)
96
short acting onset
30-60 min
97
short acting peak
2-3 hours
98
short acting duration
4-6 hours
99
short acting compatibly mixed w
NPH
100
intermediate insulin examples
NPH
101
intermediate onset
2-4 hours
102
intermediate peak
4-8 hours
103
intermediate duration
8-12 hours
104
intermediate compatibly mixed w
rapid or short acting
105
long acting insulin examples
glargine and detemir
106
long acting onset
```
4-5 hours (glargine)
2 hours (detemir)
```
107
long acting peak
none
108
long acting duration
22-24 hours (glargine)
| 14-24 hours (detemir)
109
long acting compatibly mixed w
none
110
ultra long acting examples
degludec
111
ultra long acting onset
1-2 hours
112
ultra long peak
none
113
ultra long duration
over 24 hours
114
rate of absorption of insulin from different routes
IV > IM > SQ
115
rate of absorption of insulin from different sites
stomach > buttocks and thighs
116
lower dose absorbed more ___
rapidly
117
renal failure effect on insulin
renal failure decreases insulin clearance and therefore increases insulin action
118
stress effect on insulin
stress increases insulin clearance and increases BG
119
insulin vials stable at ___ for ___
insulin vials stable at room temperature for 28 days
exception : levemir stable for 42 days
insulin pens are variable (7-56 days)
120
opened insulin vials should be discarded ___
after 28 days
121
pre-filled syringes are stable for ___
28 days with refrigeration as long as not mixed; 10-28 days at room temperature
122
mixed insulin stability
regular/NPH: 7 days in fridge
aspart, glulisine or lispro with NPH: give immediately
glargine and detemir with other insulin: NEVER
123
hypoglycemia s/sx
tremors, tachycardia, diaphoresis, confusion, slurred speech, drowsiness, weakness, agitation, blurred vision
124
hypoglycemia tx
- 15-30 gm carbohydrate (start w 15 gm unless BS 1 hr away) ex: granola bar, 1/2 PBJ, apple and cheese, crackers
- glucagon for severe patients, 1 mg SQ, IM or IV
125
examples of 15 gm carbs
4 oz OJ, 6 oz cola, 5-6 livesavers, 2 tsp sugar, 1 tbsp honey, glucose tabs (4-5 gm/tab) or gel
126
complications of insulin Tx
hypoglycemia, weight gain, lipohypertrophy, lipoatrophy, allergic rxn
127
rapid acting insulin advatages
decrease PPG, fewer overall occurances of hypoglycemia, flexibility, can give after meal based on what was eaten, stimulates physiologic insulin secretion relative to meals
128
rapid acting insulin disadvantages
risk without meal, need to combine with longer acting, give immediately after mixing
129
long acting insulin advantages
24+ hours coverage without peaking, helpful for nocturnal hyperglycemia
130
long acting insulin disadvantages
cannot be mixed, cost
131
changing therapy: NPH to glargine/detemir/degludec
keep dose the same
132
changing therapy: lantus to tuojeo
same dose, but may need increased dose
133
changing therapy: BID NPH to glargine/detemir/degludec
decrease dose by 20%
134
insulin dose in T1DM
start with 0.1-0.4 units/kg/day
| end with 0.5-0.6 units/kg/day (ACTUAL BW)
135
ideal testing in T1DM
before meals and at bedtime (QID)
| occasionally at 3 am to adjust doses
136
basal bolus is usually __:__
50:50
| can be 50-70:30-50
137
basal bolus dosing w NPH and short-acting
2/3 AM and 1/3 PM
2/3 of each dose NPH and 1/3 short acting
less flexibility w dose adjustments
138
NPH in basal bolus can be given
PM or HS
139
T2DM starting insulin
usually long-acting or intermediate is started in combination with oral agents
- usually betime
- some orals (often SU and TZDs) may be discontinued, esp w basal/bolus initiate
140
T2DM insulin starting dose
0.15-0.2 U/kg/day
10-15 U
FBS/18
kg/10
141
T2DM dose adjustments
adjust every 3-4 days
- adjust by 1-2U for every 20 mg/dL of FBS over 100 mg/dL or by 2-4 U for every 50 mg/dL of FBS over 150 mg/dL
- increase by 1-2U/day until FBS 80-130 mg/dL
142
