1
Q
Characteristics of adults who should be screened for diabetes?
A
Adults:
- BMI ≥ 25 (Asian Am ≥23) + ≥1 risk factor
- Prediabetes Dx
- ≥ 45yo
2
Q
Characteristics of children who should be screened for diabetes?
A
overweight + ≥ 2 additional risk factors
3
Q
Criteria for prediabetes diagnosis
A
Any one of:
- FPG 100-125 mg/dL
- 2hr PG 140-199mg/dL after 75g OGTT
- HbA1c 5.7-6.4%
4
Q
Criteria for diabetes diagnosis
A
Any one of*
- FPG ≥ 126
- 2hr PG ≥ 200 after 76g OGTT
- Random PG ≥200 + classic Sx hyperglycemia
*repeat test to confirm unless unequivocal hyperglycemia
5
Q
Sx Hypoglycemia
A
• Confusion • Diaphoresis • Tachycardia • Nausea • Tremulousness • Weakness • Coma • Seizures
6
Q
BBs and hypoglycemia
A
BBs can match Sx e.g., tachycardia & tremors
7
Q
Significance of hypoglycemic events
A
1+ severe hypoglycemic events = more likely to die in next 5yrs
8
Q
Studies that showed evidence for tight glycemic control
A
DCCT
EDIC
UKPDS
ADVANCE
9
Q
DCCT
A
Diabetes Control & Complications Trial
• check BG, intensive insulin, diet + exercise, monthly visits → reduced diabetic retinopathy nephropathy, neuropathy
10
Q
EDIC
A
Epidemiology of Diabetes Interventions & Complications
10 more years w/DCCT Ptsl→ reduced CVD, nonfatal MI, stroke, death from CV cause
11
Q
UKPDS
A
UK Prospective Diabetes Study 10 yr RCT
- diet alone vs intensive Tx w/insulin & sulfonylurea +/- metformin if needed
- tight BP control w/ACEi, BB, or CCB
GC & BP control → reduced microvascular complications metformin significantly reduced risk MI & stroke
12
Q
ADVANCE
A
Action in Diabetes & Vascular Disease: Preterax & Diamicron Modified Release Controlled Evaluation
- Perindopril + indapimide reduced mortality compared to placebo
- HbA1c <6.5% no change in mortality
- 6yr f/u study confirmed initial findings
- HbA1c target reduced progression to ESRD
13
Q
Recommended Goal HbA1c (ADA)
A
6.0-6.5% in selected pts
<7% most adult pts
14
Q
HbA1c Treatment goals Advanced Age (ADA)
A
- Usual goals if pt functional, cognitively intact, significant life expectancy
- May consider lower, e.g., <8% if above criteria not met
15
Q
HbA1c Treatment goals Pediatric
A
<7.5% pediatric patients w/DMI
16
Q
When should HbA1c Treatment goals be more liberal? (ADA)
A
More liberal goals if - episodes of severe hypoglycemia / hypoglycemia unawareness - complex comorbid conditions, limited life expectancy (3-5years before benefits of tight glyc control seen. Focus on BP or lipids instead)
17
Q
General guidelines for non-pharm therapy? (ADA)
A
- Medical nutrition therapy
- Wt loss if overweight (≥ 7%)
- Whole grains & fibers
- reduced sat & trans fats, sugary bevs, sodium
- etoh in moderation
- 150 min/week moderate intensity aerobic
- resistance training 2x week unless C/I’d
- Separate recs for pedi, e.g., ~ 1 hr daily
18
Q
Guidelines for non-pharm therapy in advanced age? (ADA)
A
- Symptomatic hyper/hypoglycemia should always be prevented / treated
- Lifestyle & metformin comparable in younger, but older pts shown to have no benefit from metformin but significant benefit from lifestyle modification (Caspersen et al., 2012)
19
Q
2015 ADA guidelines emphasize…
A
individualized Tx plan: patient preference, comorbidities
20
Q
Guidelines for DMI pharm therapy in adults (ADA)
A
Insulin (basal, bolus, correction regimen, continuous infusion or pump)
21
Q
Guidelines for DMII pharm therapy in adults (ADA)
A
- first line: metformin unless C/I’d
- +/- insulin if symptomatic and/or markedly elevated A1c or glucose
- Add second PO drug, GLP-1 agonist, or insulin if goal A1c not achieved w/max tolerated dose after 3 mths
22
Q
Guidelines for DMI pharm therapy in kids (ADA)
A
Insulin (basal, bolus, correction regimen, continuous infusion or pump)
23
Q
Guidelines for DMII pharm therapy in kids (ADA)
A
10-18yo w/random BG ≥ 250mg/dL, HbA1c >9%, or w/ketoacidosis: same as DMI
10-18yo w/o above features: Glucophage (metformin)
Always w/lifestyle modifications
24
Q
Sulfonylureas: indication
A
DMII
Need some β cell function
25
Sulfonylureas: MOA/PK
* Binds to ATP dependent K+ channel in β cell.
