Transcript Insulin Therapy in Diabetes

BASAL INITIATION AND
KNOWLEDGE SHARING (LINKS)
INSULIN INITIATION AND OPTIMIZATION
STRATEGIES WITH BASAL INSULINS
Dr. Ravi Kant
M.D (Medicine),P.Gd(Preventive cardiology),
Master (European and American Heart Association),
P.Gd.Diabetology (Boston University)
Associate Professor
Department of Internal Medicine
All India Institute of Medical Sciences
Rishikesh, Uttarakhand
Chair Texila American University
STARTING BASAL INSULIN
THERAPY IN DIABETES
When to Consider Starting Insulin
Anytime a patient with diabetes . . .
•
Is significantly hyperglycemic
•
Has inadequate glycemic control on other therapies
•
Is intolerant of oral hypoglycemic/other agents
•
Requires high-dose glucocorticoids
•
Is hospitalized with an acute myocardial infarction or another
acute illness
•
Is in a perioperative/intensive care setting
Decline in -Cell Function
with Diabetes Progression: UKPDS

At diagnosis of diabetes:
•
Explain the natural history of progressive decline in beta-cell
function
•
That insulin is one of the options available
to manage diabetes
•
Insulin may the best way for maintaining glucose control in the
longer term
•
Most people with diabetes eventually require
insulin therapy
What do the guidelines state about when to start
insulin therapy?

All guidelines suggest insulin as an option for initial therapy in
those with very high A1c (> 9 – 10%), especially with
symptoms.

ADA/EASD: Consider as option if A1c > target after metformin
± 1 or 2 other therapies

AACE: Generally recommended after metformin + 2 other
therapies

IDF: As an option as third or fourth line therapy

NICE: Start after metformin and sulfonylurea
Healthy eating, weight control, increased physical activity & diabetes education
Monotherapy
Metformin
Efficacy*
Hypo risk
Weight
Side effects
Costs
high
low risk
neutral/loss
GI / lactic acidosis
low
If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
Dual
therapy†
Efficacy*
Hypo risk
Weight
Side effects
Costs
Metformin
Metformin
Sulfonylurea
Thiazolidinedione
DPP-4
inhibitor
high
moderate risk
gain
hypoglycemia
low
high
low risk
gain
edema, HF, fxs
low
intermediate
low risk
neutral
rare
high
+
+
Metformin
Metformin
+
Metformin
+
+
Metformin
+
SGLT2
inhibitor
GLP-1 receptor
agonist
Insulin (basal)
intermediate
low risk
loss
GU, dehydration
high
high
low risk
loss
GI
high
highest
high risk
gain
hypoglycemia
variable
If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
Metformin
+
Triple
therapy
Sulfonylurea
+
TZD
Metformin
+
Thiazolidinedione
+
Metformin
Metformin
+
+
DPP-4
Inhibitor
+
SU
SGLT-2
Inhibitor
+
SU
SU
Metformin
+
GLP-1 receptor
agonist
+
Metformin
+
Insulin (basal)
+
TZD
SU
or
DPP-4-i
or
DPP-4-i
or
TZD
or
TZD
or
TZD
or
DPP-4-i
or
SGLT2-i
or
SGLT2-i
or
SGLT2-i
or
DPP-4-i
or
Insulin§
or
SGLT2-i
or
Insulin§
or
Insulin§
or GLP-1-RA
or GLP-1-RA
or
or
Insulin§
or GLP-1-RA
Insulin§
If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add
basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:
Metformin
Combination
injectable
therapy‡
+
Basal Insulin +
Mealtime Insulin or
GLP-1-RA
ADA/EASD
Approach
to starting
&
adjusting
insulin in
T2DM
Basal Insulin
(usually with metformin +/other non-insulin agent)
• Start: 10U/day or 0.1-0.2 U/kg/day
• Adjust: 10-15% or 2-4 U once-twice weekly to
reach FBG target.
• For hypo: Determine & address cause;
ê dose by 4 units or 10-20%.
Add 1 rapid insulin* injections
before largest meal
If not
controlled after
FBG target is reached
(or if dose > 0.5 U/kg/day),
treat PPG excursions with
meal-time insulin.
(Consider initial
GLP-1-RA
trial.)
Change to
premixed insulin* twice daily
• Start: 4U, 0.1 U/kg, or 10% basal dose. If
A1c<8%, consider ê basal by same amount.
• Start: Divide current basal dose into 2/3 AM,
1/3 PM or 1/2 AM, 1/2 PM.
• Adjust: é dose by 1-2 U or 10-15% oncetwice weekly until SMBG target reached.
• Adjust: é dose by 1-2 U or 10-15% oncetwice weekly until SMBG target reached.
• For hypo: Determine and address cause;
ê corresponding dose by 2-4 U or 10-20%.
• For hypo: Determine and address cause;
ê corresponding dose by 2-4 U or 10-20%.
If not
controlled,
consider basalbolus.
Add ≥2 rapid insulin* injections
before meals ('basal-bolus’†)
• Start: 4U, 0.1 U/kg, or 10% basal dose/meal.‡ If
A1c<8%, consider ê basal by same amount.
• Adjust: é dose by 1-2 U or 10-15% once-twice
weekly to achieve SMBG target.
• For hypo: Determine and address cause;
ê corresponding dose by 2-4 U or 10-20%.
If not
controlled,
consider basalbolus.
ADA/EASD: Approach to starting basal insulin