bolus in T2DM
0.1 U/kg/meal or 1-2 units of insulin for every 15 gm CHO in the meal
143
when AIC > 10%, 70% of the problem involves ___
FBS
144
when A1c
PPG
145
adjust insulin every _-_ days
3-7 days until goals are met
146
CF at bedtime
only give 50% of dose
147
empiric starting poins
T1DM: increase insulin by ~2 units decreases BG by ~50 mg/dL
T2DM: increase insulin by ~4 units decreases BG by ~50 mg/dK
148
U500 used
when pts exceed 300 units of total insulin daily
149
T1DM carbohydrate ratio
1 unit:15 gm CHO (start)
150
T2DM carb ratio
1 unit:10-15 gm CHO (adult)
| 1 unit:20-30 CHO (kids)
151
rule of 500
500/total insulin = g CHO/unit of bolus insulin
| may have more than one CHO ratio each day depending on CHO intake at meal
152
rule of 1800
(1500 for regular)
1800/total daily insulin dose = mg/dL BG will drop per unit of insulin
used to add a dose of prandial when BG is elevated before a meal
153
illness and DM
- continue insulin even if food intake is decreased (stress increases insulin requirements)
- maintain fluid intake (12, 8 oz glasses/day)
- test BG q4h
- test urine for ketones w each urination
154
ideal non-insulin treatment would...
preserve B cell fxn, prevent weight gain, prevent hypoglycemia
155
oral agents
metformin, SU, DPP-4 inhibitors, TZDs, meglitinides, alpha glucosidase inhibtors, SGLT2 inhibitors, bile acid sequestrats
156
injectable non-insulin agents
GLP-1 agonists, pramlintide
157
metformin MOA
DRUG OF CHOICE FOR T2DM
- improves insulin sensitivity
- increase tissue uptake and utilization of glucose by muscle
- decreases hepatic production of glucose
158
metformin clinical applications
- adjunct to diet in T2 uncontrolled
- in combination with insulin and other non-insulin agents in T2DM
- ADA recommendations: use for all T2DM if tolerated and not CI
- reduces risk of mortality and CV death
- first-line agent
159
metformin efficacy
- A1C decrease 1.5-2% (up to 3%)
| - FBG decrease 60-80 mg/dL
160
metformin pharmacokinetics
excreted unchanged in the urine
161
metformin advantages
- less risk of hypoglycemia (no insulin release)
- decrease TG and LDL 8-15%
- no weight gain or even loss (2-3 kg)
- cheap
- CV protection
- decrease macrovascular complication and risk of total mortality
- decrease risk of stroke and all-cause mortality (compared to insulin and SU)
- decrease diabetes-related death and MI (vs conventional treatment)
162
metformin disadvantages
may cause lactic acidosis, GI effects (N/V, diarrhea, flatulence)
-take w largest meal and titrate
163
metformin cautions and CI
renal dysfunction, HF (esp class III and IV), alcoholics, increased risk of lactic acidosis
164
metformin and renal dysfunction
caution in males w SCr > 1.5 mg/dL
caution in females with SCr > 1.4 mg/dL
caution in patients w CrCl
165
metformin and HF
```
CONTRAINDICATED in class III and IV
class I and II are low risk
```
166
metformin and alcoholics
watch excessive intake and avoid use with heavy intake
| overall increased risk of LA in these pts
167
patient at risk for LA
post MI, COPD, hepatic failure, shock, surgery/procedure (hold metformin 2-3 days)
168
metformin dosing
- start: 500 mg po BID or 850 mg PO QD with meals
- titrate weekly and increase 250-500 mg
- maximum clinical dose: 2 gm/day
- max package insert dose: 2.550 gm/day
169
metformin dosing in renal insufficiency
- GFR > 60; no renal CI, monitor SCr annually
- GFR 60-45; continue use, monitor SCr q3-6mo
- GFR 30-45; reduce dose by 50%, monitor SCr q3mo
- GFR
170
SU MOA
stimulate insulin release from B cells
| may increase binding between insulin and receptors or increase number of receptors
171
SU clinical applications
adjunct to diet and exercise in T2DM
used in combination with insulin and non-insulin agents
HAVE TO HAVE ABILITY TO PRODUCE INSULIN
172
SU efficacy
A1C decrease 1.5-2%
| FBG decrease 60-70 mg/dL
