Interactive Patient Case

Management #1
 Case : Umar
• 63 year old accountant
• Type 2 diabetes without complications x 22 years
• Current therapy:
•Metformin 1000 mg BID
•Gliclazide MR 120 mg OD
•Statin
•ACE inhibitor
How can we overcome
–BP : 124/78
–A1c : 7.9% his reluctance ?
–eGFR : 72 ml/min

• Patient is reluctant to initiate insulin

therapy when you offer this
possibility.
 Case : Umar
• 63 year old accountant
• Type 2 diabetes without complications x 22 years
• Current therapy:
•Metformin 1000 mg BID
•Gliclazide MR 120 mg OD
•Statin
•ACE inhibitor
What should we do
–BP : 124/78 with the current
–A1c : 7.9% antihyperglycemic agents?
–eGFR : 72 ml/min

• Patient is reluctant to initiate insulin

therapy when you offer this
possibility.
 What Do You Do with Background Antihyperglycemic
Agents When a Patient is Started on Insulin?

Class Kept? Why?

Metformin YES
Studies have shown efficacy of these agents in
DPP-4 inhibitors YES
presence of insulin, with less hypoglycemia and
GLP-1RAs YES weight gain vs. insulin alone.
SGLT2 inhibitors YES
Acarbose YES
Insulin secretagogues +/- May be associated with more hypoglycemia and
weight gain, but also reduced insulin dosing and less
need for > 1 injection of insulin per day. Consider
reducing the dose of insulin secretagogues when
initiating insulin.
Thiazolidinediones NO Cause water retention and edema. These side effects
have been shown to be more frequent in presence of
insulin, with an increase in the risk of heart failure.
Note: When continuing non-insulin agents with insulin, the costs should be considered in addition to the
benefits.
SGLT2: sodium-glucose cotransporter 2; DPP-4: dipeptidyl peptidase-4; GLP-1RAs: glucagon-like peptide-1 receptor agonists
Adapted from: CDA Clinical Practice Guidelines Expert Committee. Can J Diabetes 2013;37:S61-68; 4
Swinnen SG, et al. ADA 2010. Abstract 0037-OR.
 Case : Umar
• 63 year old accountant
• Type 2 diabetes without complications x 22 years
• Current therapy:
•Metformin 1000 mg BID
•Gliclazide MR 120 mg OD
•Statin
•ACE inhibitor
What basal insulin
–BP : 124/78 would you choose ??
–A1c : 7.9%
–eGFR : 72 ml/min

• Patient want to initiate insulin

therapy when you offer this
possibility.
 Comparison of Basal Insulins

NPH Detemir Glargine Glargine

U100 U300
Commercial denominations Humulin N Levemir Lantus/ Toujeo
Novolin NPH Basaglar
Duration of action 16h 20h 24h > 24h
Potency to reduce A1c (%) > 0.9 % > 0.9 % > 0.9% > 0.9 %
Hypoglycemia Nocturnal 1 ↓ ↓ ↓↓
Risk (RR) All Day 1 ↓ ↓ ↓↓
Effects on Body Weight (Kg) +1 0 +1 + 0.6
Long-term Safety UKPDS ORIGIN

12
Vora J. et al. Diabetes Ther. 2014;5:435-446
Freemantle N et al. BMJ Open 2016; 6:e009421
Tsapas A et al. Abstract 841. EASD 2016
 Case 1 : Umar
• 63 year old accountant
• Type 2 diabetes without complications x 22 years
• Current therapy:
•Metformin 1000 mg BID
•Gliclazide MR 120 mg OD
•Statin
•ACE inhibitor What titration regimen
–BP : 124/78 would you choose ??
–A1c : 7.9%
–eGFR : 72 ml/min

• Patient is reluctant to initiate insulin therapy when you offer this

possibility.
 Basal insulin titration in EDITION studies in T2DM
Gla-300 was always given in the evening1-7
Titration steering committee was in place
Adjustments at investigators’ discretion for safety
Dose adjustments, U/day
EDITION 1, 2 & 3 EDITION JP 2
Median fasting SMPG from last 3 days in the range of:2,4,6,7
Gla-100 or Gla-300 Gla-300 Gla-100
≥140 mg/dL (≥7.8 mmol/L) +6 +3 +2