Start: 0.1 – 0.2 U/kg/day. Higher doses 0.3 – 0.4 U/kg/day
may be used when severely hyperglycemic

Adjust 10 – 15% (2 – 4 units) once or twice weekly to reach
FBG goal

Hypoglycemia: Determine and address cause. Decrease dose
by 10 – 20%
Addition of Basal Insulin


Basal insulin will counteract hepatic glucose output
between meals and overnight
Use of NPH, glargine, or detemir insulins recommended
by ADA/EASD, AACE, IDF



NICE recommends NPH as initial basal. Analogues can be used
in pts needing BID NPH, with hypoglycemia or need of
assistance with injections
Most individuals with type 2 diabetes will achieve
adequate control with the addition of basal insulin alone
NICE: consider twice-daily premixed particularly if A1c≥
9.0%
A Balanced Approach for Insulin Therapy in T2DM
Total hyperglycemia (%)
Relevance of Different Components of Dysglycemia:
FPG & PPG contributions by HbA1c level
100
24
21
21
20
80
60
40
76
78
79
<8.0
8.0–<8.5
8.5–<9.0
79
80
On baseline OADs,
fasting hyperglycemia dominates over
a wide range of A1C levels
20
0
A1C
Total hyperglycemia (%)
22
Postprandial Hyperglycemia
Fasting or Basal Hyperglycemia
9.0–<9.5
9.5
100
80
58
59
58
57
52
42
41
42
43
48
7.0–<7.5
7.5–<8.0
8.0
60
40
20
0
A1C
<6.5
6.5–<7.0
Following treatment intensification,
fasting hyperglycemia contributes
>40% to overall hyperglycemia
Fix Fasting First
Basal
Insulins
Elevated Fasting Hyperglycemia and HGO
Normal Fasting Blood Glucose
Hence need to fix fasting first
Glycemic Changes with Basal Insulin by
Baseline OAD Use†
-1.4
8.9
0/1 OAD
 HbA1c
-1.6
8.7
2 OADs
9.1
MET only
-1.7
8.8
SU only
8.7
MET + SU
-1.7
-1.7
Mean HbA1c
at baseline
-1.8
-1.8
p = 0.0198
-2.0
-2.0
p = 0.0006
-2.2
7.1
7.0
6.9
7.1
7.0
54.7
52.7
68.1*
50.4
56.4
† Pooled analysis , * p = 0.0001 vs all taking SU
Mean HbA1c
at 24 weeks
HbA1c <7%
(% patients)
p=0.0122
40
p=0.0006
35.4
34.7
30
20
10
0
18.8
17.3
9.0
0/1
2 MET SU MET
OAD OAD only only + SU
Baseline OAD number/class
4
(kg)
50
No significant difference
in change in body weight
Significantly less hypoglycemia
in MET only patients
Change in body weight
(% pts with BG < 50 mg/dL)
Confirmed hypoglycemia
Hypoglycemia and Weight with Basal Insulin by
Baseline OAD Use: Pooled Analysis
p=0.9547
p=0.1830
3
2
2.1 2.0
2.3
1.6
2.0
1
0
0/1
2 MET SU MET
OAD OAD only only + SU
Baseline OAD number/class
p values were calculated from an analysis of variance model with study
and baseline OAD class as factors and baseline HbA1c or bodyweight as a covariate
When starting insulin therapy

Patient education
 Proper technique for administration of insulin
 Frequent self-monitoring
 Teach dose titration
 Prevention and management of hypoglycemia
 Management of acute changes in glucose

Continuous telephone support
What to do with Other Medications?

