Clinical Consideration in the

Individualized Treatment of Patients

with Type 2 Diabetes

Karel Pandelaki

Division of Metabolism and Endocrine Department of Internal Medicine

Faculty of Medicine University of Sam Ratulangi / Prof.R.D.Kandou
General Hospital Manado
 Mechanisms of hyperglycemia in T2DM
Decreased
Incretin
Effect

Islet b-cell

Increased
Lipolysis
Impaired
Insulin Secretion
Islet a-cell

Increased Increased Glucose

Glucagon Secretion Reabsorption

Increased
HGP Decreased Glucose
Neurotransmitter Uptake
Dysfunction
 Case 1

• Mr. SS is a 58 year old Chinese dentist who

first saw me on 28/12/15
• T2DM since 2011 initially on diet and exercise
• Metformin 500 mg b.d for 3 years
• Height 166 cm; weight 63.2 Kg. BMI 22 Kg/m2
 Case 1

• Examination was unremarkable

• BP 130/80 mmHg, uncomplicated.
• HBA1c 8.0 %
• He has bloating with metformin
• Concerned about increasing the dose.
• Meals were sometimes erratic due to work
 Would you intensify the anti-
diabetic therapy?

A. Yes
B. No

He needs no increase body weight

 Possibilities after metformin

A. Increase metformin
B. Add Gliclazide MR
C. Add DPP-4 inhibitor
D. Add SGLT2 inhibitor
E. Add Insulin
F. Add Liraglutide or Exenetide
 Tolerability of metformin
• Main tolerability issue is in the gastrointestinal
tract
• Treatment discontinuation in <5% of patients
• Impact can often be minimised
– take with meals
– start with low dose
– cautious titration
– dose reduction if necessary
• Prolonged-release metformin (Glucophage
XR) may improve tolerability

1. Scarpello JHB. Br J Diabetes Vasc Dis 2001;1:28-36

2. Davidson J et al. Br J Diabetes Vasc Dis 2004;4:273-7
 How to choose the next medication after
metformin
• HbA1c reduction (efficacy)
• Impact on body weight and BMI
• Not potential for hypoglycemia
• No increase in CV risk
• Co-morbidities: CAD, heart failure, CKD, liver
dysfunction
• Patient factors: adherence to medications
• Side effects
 Efficacy
Class
A1C
Reduction
Metformin 1.5
Basal insulin analog 1.5–2.5
Rapid-acting insulin 1.5–2.5
Sulfonylureas 1.5
Thiazolidinediones 0.5–1.4
Short-acting GLP-1 RAs 0.5–1.0
Long-acting GLP-1 RAs ~1.5
Alpha-glucosidase inhibitors 0.5–0.8
DPP-4 inhibitors 0.6–0.8
SGLT-2s 0.8-1.0

Adapted from: Nathan DM, et al. Diabetes Care. 2007;30(3):753-759. Nathan DM, et al. Diabetes Care. 2006;29(8):1963-1972. Nathan DM, et al. Diabetes
Care. 2009;32(1):193-203. ADA. Diabetes Care. 2008;31:S12-S54. Buse J, et al. Lancet. 2009;374(9683):39-47
 Sitagliptin v.s SU as add-on agent to
Metformin
change from baseline: –0.7%
8.2

8.0
Sulfonylureaa + metformin (n=411)
7.8
Sitagliptinb + metformin (n=382)
7.6
HbA1c, % ±SE

7.4

7.2 Comparable Efficacy

7.0

6.8

6.6

6.4

6.2
0 6 12 18 24 30 38 46 52
Weeks

Adapted from Nauck MA, Meininger G, Sheng D, et al, for the Sitagliptin Study 024
Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared
a
Specifically glipizide ≤20 mg/day;
with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled
b
Sitagliptin 100 mg/day with metformin (≥1500 mg/day).
on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Per-protocol population; LSM=least squares mean. 27
Metab. 2007;9:194–205 with permission from Blackwell Publishing Ltd., Boston, MA. SE=standard error.
Considerations for Selecting Therapies
• HbA1c reduction

• Impact on body weight and BMI

• Potential for hypoglycemia
• No increase in CV risk
• Co-morbidities – CAD, heart failure, CKD, liver dysfunction
• Patient factors – adherence to medications and lifestyle
changes, oral vs injected therapy
• Economic considerations

Inzucchi et al. Diabetes Care 2012; 35:1364-79.