>100 and <140 mg/dL (5.6–7.8 mmol/L) +3 +1.5 +1

Glycemic target: 80–100 mg/dL (4.4–5.6 mmol/L) No change

≥60 and <80 mg/dL (3.3–4.4 mmol/L) -3
<60 mg/dL (<3.3 mmol/L) or occurrence of ≥2 symptomatic or 1 severe
-3 or at investigator’s discretion
hypoglycemia episode(s) in the preceding week

• Dose adjustment was generally once weekly, but no more often than every 3 to 4 days 1,3,5,7
• The dose of basal insulin was generally unchanged at entry; however, the dose was reduced by 20% if two daily NPH
injections were previously used1,3,7

NPH, neutral protamine Hagedom; SMPG, self-measured plasma glucose; T2DM, type 2 diabetes mellitus
1. Riddle MC et al. Diabetes Care. 2014;37:2755-62; 2. Data on file, EDITION 1 CSR (6 months) pg 26-28; 3. Yki-Järvinen H et al. Diabetes Care. 2014;37:3235-43;
4. Data on file, EDITION 2 CSR (6 months) pg 26-28; 5. Bolli GB et al. Diabetes Obes Metab. 2015;17:386-94; 6. Data on file, EDITION 3 CSR (6 months) pg 30-31;
7. Terauchi Y et al. Diabetes Obes Metab. 2016;18:366-74 (main article and Supplementary Table 1)
8
 Insulin titration in clinical practice
• When initiated, insulin is ideally titrated from a low starting dose (usually
10 U/day) to achieve therapeutic efficacy using various titration algorithms
ADA/EASD 20061* AACE 20132 IDF 20123 CDA 20134

0.1–0.2 U/kg if HbA1c <8%

Initial dose/ day 10 U or – 10 U
0.2–0.3 U/kg if HbA1c >8% Diabetes &
its complications
Titration 2 U every 3 days 1-4 U every 2-3 days caused
2 U every 3 days5.1 million
1 U every day
deaths
Target FPG, in 2013
70–130 <110 <115 72–126
mg/dL

Target HbA1c, % <7.0 <7.0 <6.5 ≤7.0

• However, inadequate dose titration remains a barrier to optimal insulin therapy in

clinical practice5–8
– Poor target achievement suggests suboptimal titration by patients and/or their
physicians in the real-world setting8
*ADA/EASD 2012 guidelines do not provide a prescriptive algorithm for titration
CDA, Canadian Diabetes Association
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972; 2. Garber AJ et al. Endocr Pract. 2013;19:327-36;3. IDF. Global Guideline for Type 2 Diabetes. Available at;
http://www.idf.org/global-guideline-type-2-diabetes-2012 Accessed August 2014; 4. 2013 CDA Clinical Practice Guidelines. Available at: http://guidelines.diabetes.ca/Browse.aspx
Accessed August 2014; 5. Garber AJ. Diabetes Obes Metab. 2009;11 Suppl 5:10-3; 6. Riddle MC et al. Diabetes Care 2003;26:3080–3086;
7. Baser O et al. Clinicoecon Outcomes Res. 2013;5:497-505; 8. Hamaty M. Cleve Clin J Med. 2011;78:332-42

SAGLB.DIA.14.06.0065a(1) / 2014.09
Interactive Patient Case
Management #2
 Case : Samia
• 72 year old frail woman
• Type 2 diabetes for 16 years
• Renal failure: eGFR 28
ml/min

GLYCEMIA
• Stable retinopathy
• Macular edema treated by
photocoagulation last year
• Moderate neuropathy
• Myocardial infarct 6 months
ago. No heart failure
• Current treatment:
–Gliclazide 120 mg AM
–Bisoprolol 5 mg AM
–Telmisartan 40 mg AM Could Glargine 300 units/ml help Samia?
–Clopidogrel 75 mg AM
–Rosuvastatin 40 mg AM 1) Improved glucose control
2) With minimal risk of
–A1c 8,6%
hypoglycemia
12
 EDITION 1-2-3 T2D: Elderly (6 Months)