173
first generation SU
acetohexamide, chlorpropamide, tolazamide, tolbutamide
174
second generation SU
glyburide (diabeta, micronase, glynase)
glipizide (glucotrol)
glimepiride (amaryl)
175
PK of 2nd gen SU
glyburide and glipizide more effective when take 30 minutes AC
metabolized by liver
some excreted in urine
176
SU AE
hypoglycemia (renal/hepatic insufficency pts, elderly or malnourished pts, concurrent hypoglycemic drugs)
weight gain and GI upset
hematologic: leucopenia, thrombocytopenia, aplastic anemia
allergic rxns/photosensitivity
177
SU drug interactions
- increased hypoglycemic effect: warfarin, azole antifungals, gemfibrozil, clofibrate, sulfonamides, MAOIs, trycyclic antidepressants, alcohol, cimetidine, aspirin and concominant agents for DM
- decreased hypoglycemic effect: beta-blockers, CCBs, choletyramine, GC, phenytoin, OC, rifampin, thiazides, niacin
178
general SU dosing
start low
increase dose every 1-2 weeks until at max
exceeding max increases SE but does not decrease BG
current max now being questioned
179
use SU cautiously in these pts due to increased risk of hypoglycemia
elderly or pts w renal/hepatic disease, irregular dietary intake, alcoholics, pts taking concimitant hypoglycemic agents
180
best SU candidates
no T1DM, short duration of DM, FBS
181
SU treatment failure
25% primary - poor blood sugar control after a trial of 6-12 weeks on medications and diet
50-75% secondary - failure of medication after initial control, common for these medications to fail after 6-12 months, place in therapy is declining
182
short acting insulin secretagogues or meglitinides
repaglinide (Prandin) and Nateglinide (Starlix)
183
meglitinides MOA
non-sulfonylurea moiety of glyburide
| stimulates release of insulin from pancreatic beta cells
184
meglitinides clinical applications
- adjunct to diet and exercise to patients with uncontrolled T2DM
- in combination with metformin to lower BS in pts who are uncontrolled w diet, exercise and either agent alone
- rapid onset and short duration of action, so given with meals to enhance PPG utilization
- can be used in pts w renal insufficiency
- alternative in patients experienceing hypoglycemia with low-dose SU
- no added benefit in combination w SUs
185
meglitinides efficacy
AIC decrease 0.8-1%
FBG decrease 40 mg/dL
decrease PPG
186
meglitinides PK
- rapidly absorbed and short t1/2 of 1-1.5 hours
- metabolized by liver into inactive metabolites
- mostly eliminated in the feces
- watch dosing w hepatic insufficiency
187
meglitinides AE
- hypoglycemia (elderly and patients with hepatic/renal dysfunction; less risk than SU)
- weight gain (~2-3 kg)
188
meglitinides drug interactions
- CYP450 3A4 metabolism, potential for interactions
- gemfibrozil increased half-life thereby increasing risk of hypoglycemia
- some noted interaction w anticonvulsants
189
meglitinides dosing
-if A1c 8%:
start 1-2 mg repaglinide or 120 mg nateglinide with each meal
-max: repaglinide: 16 mg/day but clinical 6 mg; nateglinide: 120 mg/day
-take 15-30 min AC
-adjust weekly
-skip meal = skip dose
-add meal = add dose
190
DPP4 inhibitors
sitagliptin (Januvia)
Saxagliptin (Onglyza)
Linagliptin (Tradjenta)
Alogliptin (Nesina)
191
DPP4 Inhibitors MOA
- increases activity of endogenous incretin hormones (GLP-1 and GIP)
- incretin hormones? gut hormones that enhance insulin secretion in response to food
192
GLP-1
- released from cells in ileum and colon after eating and is normally degraded quickly by DPP-4
- studies show reductions of GLP-1 after meals in T2DM
- stimulates insulin response from beta cells in a glucose dependent manner (prevents hypoglycemia; inhibits glucagon secretion by alpha cells, inhibits gastric emptying, reduces food intake and body weight)
- GLP-1 is degraded by DPP4 enzyme
193
DPP4 inhibitors clinical application