When basal insulin is added:
Provided no contraindications to continued use
 Continue metformin
 Probably continue incretin-based therapy, SGLT-2 inhibitor
 Reduce (or discontinue) thiazolidinedione
 Most recommend continue sulfonylurea therapy (but
discontinue if hypoglycemia)

Insulin Action Profiles
Rapid-acting analogues
Plasma Insulin Levels
Regular insulin
NPH
Long-acting analogues
0:00
2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00
Time
Currently Available Basal Insulins
Insulin Activity,
GIR, mg/kg/min
Within-Patient Variability (Time-Action Profiles)
NPH
7
6
5
4
3
2
1
0
0
4
8
12
16 20
Detemir
7
6
5
4
3
2
1
0
24
0
4
8
12
16
20
Glargine
7
6
5
4
3
2
1
0
24
Elapsed Time, hours
0
4
8
12
16
20
24
Treat to Target Study Insulin Glargine vs NPH Insulin
Added to Oral Therapy
•9
Insulin glargine
NPH insulin
•8
Mean A1C
(%)
•7
Target A1C (%)
•6
•0
•4
•8
60% reach target A1C < 7%
•12
Weeks
•16
•20
•24
Events per Patient-Year
Symptomatic Hypoglycemia by Time of Day
Glargine
Basal
insulin
1.4
1.2
* *
NPH insulin
*
1.0
*
*
0.8
*
*
0.6
0.4
0.2
0
20
22
24
2
4
6
8
10
12
14
16
18
Time of Day (hour)
Hypoglycemia defined as PG  72 mg/dL, by hour
*P < 0.05 vs glargine.
When using Human NPH insulin, patients should
be advised to:
1)
Adequately mix the suspension to minimize variability
2)
Ingest a bedtime snack to avoid nocturnal hypoglycemia
Start Insulin Early: Baseline A1c Affects
Success of Basal Insulin Rx
A1c change from baseline
% of patients <7% A1c
75% of participants with baseline A1c <8% attained <7%
ORIGIN Trial: Glargine vs Standard Care in Patients at High Ris
for CVD (DM, IFG, IGT)
No difference in CV Outcomes
ORIGIN Trial: Median A1C Levels Remain
relatively stable for up to 7 years
This suggests that early use of insulin can provide durable
glucose control with low risk for hypoglycemia and weight gain
ORIGIN: Hypoglycemia & Weight
Glargine
(N=6264)
Standard
(N=6273)
P
%
/100py
%
/100py
Any Non-severe
1 or more episodes
57
17
25
5
<0.001
Severe
1 or more episodes
6
1.0
2
0.3
<0.001
Weight Change Since
Randomized
Glargine
Standard
P
1.6 kg
-0.5 kg
<0.001
Physicians Delay Intensifying Therapy for
Months, Especially Initiating Insulin
10.0%
Best Rx A1C
Pre-Tx A1C
Last Rx A1C
9.5%
A1C (%)
9.0%
8.5%
8.0%
Insulin
7.5%
7.0%
9.5%
6.5%
6.0%
A1C>8%
(months)
A1C>7%
(months)
N=2319
4
16
SU + MET
MET
SU
Diet & Exercise
N=3394 17
N=513 12
N=982 26
37
26
51
Provider Barriers To Insulin Therapy
•
Initiating insulin takes time
•
Management more complicated
•
Lack of resources
•
Increased risk for hypoglycemia
•
Fear of increased CVD risk
–
ORIGIN study refutes this
•
Weight gain, worsening insulin resistance
•
Patient resistance
Reasons Patients Avoid Insulin
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Lack of knowledge/understanding
Cultural taboos and family beliefs
Fear of needles or injection pain
Fear of hypoglycemia
Fear of weight gain
Inconvenience
Diabetes seen as worse or more serious
Personal failure
Insulin causes complications
Insulin will take over my life: constant demands and
decision-making
Strategies for Overcoming Barriers