* Closes channel which depolarizes cell
* Altered resting membrane potential opens Ca++ channel.
* Ca++ influx leads to insulin secretion
* Net effect: stimulate insulin release through β cells
26
Sulfonylureas: ADRs
* Weight gain (increased glc)
* Hypoglycemia
* Rare CV deaths (may be increased w/glimepiride)
27
Sulfonylureas: Relative Efficacy
reduced A1c 1-2%
28
Sulfonylureas: special considerations
* increased glycogen, fat, protein formation
* may → β cell burnout
* avoid in sulfa allergy
29
Sulfonylureas: drug names
Diabinese (chlorpropamide)
Diabeta (glyburide)
Glucotrol (glipizide)
Amaryl (glimepiride)
30
Diabinese (chlorpropamide): Dose, peak, duration
* 250-750 mg/day
* Peak: 3-6h
* Duration: 24h
(sulfonylurea)
31
Diabinese (chlorpropamide): important considerations
* reduce dose in renal impairment
* CYP2C9 substrate
* active metabolite – can accumulate
* high risk d/t unpredictable PKs, longer acting
* rarely used
(sulfonylurea)
32
Diabeta (glyburide): Dose, peak, duration
* 2.5 – 20mg/day micronized: 1.25 – 12mg/day
* Peak: 2-4h
* Duration: ≤ 24h
(sulfonylurea)
33
Diabeta (glyburide): important considerations
* Caution in renal impairment
* CYP2C9 substrate
* risk d/t longer acting
(sulfonylurea)
34
Diabeta (glyburide): GDM
not as good as insulin or metformin in GDM (insulin recommended (sulfonylurea)
35
Glucotrol (glipizide): Dose, peak, duration
* 5-20 mg/day
* Peak: 1-3h
* Duration: 12-24h
(sulfonylurea)
36
Glucotrol (glipizide): important considerations
* CYP2C9 substrate
* recommended
(sulfonylurea)
37
Amaryl (glimepiride): Dose, peak, duration
* -5 mg/day
* Peak: 2-3h
* Duration: 24h
(sulfonylurea)
38
Amaryl (glimepiride) important considerations
* CYP2C9 substrate
* recommended
(sulfonylurea)
39
Which sulfonylurea is safe in elderly?
Amaryl (glimepiride)
no active renal metabolite = safe in elderly
40
Which sulfonylureas are recommended?
Amaryl (glimepiride)
Glucotrol (glipizide):
41
Meglinitides: typical dosing
Typically 2-3x/day
42
Meglinitides: agents
Prandin (repaglinide)
Starlix (nateglinide)
43
Meglinitides: MOA
Stimulate insulin release through β cells
Quick peak, short duration compared to sulfonylureas
44
Meglinitides: ADRs
Weight gain
hypoglycemia
45
Meglinitides: hypoglycemia risk
Important counseling: Skip a meal, skip a dose to avoid hypoglycemia
46
Meglinitides: relative efficacy
Reduces A1c A1c 1-1.5%
47
Meglinitides: important considerations
increase glycogen, fat, protein formation
Most effective for postprandial hyperglycemia
48
Prandin (repaglinide): dose, peak, duration
* 0.5-4mg ac
* Peak: 1h
* Duration: 4-6h
(Meglinitide)
49
Prandin (repaglinide): metabolism
CYP3A4 substrate
| (Meglinitide)
50
Starlix (nateglinide): dose, peak, duration
* 60-120mg ac
* Peak: 1h
* Duration: 4h
\*no dose titration required!