Incidence of Hypoglycemic Events in

Older People (Aged ≥65 Years)
Participants with ≥1 confirmed* or severe hypoglycemic event

Protocol Defined Hypoglycemia at any

Nocturnal hypoglycemia time (24 h)
90 (00:00–05:59 h)
% Participants ≥1 Confirmed* or Severe Event

RR 0.93
(95% CI 0.85–1.01)
80 300 U/mL (N=327)
70 77.4 100 U/mL (N=332)
71.6
60
RR 0.70
50 (95% CI 0.57-0.85)

40 44.9

30
31.8 *Confirmed, ≤ 70 mg/dL
20

10

0
1 3
Baseline to Month 6
13
Yale et al., Abstract presented at 75th American Diabetes Association congress (2015) abstract 991-P
 Current Long-Acting Basal Insulins

ORIGIN: Effect of Basal Insulin Glargine on

Cardiovascular Outcomes
Myocardial infarction, stroke or death from CV causes
ORIGIN
• 12,537 patients with high CV
risk and IFG or IGT or newly
detected or early T2D
• Randomized to standard
glycemic care or insulin
glargine (to FPG goal ≤5.3
mmol/L)
• Median follow-up of 6.2
years

FPG, fasting plasma glucose;

IFG, impaired fasting glucose
IGT, impaired glucose tolerance

Insulin glargine had a neutral effect on CV outcomes

14
The ORIGIN Trial Investigators. N Engl J Med. 2012;367:319-328
 Comparison of Basal Insulins

NPH Detemir Glargine Glargine

U100 U300
Commercial denominations Humulin N Levemir Lantus Toujeo
Novolin NPH Basaglar Lantus XR
Duration of action 16h 20h 24h > 24h
Potency to reduce A1c (%) > 0.9 % > 0.9 % > 0.9% > 0.9 %
Hypoglycemia Nocturnal 1 ↓ ↓ ↓↓
Risk (RR) All Day 1 ↓ ↓ ↓↓
Effects on Body Weight (Kg) +1 0 +1 + 0.6
Long-term Safety UKPDS ORIGIN

12
Vora J. et al. Diabetes Ther. 2014;5:435-446
Freemantle N et al. BMJ Open 2016; 6:e009421
Tsapas A et al. Abstract 841. EASD 2016
Interactive Patient Case
Management #3
CASE : A.A. 71/ male, Asian

Oct 2009, at age 63 y.o, 5’10” tall BMI = 21 kg.m2

admitted at another hospital for cellulitis / gangrene
with incidental finding of glucose at 450 mg/dL

antibiotics, insulin and

below-knee amputation

Home Rx: NPH 30 u AM and 15 u PM, telmisartan, amlodipine

carvedilol, ISMN, aspirin, atorvastatin 20 mg
advised follow-up care with endocrinologist near his residence
 CASE : A.A. 71/ male, Asian

Nov 2009, at age 63 y.o : referred to Endocrinologist

Labs: HBA1c = 11.9% eGFR = 62%, hunger pangs at 2AM
SMBG: AM 99 to 148 mg/dl; 153 – 243 mg/dL pre dinner
Plan: Revise NPH 35 u AM, no evening dose of NPH; Start Glipizide
5 mg before dinner, Metformin 1000 mg after dinner

From 2009 to 2013: visits endocrinologist 3x a year

Serial SMBG’s and HBA1c range stable at 6.2 to 7.2%; occasional
episodes of hypoglycaemia at night (stopped Glipizide); NPH dose
titrated up to 40 u daily in AM; Metformin, telmisartan,
amlodipine, ISMN, carvedilol, aspirin, atorvastatin 20 mg
maintained; eGFR down to 55% in 2013 at age 67
CASE : A.A. 71/ male, Asian

January 2014, at age 67 y.o : Thrombotic Ischemic stroke

Labs: HBA1c = 6.7% eGFR = 54% 2DE: concentric LV
hypertrophy, adequate wall motion and contractility and systolic function
Added Aspirin + Clopidogrel, Ator shifted to Rosuvastatin 20 mg
Discharge meds: NPH 38 u in AM; resumed Metformin 1000 mg at home