Involve patient in therapeutic decision-making process
Frame message properly (don’t “blame” patient)
Discuss real risk of hypoglycemia (low)
Address cultural taboos and family beliefs
Fear of weight gain: minimize w/ diet, exercise, other
medications
Starting insulin: get help from you office staff:
consider group instruction
Needle phobia: show fine needles, pens
Begin therapy with simple regimen
Starting Insulin: Talking Points





Insulin is most “natural” therapy, replacing what is missing
(use thyroid hormone analogy).
No drug interactions
It prevents complications
It can be successfully used in most patients with minimal
weight gain and hypoglycemia (especially when given early)
Offer to let them stop in a month, if they don’t feel like it is
helping them
Optimizing medication adherence in type 2
diabetes
Patient education
Role of medications, hypoglycemia, need for SMBG
 Essential for successful implementation of
insulin therapy
Incorporation of medication regimen into daily routine
Established patterns help patients remember to take meds
Assess patient’s preferences and provide strategies to tailor the
timing of taking his medication to fit their lifestyle
Medication adherence is higher in QD vs more frequent
Practical Pointers
Insulin pens preferred 3:1 by patients
(Don’t forget the pen needles)
Have patient give first injection in the
office
Discuss prevention and treatment of
hypoglycemia
Provide a self titration schedule
Follow up in 1-2 weeks to review SMBG, dosing data (good time to
have patient see a staff person to reinforce education and evaluate
titrations
Cases
Case 1

Mrs. S is a 63 year old female with 8 year history of type 2
diabetes, with past history of congestive heart failure,
hypertension, hyperlipidemia

Current treatment: Metformin 850 mg BID, Glipizide 10 mg
QD, Losartan 100 mg daily, Furosemide 20 mg QD,

Atorvastatin 20 mg QHS

Testing BG QD, ranging 160 – 200

She is reluctant to start insulin
Case 1 - continued

Ht – 157 cm, Wt – 64 kg, BMI – 26

BP – 134/75, P – 76, normal eye grounds, cardiac exam, 1+
pedal edema, intact sensation

Labs - A1c – 8.1%, eGFR – 59, Lipids – TC – 155 mg/dl, HDL-C
– 37 mg/dl, TG – 185 mg/dl, LDL-C – 81 mg/dl
What is your recommendation?

Titrate glipizide

Add pioglitazone

Add premix insulin

Add basal insulin
What is your recommendation?

Titrate glipizide – A1c very unlikely to reach target

Add pioglitazone – relatively contraindicated with CHF

Add premix insulin – at her current A1c, associated with
higher weight gain and hypoglycemia, with no glycemic
advantage over glargine

Add basal insulin – best choice for her
How would you try to convince her to start insulin?
Strategies for Overcoming Patient Barriers for Starting
Insulin








Involve patient in therapeutic decision-making process
Frame message properly (don’t “blame” patient)
Discuss real risk of hypoglycemia (low)
Address cultural taboos and family beliefs
Fear of weight gain: minimize w/ diet, exercise, other
medications
Needle phobia: show fine needles, pens
Begin therapy with simple regimen
Offer a one month trial
Starting Insulin Glargine

Starting Dose?

Timing of Insulin Administration?

Instructions for SMBG?

Instructions for self-titration?

Follow up?
Starting Insulin Glargine

Starting Dose? 12 units (0.2 U/kg)

Timing of Insulin Administration? Help her determine the
time that fits into her schedule

Instructions for SMBG? Test daily in AM

Instructions for self-titration? Set target BG Depending upon
her comfort level:
 2 units very 3 days OR
 1 units every day
Starting Insulin Glargine – Follow up

Recommend follow up in 1 – 2 weeks by telephone, email
or in person to make sure she is titrating appropriately

Next visit in 4 – 6 weeks to review progress
Case 2

Mr. K is a 62 year old male with 9 year history of type 2
diabetes, complicated by neuropathy and coronary artery
disease. Also has hypertension and hyperlipidemia

Current medications: Metformin 500 mg BID, Glimepiride 4
mg daily, Insulin glargine 20 units QD, Lisinopril-HCTZ 20/25,
Metoprolol XL 50 mg daily, Atorvastatin 40 mg QD,
ASA 81 mg QD.