(Meglinitide)
51
Starlix (nateglinide): metabolism
CYP2C9 & CYP3A4 substrate
| (Meglinitide)
52
Meglinitides - hepatic or renal impairment
no adjustment
53
Biguanides: agents
Glucophage (metformin)
54
Glucophage (metformin): Dose
1000-3000mg QD divided into 2 doses or as ER formulation
55
Glucophage (metformin): renal / hepatic impairment
AVOID in renal impairment (men SCr \>1.5mg/dL, women SCr \>1.4mg/dL) (Biguanide)
56
Glucophage (metformin): MOA/PK
* Reduce A1c 1-1.5%
* hepatic gluconeogenesis
* Increase insulin sensitivity – often insulin resistance is the problem & not lack of insulin (Biguanide)
57
Glucophage (metformin) ADRs
GI distress, vit B12 deficiency, lactic acidosis (Biguanide)
58
Glucophage (metformin) hypoglycemia
No! except in combo w/other agents (Biguanide)
59
Glucophage (metformin) relative efficacy
Reduce A1c 1-2%
| (Biguanide)
60
Glucophage (metformin): how to minimize GI effects
Minimize GI SEs via slow titration -start low, go slow!
(Biguanide)
61
Glucophage (metformin): when to avoid
Avoid in renal impairment, dehydration, CHF, or recent contrast dye administration
(Biguanide)
62
Glucophage (metformin): weight
weight neutral
| (Biguanide)
63
Glucophage (metformin): GDM
GDM: did better than insulin for weight gain, but earlier births, etc. Insulin still rec’d.
(Biguanide)
64
THIAZOLIDINEDIONES: Agents
Actos (pioglitazone)
Avandia (rosiglitazone)
65
Actos (pioglitazone): dose
15-45mg PO QD
| (thiazolidinediones)
66
Actos (pioglitazone): renal or hepatic impairment
AVOID in hepatic impairment (thiazolidinediones)
67
Actos (pioglitazone): MOA
Increase peripheral insulin sensitivity by activating PPAR gamma
PPAR gamma influences the production of gene products involved in glc and lipid metabolism. Abundant in renal collecting tubules
(thiazolidinediones)
68
Actos (pioglitazone): ADRs
Edema, anemia, HF, weight gain, increase bone fractures in women
(thiazolidinediones)
69
THIAZOLIDINEDIONES: hypoglycemia?
No!
70
Actos (pioglitazone): relative efficacy
reduce A1c 1-1.5%
| (thiazolidinediones)
71
Actos (pioglitazone): β cell function
May preserve β cell function
| (thiazolidinediones)
72
Actos (pioglitazone): avoid in...
Avoid in CHF (edema), hepatic impairment
(thiazolidinediones)
73
Avandia (rosiglitazone): special considerations
Associated w/increased risk MI
Only available through REMS program for pts w/o other options including Actos
Well studied in pedi. Controversy over whether FDA overreacted
74
What are DPP-4 Inhibitors?
Dipeptidyl Peptidase-4 Inhibitors
75
DPP-4 Inhibitors MOA
Increase glucose-dependent insulin release, suppress glucagon secretion
76
DPP-4 Inhibitors: ADRs
Rhinitis, HA, URIs, rare angioedema, pancreatitis
77
DPP-4 Inhibitors: hypoglycemia?
No!
78
DPP-4 Inhibitors: relative efficacy
decrease A1c 0.6-0.8%
79
DPP-4 Inhibitors: β cell function
May preserve β cell function
80
DPP-4 Inhibitors vs sulfonylureas
more $ than sulfonylureas
81
DPP-4 Inhibitors: agents
Januvia (sitagliptin)
Onglyza (saxagliptin)
Tradjenta (linagliptin)
82
DPP-4 Inhibitors: special considerations
* ø combine w/meglinitide or sulfonylurea as both act on β cell.