Weight loss in provides multiple benefits

Clinical criteria (n=1000/5145) The Look AHEAD study

at 1 year after a weight loss of
0.05% in HbA1c ≥5% to <10%
5 mmHg in SBP
5 mmHg in DBP
5 mg/dL in HDL cholesterol
40 mg/dL in triglycerides

This study was an observational analysis of participants in the Look

AHEAD study conducted at 16 US sites in 5,145 participants (40.5%
male, 37% from ethnic/racial minorities).

AHEAD, Action for Health Diabetes; CI, confidence interval; CVD, cardiovascular disease; DBP,
diastolic blood pressure; HDL, high-density lipoprotein, SBP, systolic blood pressure. Wing RG,
et al. Diabetes Care 2011;34:1481–6.
 Glucose-lowering medications:
weight profile
Weight gain Weight reduction
• SU and Glinides • Metformin
• TZDs • GLP-1 receptor agonists
• Insulin • SGLT2 inhibitors

Weight-neutral
• α-glucosidase inhibitors
• DPP-4 inhibitors
Considerations for Selecting Therapies
• HbA1c reduction
• Impact on body weight and BMI

• Potential for hypoglycemia

• No increase in CV risk
• Co-morbidities – CAD, heart failure, CKD, liver dysfunction
• Patient factors – adherence to medications and lifestyle
changes, oral vs injected therapy
• Economic considerations

Inzucchi et al. Diabetes Care 2012; 35:1364-79.

 Risk of Hypoglycemia
Hypo-
Class
glycemia

Metformin No

Basal insulin analog Yes

Rapid-acting insulin Yes

Sulfonylureas Yes

Thiazolidinediones No

Short-acting GLP-1 RAs No

Long-acting GLP-1 RAs No

Alpha-glucosidase inhibitors No

DPP-4 inhibitors No

SGLT-2s No

Adapted from: Nathan DM, et al. Diabetes Care. 2007;30(3):753-759. Nathan DM, et al. Diabetes Care. 2006;29(8):1963-1972. Nathan DM, et al. Diabetes
Care. 2009;32(1):193-203. ADA. Diabetes Care. 2008;31:S12-S54. Buse J, et al. Lancet. 2009;374(9683):39-47
Considerations for Selecting Therapies
• HbA1c reduction
• Impact on body weight and BMI
• Potential for hypoglycemia

• No increase in CV risk
• Co-morbidities – CAD, heart failure, CKD, liver dysfunction
• Patient factors – adherence to medications and lifestyle
changes, oral vs injected therapy
• Economic considerations

Inzucchi et al. Diabetes Care 2012; 35:1364-79.

 CVOTs in patients with T2DM: DPP4 inhibitors

Saxagliptin Alogliptin Sitagliptin

(SAVOR-TIMI 53 Trial )
1
(EXAMINE Trial )
2
(TECOS Trial3)

N=16,492 N=5380 N=14,671

14 24
12 15 Placebo
10 18
Patients, %

Placebo Placebo
8 10 Sitagliptin
12
6 Saxagliptin Alogliptin
4 Hazard ratio: 1.00 Hazard ratio: 0.96 5 Hazard ratio: 0.98
6 (95% CI: 0.89, 1.08)
2 (95% CI: 0.89–1.12) (upper boundary of one-
P < 0.001 (noninferiority) sided repeated 95% CI: 1.16) P=0.65
0 0 0
0 180 360 540 720 900 0 6 12 18 24 30 0 4 8 12 18 24 30 36 42 48
Days Months Months

Composite of CV death, MI, or ischemic Composite of CV death, non-fatal MI Composite of CV death, non-fatal MI,
stroke or non-fatal stroke. non-fatal stroke, or hospitalization for
unstable angina

1. Scirica, BM, et al. New Eng J Med. 2013 Oct 3;369(14):1317-26.

2. White WB, et al. N Engl J Med. 2013 Oct 3;369(14):1327-35.
3. Green JB, et al. N Engl J Med. 2015 Jul 16;373(3):232-42.
Considerations for Selecting Therapies
• HbA1c reduction
• Impact on body weight and BMI
• Potential for hypoglycemia
• No increase in CV risk

• Co-morbidities
• Patient factors – adherence to medications and lifestyle
changes, oral vs injected therapy
• Economic considerations

Inzucchi et al. Diabetes Care 2012; 35:1364-79.