Tests BG QAM – range 160 - 200
Case 2 (continued)

He admits that he quit titrating because he was afraid he was
taking too much insulin.

Ht – 170 cm, Wt – 73 kg, BMI – 25.3

BP – 125/70, P – 64, normal eye grounds, cardiac exam,
absent pedal sensation

Labs - A1c – 8.5%, eGFR – 60, Lipids – TC – 135 mg/dl, HDL-C
– 34 mg/dl, TG – 205 mg/dl, LDL-C – 60 mg/dl
What would you recommend for treatment?

What is your A1c target?

Titrate metformin

Titrate glimepiride

Add pioglitazone

Add rapid acting insulin

Titrate glargine insulin further
What do you recommend?






What is your A1c target? By age, A1c < 7%, but with his
history of CAD, need to avoid hypoglycemia.
Titrate metformin – unlikely to get to target
Titrate glimepiride – unlikely to get to target
Add pioglitazone – relative contraindication with insulin
Add rapid acting insulin – is an option, but glargine is not at
optimal goal. Currently at 0.27 U/kg (Treat to target average
0.5U/kg)
Titrate glargine insulin further
Titration of Insulin Glargine

Ensure that the timing of insulin administration fits into
patients lifestyle (AM vs HS)

Patients should know their target for fasting SMBG (generally
< 100 mg/dl)

Instruct them that starting dose is low and that average dose
is 0.5 U/kg

Consider using titration of 1 unit per day until fasting BG
reaches target
Case 3

Mrs. D is a 72 year old female with 11 year history of type 2
diabetes. She has hypertension, hyperlipidemia, stage 3 CKD,
peripheral neuropathy, history of CVA.

Current medications: Glipizide 10 mg QAM, NPH 15 units BID,
Lisinopril 10 mg QAM, Chlorthalidone 15 mg QD, Atorvastatin
20 mg QD, ASA 81 mg daily

She reports awakening frequently at 2 am with tremors and
sweats
Case 3 (continued)

Ht – 150 cm, Wt – 62 kg, BMI – 27

BP – 125/70, P – 64, normal eye grounds, cardiac exam,
absent pedal sensation

Labs - A1c – 8.8%, eGFR – 35, Lipids – TC – 148 mg/dl, HDL-C
– 40 mg/dl, TG – 195 mg/dl, LDL-C – 69 mg/dl
What is your recommendation?

What is your A1c target?

What would you do with her hyperglycemic
regimen?
Add metformin
 Titrate Glipizide
 Titrate NPH
 Switch to Glargine, with titration to goal

What is your recommendation?


What is your A1c target? – with her age and comorbidities, it
would be appropriate to target an
A1c < 8.0%
What would you do with her hyperglycemic regimend?
 Add metformin – relative contraindication with eGFR
 Titrate Glipizide – unlikely to reach goal – already having
probable hypoglycemia
 Titrate NPH – likely to increase her probable hypoglycemia
 Switch to Glargine, with titration to goal – best answer
Events per Patient-Year
Treat to Target: Symptomatic Hypoglycemia by Time of
Day
Glargine
Basal
insulin
1.4
1.2
* *
NPH insulin
*
1.0
*
*
0.8
*
*
0.6
0.4
0.2
0
20
22
24
2
4
6
8
10
12
14
16
18
Time of Day (hour)
Hypoglycemia defined as PG  72 mg/dL, by hour
*P < 0.05 vs glargine.
Transitioning from NPH to Glargine

If QD – convert 1:1 and titrate

If BID – lower dose by 20% and titrate

Older individuals may need additional support for titration –
family member, home nurse, more frequent office visits.

Reinforce consistency of diet and exercise
Summary

Guidelines recommend insulin therapy after failure of one or more
non-insulin therapies or when A1C ≥ 9%

Start simple with basal insulin

Treatment with glargine insulin has lower incidence of nocturnal
hypoglycemia than human NPH insulin and analogue premix insulin

Patient-specific considerations regarding insulin use

Individualized glycemic targets

Availability of glucose monitoring

Socieconomic considerations

Education of prevention and management of hypoglycemia

Promote continued adherence to a healthy diet and regular
physical activity

Be enthusiastic and confident to encourage and empower
your patients!
THANK YOU