- monotherapy and add on therapy with metformin or TZDs in T2DM; can be used in combo w SU
- reduced A1C by itself and in combo w metformin or pioglitazone, helped patients reach A1C goals, effective as a therapy add on to metformin and SU
194
DPP4 inhibitors efficacy
A1C decrease 0.7-1%
FBS decrease 20 mg/dL
PPG decrease 20-40 mg/dL
weight neutral
195
DPP4 inhibtors PK
- excreted unchanged in the urine
| - adjust dose for renal function (exception: linagliptin)
196
DPP4 inhibtors AE
- nasopharyngitis
- URIs
- HA
- joint pain (sx usually resolve within one month of drug discontinuation)
- acute pancreatits - counsel s/sx
197
DPP4 inhibitors drug interactions
- small increase in digoxin conc w sitagliptin
- saxagliptin and ketoconazole/itraconazole, PIs, clarithromycin, telithromycin, and rifampin which decreases saxagliptin AUC by 76%
198
sitagliptin dosing
100 mg QD for CrCl >50 mL/min
50 mg QD for CrCl 30-50 mL/min
25 mg QD for CrCl
199
saxagliptin dosing
2. 5-5 mg QD
| 2. 5 mg QD for CrCl
200
Linagliptin dosing
5 mg QD
201
alogliptin dosing
25 mg QD
12. 5 mg QD CrCl 30-60
6. 25 CrCl
202
SGLT2 inhibitors
Canagliflozin (Invokana)
Dapagliflozin (Farxiga)
Empagliflozin (Jardiance)
203
SGLT2 inhibitors MOA
- SGLT2 is major transporter of renal glucose to assist in glucose reabsorption
- inhibiton of SGLT2 leads to renal glucose excretion
204
SGLT2 inhibtors clinical application
adjunct to diet and exercise in patients w targeted CrCl
| benefits to empagliflozin: significantly lower rates of CV death, HF hospitilizations and death overall
205
SGLT2 inhibitors efficacy
A1C decrease 0.6 - 1%
| weight decrease
206
SGLT2 inhibitors PK
glucuronidation by UGT1A9 and UGT2B4 to inactive metabolites
CYP3A4 metabolism is minimal
excreted mostly in feces but 1/3 in urine
207
SGLT2 inhibitors AE
- UTI, female genital fungal infections, increased urination
- less common: hypoglycemia, hypotension, hyperkalemia, increased cholesterol
- FDA warning for DKA (possibly triggered by illness, decrease food or water intake, and decrease insulin dose)
- bone fractures
208
SGLT2 drug interactions
canagliflozin increases digoxin levels
| rifampin, phenytoin, phenobarbital and ritonavir can decrease canagliflozin (they induce UGT)
209
canagliflozin dosing
Contraindicated if CrCl
210
TZDs
pioglitazone (actos)
| rosiglitazone (Avandia)
211
TZDs MOA
- Bind to peroxisome proliferator activator receptor-γ (PPAR-γ) on fat cells and vascular cells
- Improves cellular response to insulin w/o increasing pancreatic insulin secretion
- Decreases insulin resistance
- Decreases hepatic glucose production
- results in reduction in exogenous insulin dosage when used in combination
212
TZDs benefits
- Pioglitazone can ↓ TG by 10-20%
- LDL remains unchanged on pioglitazone
- -Some rosiglitazone studies have shown ↑ in LDL
- Both meds convert small atherogenic LDL particles to large fluffy ones
- Both medications ↑ HDL by 3-9 mg/dL
- Endothelial function has improved and blood pressure may decrease slightly
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TZD clinical application
- As an adjunct to diet and exercise
| - In combination with a sulfonylurea, metformin, DPP-4, or insulin
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TZD efficacy
A1C decrease 0.5-1.5%
| FBG decrease 60-70 mg/dL
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TZD PK
- 99% protein bound
| - Metabolized hepatically
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TZD AE
- hepatatoxicity (check baseline LFTs, dont start in pts w baseline LFTs > 2.5x normal, check LFTs periodically, d/c if LFTs > 3x normal, monitor NV, abdominal pain, fatigue, anorexia, dark urine)
- resumption of ovulation
- exacerbation of HF (caution in NYHA class III and IV, increased edema, > 10 lb weight gain in some pts)
- macular edema
- inc fracture risk
- inc CV and MI ?