* All can combine w/metformin
83
Januvia (sitagliptin): dose & peak
100mg QD
Peak: 1-4h
(DPP-4 Inhibitor)
84
Onglyza (saxagliptin): dose & peak
* 2.5-5mg QD
* Peak: 2h
(DPP-4 Inhibitor)
85
Tradjenta (linagliptin): dose & peak
* 5mg QD
* Peak: 1.5h
(DPP-4 Inhibitor)
86
Januvia (sitagliptin): hepatic & renal impairment
reduce in renal impairment
| (DPP-4 Inhibitor)
87
Onglyza (saxagliptin): when to reduce dose
reduce in renal impairment
reduce w/strong CYP3A4/5 inhibitors
(DPP-4 Inhibitor)
88
Tradjenta (linagliptin): hepatic & renal impairment
no adjustments!
| (DPP-4 Inhibitor)
89
Onglyza (saxagliptin): special considerations/ADR
* ? association w/HF
90
SGLT-2 Inhibitors: Agents
Invokana (canagliflozin)
Farxiga (dapagliflozin)
Jardiance (empagliflozin)
91
SGLT-2 Inhibitors: Hepatic & renal dose adjustment?
AVOID in ESRD
92
SGLT-2 Inhibitors: MOA
Unique mechanism Inhibits sodium-glucose-transporter (SGLT)-2 which is responsible for ~90% of glc resorption in the kidney
Results in glucosuria
93
SGLT-2 Inhibitors: ADRs
Hypotension, fungal infections, thirst, nausea, constipation, polyuria, increased LDL-C
94
SGLT-2 Inhibitors: hypoglycemia?
No!
95
SGLT-2 Inhibitors: relative efficacy?
Reduce A1c 0.7-1%
96
SGLT-2 Inhibitors: weight
• May cause weight loss
97
SGLT-2 Inhibitors: BP
• Beneficial effects on BP
98
SGLT-2 Inhibitors: Avoid in...
• Avoid in ESRD, volume-depleted pts
99
Invokana (canagliflozin): dosing
100-300mg QD
Reduce in renal impairment
(SGLT-2 Inhibitor)
100
Farxiga (dapagliflozin): dosing
5-10mg QD
Reduce in renal impairment
(SGLT-2 Inhibitor)
101
Jardiance (empagliflozin): dosing
1—25mg QD
AVOID in renal impairment
(SGLT-2 Inhibitor)
102
(GLP-1) MIMETICS: stands for
GLUCAGON-LIKE POLYPEPTIDE-1 MIMETICS
103
GLP-1 Mimetics: Agents
Byetta (exanatide)
Victoza (Liraglutide)
Tanzeum (albiglutide)
Trulicity (dulaglutide)
104
GLP-1 Mimetics: MOA
Stimulates insulin release in presence of glucose, suppresses glucagon release, slows gastric emptying, early satiety
105
GLP-1 Mimetics: ADRs
N/V/D, HA, rare necrotizing pancreatitis Some believe wt loss d/t emesis and diarrhea
106
GLP-1 Mimetics: hypoglycemia?
No! Except in combo w/sulfonylureas
107
GLP-1 Mimetics: relative efficacy?
A1c ~1%
108
GLP-1 Mimetics: formulation
• Only available as injection
109
GLP-1 Mimetics: advantages
* Weight loss (Victoza – also for chronic weight loss)
* May preserve β cell function
110
GLP-1 Mimetics: Avoid in...
Avoid in DMI, severe GI problems, DKA, _FH or personal history medullary cancer or multiple endocrine neoplasm type 2_
111
Byetta (exanatide): dosing
* 5-10mcg SQ BID
* ER: 2mg SQ weekly
* Peak: 2h
(GLP-1 Mimetics)
112
Victoza (Liraglutide)
* 0.6-1.8mg SQ QD
* Peak: 8-12h
(GLP-1 Mimetics)
113
Tanzeum (albiglutide)
* 30mcg SQ weely, may increase to 50mcg weekly
* Peak: 3-5days
(GLP-1 Mimetics)
114
Trulicity (dulaglutide)
* 0.75 mg SQ weekly, may increase to 1.5mg SQ weekly
* Peak: 24-72h
(GLP-1 Mimetics)
115
AMYLINOMIMETICS: agents
Symlin (pramlinide)
116
Symlin (pramlinide): dosing
* DMI: 15-60mcg
* DMII: 60-120mcg SQ ac
(amylinomimetic)
117
Symlin (pramlinide): MOA
Binds w/amylin receptors which suppresses glucagon release, slows gastric emptying, early satiety
(amylinomimetic)
118
Symlin (pramlinide): ADRs
Weight loss, nausea, anorexia
| (amylinomimetic)
119
Symlin (pramlinide): Hypoglycemia
Yes!