From 2014 to 2015: visits endocrinologist 3x a year

HBA1c range stable at 6.6 to 6.8%; eGFR down to 48-50% so
Metformin dose reduced to 850 mg daily

April 2016 at age 69 yo: HBA1c = 8.9%; SMBG = 141-265 mg/dL

NPH increased to 43 u; Gliclazide 60 mg MR added pre-
dinner, metformin same dose 850 mg after dinner
CASE : A.A. 71/ male, Asian

April 2016 age 69 y.o.: HBA1c = 8.9%; SMBG = 141-265 mg/dL

eGFR 51%: NPH increased to 43 u; Gliclazide 60 mg MR added
pre-dinner, metformin 850 mg after dinner

Aug 2016: HBA1c = 8.0%

shifted to NPH 70% +Regular 30% at 36 u SC pre
breakfast; same dose Gliclazide 60 mg MR; Metformin 850 mg

After 2 weeks, FBS = 89 mg/dL; SMBG: 116-121 postprandial

Dec 2016 age 70 y.o.: HBA1c = 7.8%; SMBG = 138-158 mg/dL

eGFR 46%: increased NPH+Regular 38 u; same Gliclazide 60 mg
MR pre-dinner, reduced metformin 500 mg after dinner
CASE : A.A. 71/ male, Asian

April 2017 age 70 y.o.: HBA1c = 7.8% SMBG 98 – 160 mg/dL pre
breakfast and 128 – 150 mg/dL 2 hours post meals;
hypoglycemia at 10 AM and at 2 to 4 AM.
Reduce NPH+Regular insulin to 36 u. Reduce Gliclazide to 30 mg,
same dose Metformin 500 mg after breakfast

July 2017, age 71 y.o.: HBA1c = 8.5%, FBS = 146 mg/dL

eGFR 47% peripheral neuropathy, cataracts

Glargine U300 at 28 u SC at 8 AM (+3H) (78% of pre-mix dose 36)

Glulisine 7 u SC before or right after lunch
Metformin 850 mg after dinner

After 2 weeks: SMBG AM= 95-128 mg/dL; 140-160 mg/dL hours ppg
NO HYPOGLYCEMIA; HBA1c, creatinine due October
 CASE Learning Points

• Diabetes presentation can be catastrophic in people who do not

get screened regularly
• Even when we control their sugars and try to give standard of care
for BP, lipids, heart, they are still prone to develop comorbidities
with age, such as stroke and chronic kidney disease.
• As they age, more problems appear and we should be cautious of
HYPOGLYCEMIA: Glargine U300 is proven to have less hypo
• FLEXIBILITY is also important: basal-plus regimen is flexible
• INDIVIDUALIZED treatment strategy to reach targets safely
• We take care of our patients for the rest of their lives and we
become part of their “extended family”
22
Interactive Patient Case
Management #4
AGC,
58/Female,

came in for
weakness & palpitations
Case 2: AGC, 58/F, Weakness & Palpitations

● T2DM for 5 years

● Came in for weakness and palpitations
for 2 months
● Initially on DPP4-I and Metformin
combination
● Started to Detemir insulin because of
uncontrolled FBS ~ 180 mg/dl
● Started on 10 units of Detemir, up-
titrated and is presently on 18 units at
bedtime.
● However, patient started to experience
weakness and palpitations at early
morning and would wake up and drink
softdrink for relief
Case 2: AGC, 58/F, Weakness & Palpitations

• Current findings
– BMI 27 kg/m2
– BP 145/90 mmHg
– Fundi: moderate, non-proliferative
diabetic retinopathy
– External: decreased pinprick
sensation in both feet

• Current laboratory results

– HbA1c: 8.4 %
– FPG: 90 mg/dl
– LDL-C: 84 mg/dl
Self Glucose Monitoring

80
280

100
230

62
197 226
 Points for Discussion

• Is the patient ideal to be switched to

Glargine U300? Why ?
• Is hypoglycemia a problem in the
management of T2DM?
• How would you initiate and titrate Glargine
U300 dose for this patient?
 Points for Discussion

●How would you manage this patient now?

a) Instruct patient to decrease intake of complex
carbohydrates at lunch and dinner
b) Instruct patient to consume more snacks at
bedtime
c) Increase the dose of Detemir BID
(12 u BID from 18 u at HS)
d) Switch to insulin Glargine 300
 Titration Schedule