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TZD dosing
pioglitazone: initial 15-30 mg daily; max 30-45 mg daily
rosiglitazone: initial 4 mg daily; max 8 mg daily
titrate every 12 weeks
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alpha-glucosidase inhibitors
Acarbose (Precose)
| Miglitol (Glyset)
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alpha-glucosidase inhibitors MOA
- Competitive reversible inhibition of intestinal alpha-glucosidase (enzyme that breaks down polysaccharides to glucose)
- Delays glucose absorption and lowers postprandial hyperglycemia
- Does not enhance insulin secretion
- Less chance for hypoglycemia
- No effect on weight or lipids
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alpha-glucosidase inhibitors clinical application
- As an adjunct to diet and exercise in type 2 diabetes
| - In combination with other agents
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alpha-glucosidase inhibitors efficacy
A1C decrease 0.3 - 1%
FBG minimal effect
PPG decreased 40-50 mg/dL
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alpha-glucosidase inhibitors
| AE
GI (flatulence, diarrhea, abdominal pain/cramping - MUST TITRATE), rashes, increased LFTs
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alpha-glucosidase inhibitors CI
DKA, IBD, colonic ulceration, intestinal obstuction, hypersensitivity
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alpha-glucosidase inhibitors drug interactions
acarbose and miglitol can decrease digoxin levels
| miglotil can decrease propranolol, ranitidine, glyburide and metformin
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managing hypoglycemia that occurs w alpha-glucosidase inhibitors
use dextrose, complex sugars in juices/sodas will NOT be broken down, glucose tabs and gel are good
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alpha-glucosidase inhibitors dosing
25 mg QD w first-bite of main meal for 7-14 days, 25 mg BID week 3-4, 25 mg TID weeks 5-12, 50 MG TID (max if 50 kg)
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Colesevelam
- Bile acid sequestrant
- Mechanism to lower blood glucose is not fully known
- 0.4% A1C reduction
- May also lower LDL and is considered weight neutral
- 3.75 mg per day, and this may be split into two doses
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Bromocriptine
- Dopamine agonist
- Mechanism to lower blood glucose is not fully known
- 0.1-0.4% A1C reduction
- 0.8-1.6 mg PO daily, up to 4.8 mg daily
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Glucovance
glyburide/metformin
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Metaglip
glipizide/metformin
231
Actoplus Met
pioglitazone/metformin
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Duetact
pioglitazone/glimepiride
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Janumet
sitagliptin/metformin
234
Jentadueto
linagliptin/metformin
235
Kazano
alogliptin/metformin
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Juvisync
sitagliptin/simvastatin
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Kombiglyze
saxagliptin/metformin
238
Glyxambi
empagliflozin/linagliptin
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Invokamet
canagliflozin/metformin
240
Xigduo XR
dapagliflozin/metformin
241
Avandamet
rosiglitazone/metformin
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Avandaryl
rosiglitazone/glimepiride
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Oseni
pioglitazone/alogliptin
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future agents
- IL-1 beta cell receptor antagonists
- Oral insulin
- Islet cell transplantation
- Artificial pancreas