| (amylinomimetic)
120
Symlin (pramlinide): Relative Efficacy
Reduces A1c 0.4-0.6% - marginal
| (amylinomimetic)
121
Symlin (pramlinide): special considerations
Nausea is significant barrier to adherence
(amylinomimetic)
122
Insulin: major effects in liver
* Inhibits glycogenolysis, formation of keto acids;
* Promotes storage of glc as glycogen;
* increases TG and VLDL synthesis
123
Insulin: major effects in fat
increased TG storage, inhibits intracellular lipase
124
Insulin: major effects in muscle
increased glycogen synthesis, increased glc transport
125
Graphical representation: onset, peak, duration of rapid, regular, NPH, detemir and glargine
* Far left: ultra rapid acting – mimics what insulin would do w/high carb meal
* Regular: short but not as rapid as Rapids. Inject before eat to coincide w/peak in bg
* NPH: used to be used often as basal regimen. Delayed peak and prolonged lower peak. Maybe time around big breakfast, big dinner, w/effects between
* Long acting: detemir – little peak, tapers off. Usually BID, but QD for some
* Glargine: QD – low peak and stays
126
Types of insulin
Rapid: Novolog (aspart), Humalog (lispro), Apidra (glulisine)
Short: Regular
Intermediate: NPH
Long: Levemir (detimir), Lantus (glargine)
127
Insulin: MOA
Small endogenous protein normally present at low levels throughout the day interspersed w/increased levels following stimuli such as glc. See effects on liver, fat, muscle.
128
Insulin: ADRs
Weight gain
Hypokalemia
Hypoglycemia
Rare hypersensitivity reactions
129
Insulin: relative efficacy
Most effective!
130
Insulin: administration
All subQ except regular can be IV
Do not mix long-acting w/other agents
131
Insulin: analogs vs human
* Insulin analogs (glargine, detemir, lispro, aspart)
* human insulin (NPH, regular)
132
Insulin: regimens
Various regimens: Sliding scale, Single nightly dose, Basal-bolus-correction
## Footnote
*Sliding scales associated w/more hypo/hyperglycemia*
133
Rapid acting Insulin: P, O, D
Onset: 10-15min
Peak: 1-2h
Duration: 3-5h
Novolog (aspart)
Humalog (lispro)
Apidra (glulisine)
134
Intermediate-acting Insulin: P, O, D
Onset: 1-3h
Peak: 4-10h
Duration: 10-18h
NPH
135
Short acting Insulin: P, O. D
Onset: 30-60min
Peak: 2-4h
Duration: 4-8h
Regular
136
Long acting insulin: P, O, D
Levemir (detimir)
* Onset: 2-3h
* Peak: none
* Duration: 24h
Lantus (glargine)
* Onset: 1h
* Peak: none
* Duration: 24h
137
Afrezza: what is it?
Rapid acting inhaled insulin
Regular human insulin
138
Afrezza: dosing
AC or w/in 20min after starting a meal
| (inhaled insulin)
139
Afrezza: ADRs
Similar to other insulins
May cause acute bronchospasm in chronic lung dz
(inhaled insulin)
140
Afrezza: drug interactions
Albuterol increases absorption
141
Afrezza: avoid in...
Avoid in pts w/chronic lung dz (e.g., asthma, copd), active lung cancer, who smoke, or at high risk of DKA
(inhaled insulin)
142
Afrezza: monitoring & special considerations
Monitor for lung dz – spirometry, FEV1 at baseline, 6mths, then annually
Expensive and difficult to store/use
143
Diabetes in advanced age: more likely than nondiabetic to have....