Gla-300

If the patient is on a BID dosing, Gla-300

use 80% of total previous daily

basal insulin dose +3U
(ex. 20 u OD GLA 300 from 12 u BID Detemir)
+1U
 Basal insulin titration in EDITION studies in T2DM
Gla-300 was always given in the evening1-7
Titration steering committee was in place
Adjustments at investigators’ discretion for safety
Dose adjustments, U/day
EDITION 1, 2 & 3 EDITION JP 2
Median fasting SMPG from last 3 days in the range of:2,4,6,7
Gla-100 or Gla-300 Gla-300 Gla-100
≥140 mg/dL (≥7.8 mmol/L) +6 +3 +2

>100 and <140 mg/dL (5.6–7.8 mmol/L) +3 +1.5 +1

Glycemic target: 80–100 mg/dL (4.4–5.6 mmol/L) No change

≥60 and <80 mg/dL (3.3–4.4 mmol/L) -3
<60 mg/dL (<3.3 mmol/L) or occurrence of ≥2 symptomatic or 1 severe
-3 or at investigator’s discretion
hypoglycemia episode(s) in the preceding week

• Dose adjustment was generally once weekly, but no more often than every 3 to 4 days 1,3,5,7
• The dose of basal insulin was generally unchanged at entry; however, the dose was reduced by 20% if two daily NPH
injections were previously used1,3,7

NPH, neutral protamine Hagedom; SMPG, self-measured plasma glucose; T2DM, type 2 diabetes mellitus
1. Riddle MC et al. Diabetes Care. 2014;37:2755-62; 2. Data on file, EDITION 1 CSR (6 months) pg 26-28; 3. Yki-Järvinen H et al. Diabetes Care. 2014;37:3235-43;
4. Data on file, EDITION 2 CSR (6 months) pg 26-28; 5. Bolli GB et al. Diabetes Obes Metab. 2015;17:386-94; 6. Data on file, EDITION 3 CSR (6 months) pg 30-31;
7. Terauchi Y et al. Diabetes Obes Metab. 2016;18:366-74 (main article and Supplementary Table 1)
31
 Insulin titration in clinical practice
• When initiated, insulin is ideally titrated from a low starting dose (usually
10 U/day) to achieve therapeutic efficacy using various titration algorithms
ADA/EASD 20061* AACE 20132 IDF 20123 CDA 20134

0.1–0.2 U/kg if HbA1c <8%

Initial dose/ day 10 U or – 10 U
0.2–0.3 U/kg if HbA1c >8% Diabetes &
its complications
Titration 2 U every 3 days 1-4 U every 2-3 days caused
2 U every 3 days5.1 million
1 U every day
deaths
Target FPG, in 2013
70–130 <110 <115 72–126
mg/dL

Target HbA1c, % <7.0 <7.0 <6.5 ≤7.0

• However, inadequate dose titration remains a barrier to optimal insulin therapy in

clinical practice5–8
– Poor target achievement suggests suboptimal titration by patients and/or their
physicians in the real-world setting8
*ADA/EASD 2012 guidelines do not provide a prescriptive algorithm for titration
CDA, Canadian Diabetes Association
1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972; 2. Garber AJ et al. Endocr Pract. 2013;19:327-36;3. IDF. Global Guideline for Type 2 Diabetes. Available at;
http://www.idf.org/global-guideline-type-2-diabetes-2012 Accessed August 2014; 4. 2013 CDA Clinical Practice Guidelines. Available at: http://guidelines.diabetes.ca/Browse.aspx
Accessed August 2014; 5. Garber AJ. Diabetes Obes Metab. 2009;11 Suppl 5:10-3; 6. Riddle MC et al. Diabetes Care 2003;26:3080–3086;
7. Baser O et al. Clinicoecon Outcomes Res. 2013;5:497-505; 8. Hamaty M. Cleve Clin J Med. 2011;78:332-42

SAGLB.DIA.14.06.0065a(1) / 2014.09
 Who are the patients who will benefit?

Courtesy of Anne Peters, MD Medscape and Prof Baron, UC San Diego- USA