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Pramlintide
Pramlintide (Symlin®)
| non-insulin injectable
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Pramlintide MOA
- Synthetic analog of human amylin, a naturally occurring hormone
- made in Β cells and co-stored and co-secreted with insulin
- Inhibits glucagon secretion
- Delays gastric emptying -Satiety agent
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pramlintide clinical application
-In type 1 patients, A1C decreased by 0.67% after 13 weeks (QID pramlintide plus insulin vs. insulin alone)
-In type 2 patients, A1C decreased by 0.62% in 120mcg group after
52 weeks (all patients continued usual insulin regimen)
-Also being studied for weight loss (3.5kg loss in one trial with 240 mcg TID)
248
pramlintide efficacy
A1C: ↓ 0.4-0.7%
Weight: ↓ 1.5 kg
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pramlintide AE
- Risk of severe hypoglycemia with concomitant insulin administration
- Nausea, vomiting, and anorexia, but these decrease over time
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pramlintide dosing
- Type 1 patients: 15 mcg and titrate upward by 15 mcg up to 30-60 mcg, Give prior to major meals, ↓ dose of rapid-acting and short-acting insulins by 50%
- Type 2 patients: 60 mcg and titrate up to 120 mcg, titrate dose after nausea resolves, Give prior to major meals, ↓ dose of rapid-acting and short-acting insulins by 50%
- Inject SQ in abdomen and thigh
- Rotate sites of injection
- Never mix with insulin, but store like insulin
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pramlintide place in therapy
- Approved for use in type 1 and type 2 patients who are already on insulin but not achieving adequate control
- High cost: Three more syringes daily, AWP $100-$400/month, More frequent glucose monitoring
- May be a small niche of patients
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exenatide, liraglutide or albiglutide
Exenatide (Byetta®, Bydureon®), Liraglutide (Victoza®), or Albiglutide (Tanzeum®)
253
Exenatide, Liraglutide, or Albiglutide MOA
- Glucagon-Like Peptide 1 (GLP-1) agonists/analogs from salivary gland of the lizard Heloderma suspectum (exenatide) and through recombinant DNA technology (liraglutide)
- GLP-1 potentiates glucose-dependent insulin secretion by stimulating Β-cell growth and differentiation and insulin gene expression
- Has been shown to inhibit Β-cell death
- Exenatide and liraglutide are resistant to dipeptidyl peptidase IV, the enzyme that rapidly inactivates natural GLP-1
- Increases in both first and second-phase insulin secretion after meals occur
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Exenatide, Liraglutide, or Albiglutide clinical applications
- When compared to SU in type 2 patients, 10 mcg exenatide group showed decreased A1C of 0.86% vs. an increase of 0.12% in placebo group
- When compared to metformin in type 2 patients, 10 mcg exenatide group had decreased A1C of 0.8% vs. an increase of 0.1% in placebo group
- LEAD trials: Liraglutide Effect and Action in Diabetes (5 trials): Liraglutide (0.6-1.8 mg daily) compared to and used in combination with metformin, sulfonylureas, and TZDs, A1C ↓ up to 1.6% for liraglutide and weight ↓ up to 3.2 kg in liraglutide groups, Nausea was also the most frequent adverse effect (5-29% of patients)
- When compared to exenatide (10 mcg BID) in type 2 patients on maximal doses of metformin, sulfonylurea, or both, liraglutide (1.8 mg daily) decreased the A1C by 1.12% vs. 0.79% in the exenatide group (p
255
Exenatide, Liraglutide, or Albiglutide efficacy
* A1C: ↓ ~0.8-1% Byetta®; ↓ 1.6% Bydureon®; ↓ 0.8-1.5% liraglutide; ↓ 0.8-1.% albiglutide
* Weight: ↓ 1.5-3 kg