 Sitagliptin has no signal for heart failure

Study Drug Placebo Hazard 95%

n/N (%) n/N (%) Ratio CI p-Value

SAVOR
SAVOR-TIMI showed
289/8280 a 27%
228/8212
(2.8%)
1.27 statistically
1.07, 1.51 significant 0.009*
(saxagliptin vs placebo) (3.5%)
increased risk with saxagliptin
EXAMINE EXAMINEa
(alogliptin vs placebo)
19% non-significant
106/2701
(3.9%)
89/2679
(3.3%)
1.19 increased
0.89, 1.58
risk with alogliptin.
0.238

No increased risk with sitagliptin in TECOS.

TECOS 228/7332 229/7339 1.00 0.83, 1.20 0.983
(sitagliptin vs placebo) (3.1%) (3.1%)

Hospitalization
0 1 2

for Heart Failure Favors Treatment Favors Placebo

*Statistically significant increase in hospitalizations for heart failure associated with saxagliptin use in SAVOR-TIMI .
1. Scirica BM, et al. N Engl J Med. 2013;369:1317–1326. 2. White WB, et al. N Engl J Med. 2013;369:1327–1335.
3. Green JB, et al. N Engl J Med. 2015;373(3):232–242.
Considerations for Selecting Therapies
• HbA1c reduction
• Impact on body weight and BMI
• Potential for hypoglycemia
• No increase in CV risk
• Co-morbidities – CAD, heart failure, CKD, liver
dysfunction
• Adverse Events
• Economic considerations

Inzucchi et al. Diabetes Care 2012; 35:1364-79.

 Adverse Event
• Type 2 diabetes is associated with an increased
fracture risk
• This is elevated by TZDs and SGLT-2 inhibitors

Engel et al. Sitagliptin and Risk of Fractures in

Type 2 Diabetes: Results from the TECOS Trial.
ADA 2016
 Injectable GLP-1 RA are expensive and
have side effects
Long-term Comparator-Controlled Trials (N = 3223)
Exenatide Exenatide
QW1,2 BID1 Sitagliptin1 Pioglitazone1 Insulin1 MET1 Liraglutide2
Preferred Term (N = 1379) (N = 268) (N = 329) (N = 328) (N = 223) (N = 246) (N = 450)
Nausea 14.4% 34.7% 6.7% 4.6% 1.3% 6.9% 20.7%
Diarrhea 10.5% 8.6% 7.6% 5.5% 4.0% 12.6% 13.1%
Headache 7.3% 6.3% 9.1% 6.7% 7.6% 12.2% 8.4%
Nasopharyngitis 7.6% 3.4% 6.4% 5.8% 18.4% 4.5% 7.1%
Vomiting 5.7% 14.2% 2.1% 3.0% 1.3% 3.3% 10.7%
Injection Site
5.9% 1.1% NA NA 0.4% NA NA
Pruritus
Constipation 5.9% 5.2% 3.0% 1.5% 1.8% 3.3% NA
Injection Site
7.0% 0.0% NA NA 0.0% NA 1.1%
Nodule
Dyspepsia 4.2% 1.9% 2.7% 3.7% 0.9% 3.3% 6.0%
 Sitagliptin and Metformin Target the
Metabolic Defects of Type 2 Diabetes
Beta-Cell Insulin
Dysfunction Resistance
Sitagliptin improves
markers of beta-cell Metformin has insulin-
function and increases sensitizing properties.3–5
insulin synthesis and (Liver > Muscle)
release.1,2

Metformin decreases
Sitagliptin reduces HGO
HGO by targeting the liver
through suppression of
to decrease
glucagon from alpha Hepatic Glucose gluconeogenesis and
cells.6 Overproduction (HGO) glycogenolysis.4