Depression, cognitive impairment, urinary incontinence, injurious falls, persistent pain, HTN, coronary heart disease, stroke, functional disability, premature death
Multiple comorbidities, polypharmacy, limited financial resources
144
Diabetes & advanced age: short acting vs long acting agents
Shorter acting agents preferred: avoid glyburide, chlorpropamide d/t hypoglycemia
also why sliding scales should be avoided
145
Diabetes & advanced age: considerations for visual impairment
* ~30% ≥65yo have diabetic retinopathy, can lead to blindness
* Increased risk cataracts
* may increase risk primary open-angle glaucoma in women
* --\> consider insulin pen to deliver – they can hear click
146
Diabetes & advanced age: cognitive decline - risks
* 25% using insulin in UK showed CI
* increased risk dementia, alzheimers, vascular dementia
* may impair self-care, _assess social network_
* assess cognitive status regularly
147
Diabetes & advanced age: cognitive decline & pharm mgmt
5yr observational study:
* metformin may reduce dementia risk by up to 50%
* Sulfonylureas, thiazolidenidiones, insulin may increase risk
*good insulin control can help prevent cognitive decline*
148
Diabetes & advanced age: interventions to address polypharmacy
* List indication of each med, consider including in Rx instructions
* Simplify med regimens and use tools e.g., pill boxes if possible
Increased risk adverse events w/each added medencourage maintained med list!
149
Diabetes & advanced age: hypoglycemia considerations. Insulin vs other agents
* Increased risk d/t comorbidities e.g., CKD, polypharmacy, CI
* Insulin is most effective in reducing A1c. Adding insulin to SU is more effective w/less hypoglycemia than increasing SU dose
* Severe hypoglycemia 2x more likely w/insulin than SU in pts ≥65yo
* Insulin analogs (glargine, detemir, lispro, aspart) preferred over human insulin (NPH, regular)
* Basal-bolus regimens w/strict carb counting or difficult dose adjustments not appropriate for some
150
Diabetes meds that should be reduced in renal impairment
* Diabinese (chlorpropamide) - sulfonylurea
* Januvia (sitagliptin) and Onglyza (saxagliptin) - DPP-4is
* Invokana (canagliflozin) & Forxiga (dapagliflozin) - SGLT-2is
151
Diabetes meds that should be avoided in renal impairment
* Glucophage (metformin) - biguanide
* Precose (acarbose) & Glyset (miglitol) - Alpha-glucosidase inhibitors
* Jardiance (empagliflozin) - SGLT-2i
152
Diabetes meds that should be used w/caution in renal impairment
Diabeta (glyburide) - sulfonylurea
153
Diabetes meds that should be avoided in ESRD (besides those already mentioned for renal impairment)
all SGLT-2is
* Invokana (canagliflozin)
* Forxiga (dapagliflozin)
* Jardiance (empagliflozin)
154
Diabetes meds that should be avoided in hepatic impairment
* precose (acarbose) & Glyset (miglitol) - alpha-glucosidase inhibitors
* Actos (pioglitazone) - thiazolidinedione
155
ALPHA-GLUCOSIDASE INHIBITORS: agents
Precose (acarbose)
Glyset (miglitol)
156
ALPHA-GLUCOSIDASE INHIBITORS: MOA
Slows carb absorption from gut by inhibiting alpha-glucosidases
decrease postprandial hyperglycemia, insulin-sparing
157
ALPHA-GLUCOSIDASE INHIBITORS: hepatic / renal
AVOID in renal or hepatic impairment
## Footnote
Precose (acarbose)
Glyset (miglitol)
158
ALPHA-GLUCOSIDASE INHIBITORS: ADRs
GI Distress (will not go away)
## Footnote
Precose (acarbose)
Glyset (miglitol)
159
ALPHA-GLUCOSIDASE INHIBITORS: hypoglycemia?
No!
## Footnote
Precose (acarbose)
Glyset (miglitol)
160
ALPHA-GLUCOSIDASE INHIBITORS: relative efficacy
reduces A1c 0.5%
## Footnote
Precose (acarbose)
Glyset (miglitol)
161
ALPHA-GLUCOSIDASE INHIBITORS: weight gain
Weight neutral
## Footnote
Precose (acarbose)
Glyset (miglitol)
162
ALPHA-GLUCOSIDASE INHIBITORS: what if patient skips a meal?
Skip a meal, skip a dose – but not b/c will bottom out. B/c would be pointless
## Footnote
Precose (acarbose)
Glyset (miglitol)
163
ALPHA-GLUCOSIDASE INHIBITORS: avoid in...
Avoid in renal or hepatic impairment, IBD
## Footnote
Precose (acarbose)
Glyset (miglitol)
164
ALPHA-GLUCOSIDASE INHIBITORS: dietary consideration
Eat similar carbs each meal if possible
## Footnote
Precose (acarbose)
Glyset (miglitol)