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Exenatide, Liraglutide, or Albiglutide AE
- Nausea
- Hypoglycemia
- Pancreatitis—some fatalities
- Black box warning for liraglutide (also with Bydureon®) - thyroid c-call tumors
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Exenatide dosing
- 5 mcg BID within 60 minutes prior to morning and evening meals
- Do not administer after a meal
- Can increase the dose to 10 mcg BID after one month
- May be administered in thigh, abdomen, or arm
- Available in pre-filled pens with 60 doses
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Liraglutide dosing
- 0.6 mg SQ daily for one week, then increase to 1.2 mg daily
- May titrate dose to 1.8 mg daily if needed for BS control
- May be given at any time of the day, independent of meals
- May be administered in thigh, abdomen, or arm
- Available in pre-filled pens with 18 mg per pen
259
Albiglutide dosing
30 mg once a week; may increase to 50 mg weekly
- May be given at any time of the day, independent of meals
- May be administered in thigh, abdomen, or arm
- Available in single dose pens
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T2DM treatment principles
- Treat aggressively to reach goals
- Consider the following when selecting pharmacotherapy: Duration of disease, Blood glucose level to be targeted, Degree of A1C lowering needed, ADRs and the patient tolerability, Patient preference for route of administration
- Start lifestyle modifications (↓ A1C by ~1-2%) and start metformin 500 mg BID with titration to 1,000 mg BID (↓ A1C ~2%)
- If goals not achieved after 3 months, use combination therapy
- If goals not yet achieved after 3-4 months, go to triple therapy
- Do not delay insulin if that is what is truly needed
- Go to basal-bolus insulin for tight control
- For patients with postprandial hyperglycemia, target with DPP-4 inhibitors, GLP-1 analogs, amylin analog, or alpha glucosidase inhibitors
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glimeperide dosing
start 1-2 mg daily, go to 1-8 mg
262
glipizide dosing
start 2.5-5 mg daily
30 min AC, go to 2.5-40 mg
XL start 2.5-5 mg daily, go to 2.5-20 mg
263
glyburide dosing
start 1.25-5 mg daily, go to 1.25-20 mg
264
aspirin use in DM pts
-ADA recommends to consider aspirin (75-162 mg/day) for primary CVD prevention in patients with ↑ CV risk (10 year > 10%) or for men > 50 or women > 60 with one major risk factor (FH CVD, HTN, smoking, HLD)
-ADA also recommends to not use aspirin for primary prevention for those at low
CVD risk or for men
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all diabetics w HTN should be on either an ___ or ___
ACEI or ARB
266
all diuretics can ___ glucose
increase
267
ACC/AHA recommendations for lipid goals in DM pts
40-75 mod - high statin if 10y ASCVD rick > 7.5%
268
high intensity statins
Atorvastatin 40-80 mg Rosuvastatin 20 mg
269
moderate intensity statins
Atorvastatin 10-20 mg Rosuvastatin 5-10 mg Simvastatin 20-40 mg Pravastatin 40-80 mg Lovastatin 40 mg Fluvastatin 40-80 mg Pitavastatin 2-4 mg
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DKA diagnostics
- Blood Glucose: >250mg/dL
| - pH: Mild: 7.25-7.3; Moderate 7.00 to 600mg/dL, no acidosis, Bicarb >18mEq/L
271
DKA treatment
fluid replacement, insulin, electrolyte management
272
fluid replacement in DKA
- Fluid Replacement: 0.9% NaCl 15-20 mL/kg/hr or 1-1.5 L during first hour
- Na is low (
273
insulin in DKA
- Continuous IV infusion of regular insulin
| - Do not start insulin if hypokalemia (
274
electrolyte management in DKA
- Potassium Goal: Maintain 4-5mEq/L
| - Bicarb: If venous pH
275
DKA resolution
-DKA: Blood glucose 1.5mEq/L, Venous pH >7.3, Anion gap