1. Aschner P et al. Diabetes Care. 2006;29:2632–2637.

2.,Vardarli I et al. Diabetes. 2014;63:663–674.
3. Abbasi F et al. Diabetes Care. 1998;21:1301–1305.
4. Kirpichnikov D et al. Ann Intern Med. 2002;137:25–33.
5. Zhou G et al. J Clin Invest. 2001;108:1167–1174.
6. Solis-Herrera et al. Diabetes Care. 2013;36:2756–2762.
 Complementary Effects of Sitagliptin and
Metformin to Incretin hormone

Total Observations in Healthy Subjects

GLP-1 Active GLP-1 Active GIP Compared With Placebo

Sitagliptin (-)  Increases active GLP-1 and GIP

 Increases total GLP-1 and increases

No active GLP-1
Metformin IR
effect
 Does not increase active GIP

Sitagliptin
 Additive effect on active GLP-1;
+
increases active GIP
Metformin IR

In a study of drug-naïveb patients with type 2 diabetes, active GLP-1 levels were increased more
when patients received both sitagliptin and metformin IR compared with either agent alone
 Why Janumet XR? (Fixed combination of
Metformin & Sitagliptin)

• HbA1c reduction: efficacy

• Fixed dose combination improves compliance
•• Better
Weighttolerated
neutral and better GI profile
•• Improved patientrisk
No hypoglycemia compliance
when used with
metformin
• Same efficacy as the IR formulation
• No increase in CV risk
• No increase in heart failure risk, No risk of
osteoporosis
• No increase risk of UTI, well tolerated
Back to the case

27
 Case 1
• Mr. SS is a 58 year old Chinese dentist
who first saw me on 28/12/15
• T2DM since 2011 initially on diet and
exercise
• Metformin 500 mg b.d for 3 years
• Height 166 cm; weight 63.2 Kg. BMI 22
Kg/m2
 Case 1
• Examination was unremarkable
• BP 130/80 mmHg, uncomplicated.
• HBA1c 8.0 %
• He has bloating with metformin
• Concerned about increasing the dose.
• Meals were sometimes erratic due to
work
 Possibilities after metformin of
Case 1
A. Increase Metformin: Not an option
B. Add Gliclazide MR: Possible, weight gain potential,
hypoglycemia risk
C. Add DPP-4 inhibitor: Good option
D. Add SGLT2 inhibitor: Possible
E. Add insulin: Not keen, weight gain, hypoglycemia
risk
F. Add Liraglutide: not keen, possible option
 Option for Case 1
• We discussed options and he decided
on Janumet XR 50/500 mg 2 tablets
per day at dinner time.
• Tolerated the treatment and came back
to see me on 21/3/16
• Compliance improved
• HBA1c level was 5.8% and his weight
was stable
 Case 2
• Mrs. MS is a 67 year old house wife
with a history of diabetes mellitus for 4
years
• Sugars were not optimally controlled on
Gliclazide MR 120 mg in the morning
and Glucophage XR 500 mg twice a
day
 Case 2
• Urinary incontinence is a problem. Diet not
optimal. Exercises infrequently. Numbness
and cramps of the lower limb
• BP 130/80 mmHg, no evidence of peripheral
neuropathy or retinopathy
• Height 159 cm; weight 59.5 Kg. BMI 23.24
Kg/m2
Investigation Results of Case 2
20/07/17
Fasting Glucose 13.5 (243) mmol/l (mg/dl)
TG 1.73 (153) mmol/l (mg/dl)
HBA1c 9.6 %
Creatinine 63.4 Umol/l
Urine Turbid
examination nitrite negative
Leukocytes ++
 Possibility after 2 OADs and
Not controlled
A. Increase metformin: Possible, potentially
increase GI side effects
B. Add a DPP-4 inhibitor: Good option
C. Add an SGLT2 inhibitor: Risk of urinary
infection, worsening of urinary symptoms
D. Add insulin: not keen, good option
E. Add Liraglutide: not keen, possible option,
costly
 Reviewed treatment of Case 2

• After discussion, we changed her Glucophage

XR 500mg b.d to Janumet XR 50/1000 mg at
dinner time increased to 2 tablets after 1 week
• Lifestyle changes, diet and weight loss of 5-
10%
• HbA1 8%
 Case 3
• Mr. YH was 55 when he saw me in June
2012.
• T2DM since 2005 on diet and exercise, and
Glucovance 500/5 mg b.d since 2010
• Height 161.5 cm; weight 78.9 Kg. BMI 30
Kg/m2
• Weight gain 4 kg previously due to hunger
Investigation Results of Case 3

04/06/12
LDL 120 mg/dl
Fasting glucose 13.85 (250) mmol/l (mg/dl)
HBA1c 11.7 %
creatinine 77 Umol/l
 Reviewed treatment of Case 3

• Uncomplicated diabetes on examination

• Changed Glucovance 500/5 mg to Janumet
50/850 mg twice daily and continued to see
the patient
• Gradual weight loss of 3-4 kg over 1 year
 Follow up HBA1c of Case 3
HBA1c (%) Medication
03/12/12 6.7
11/03/13 6.5 Janumet 50/850 mg twice daily

19/12/13 6.5
02/04/15 7.4 Recent Travelling for work forgets
morning dose
25/07/16 7.6
Janumet XR 50/500
23/11/16 8.5 2 tablets per day

29/06/17 7.5
Janumet XR 50/1000
2 tablets per day
 Case 4
• Mrs. TBH is a 59 year old house wife with
a history of diabetes mellitus for 10 years.
First saw me 15/04/16
• Medication: Gliclazide MR 120 mg in the
morning and Glucophage XR 750 mg
daily and Saxagliptin 5 mg daily plus
Rosuvastatin 10 mg daily
 Case 4
• Exercises daily. Numbness of the lower
limb
• BP 120/80 mmHg, no evidence of
peripheral neuropathy or retinopathy
• Height 176 cm; weight 79.5 Kg. BMI
25.7 Kg/m2
Investigation Results of Case 4

18/03/16
Glucose puasa 124 mg/dl
TG 104 mg/dl
HBA1c 8.4 %
Creatinine 99 Umol/l
Patient with 3 OADs and Not controlled

A. Increase metformin: Possible

B. Continue Gliclazide MR
C. Continue DPP-4 inhibitor: Good option but changed
it from Saxagliptin to Sitagliptin due to CV profile
and Heart failure risk
D. Add SGLT2 inhibitor: Possible (choice would be
Empagliflozin 25 mg daily)
E. Add insulin: not keen, good option, increase BW
F. Add Liraglutide: not keen, possible option, potential
for reduced CV death and weight loss
 Reviewed treatment of Case 4

• After discussion, we changed her

Glucophage XR 750 mg to Janumet XR
50/500 mg 2 tablets at dinner time
• Stopped Saxagliptin, continued Gliclazide
• (Did not want injections)
• Lifestyle changes, diet and weight loss of
5-10%
 Follow up of Case 4
Date of visit HBA1c (%) Diamicron MR 120 mg daily
plus
18/03/15 8.4 2 tabs Janumet XR 50/500
01/06/15 Janumet XR 50/500 plus
22/09/15 6.6 Janumet XR 50/1000

06/04/16 7.9 Ran out of medication for 1 month

23/08/16 7.3 Increased medication
16/02/17 6.7 2 tabs Janumet XR 50/1000

29/06/17 7.0 Was on 2 week holiday in Italy. Eating a

lot of pasta
 Ringkasan
• Pengobatan DMT2 perlu kombinasi beberapa obat dengan
mekanisme kerja yang saling melengkapi
• Penggunaan obat anti diabetes harus mempertimbangkan
efektifitas, efek samping, dampak terhadap kardiovaskuler,
serta kondisi pasien secara individu
• Metformin dan Sitagliptin dalam bentuk fixed combination
efektif menurunkan HbA1c, netral terhadap berat badan,
tidak menyebabkan hipoglikemi dan aman untuk
kardiovaskuler
• Fixed combination metformin dan sitagliptin
meningkatkan keteraturan pengobatan (compliance) pasien
DMT2
THANK YOU