Strategies for Diabetes Management:

The Efficacy and Safety

of Oral Combination Therapy

Budiman Darmowidjojo
Available Oral Antidiabetics
1. Biguanides
2. Sulfonylurea
3. Meglitinide
4. Thiazolidinedione
5. Dipeptidyl peptidase IV inhibitor (DPP-4 inhibitor)
6. Alpha-glucosidase inhibitor
7. Sodium/glucose cotransporter 2 (SGLT-2) inhibitor

Others: bromocriptine and bile acid sequestrant

When Oral Combination
Therapy Should Be Used?
 When Combination Therapy Should
Be Used?
1. Failure to achieve glycemic target with monotherapy (for dual
therapy) or dual therapy (for triple therapy) within a given
time period (3 months).
2. High HbA1C when starting pharmacologic treatment. Every
guideline has a consensus on HbA1C minimum cut-off to start
dual or triple therapy.

1. American Diabetes Association. Standards of medical care in diabetes – 2017. Diabetes Care. 2017;40(Supl 1)
2. American Association of Clinical Endocrinologist and American College of Endocrinology (AACE/ACE). Consensus statement by the american association of clinical endocrinologists and
american college of endocrinology on the comprehensive type 2 diabetes management algorithm – 2017 executive summary. Endocrin Pract. 2017;23(2):207-38.
3. American Diabetes Association. Standards of medical care in diabetes – 2017. Diabetes Care. 2017;40(Supl 1)
 Minimum Cut-off for Initial
Combination Therapy
Association Dual Therapy Triple Therapy
Perkeni HbA1C >9% HbA1C >9%
AACE/ACE HbA1C ≥7.5% HbA1C >9%
ADA HbA1C ≥9% Only recommended after dual
therapy failed
Perkeni : Perkumpulan Endokrinologi Indonesia
AACE/ACE : American Association of Clinical Endocrinologist and American College of Endocrinology
ADA : American Diabetes Association

1. American Diabetes Association. Standards of medical care in diabetes – 2017. Diabetes Care. 2017;40(Supl 1)
2. American Association of Clinical Endocrinologist and American College of Endocrinology (AACE/ACE). Consensus statement by the american association of clinical endocrinologists and
american college of endocrinology on the comprehensive type 2 diabetes management algorithm – 2017 executive summary. Endocrin Pract. 2017;23(2):207-38.
3. American Diabetes Association. Standards of medical care in diabetes – 2017. Diabetes Care. 2017;40(Supl 1)
DPP-4 Inhibitors
 Available DPP-4 Inhibitors
DPP-4 Inhibitors Countries Approved Available Fixed Dose Combination
Sitagliptin Worldwide Metformin
Simvastatin
Vildagliptin Worldwide (except USA) Metformin
Saxagliptin Worldwide Metformin
Dapagliflozin
Alogliptin Worldwide Metformin
Pioglitazone
Linagliptin Worldwide Metformin
Empagliflozin
Tenegliptin Japan, South Korea, India -
Anagliptin Japan -
Gemigliptin South Korea and India Metformin
Trelagliptin Japan -
Omarigliptin Japan -
Gosogliptin Russian Federation -
Evogliptin South Korea Metformin

Cahn A, Cernea S, Raz I. An update on DPP-4 inhibitors in the management of type 2 diabetes. Expert Opin Emerg Drugs. 2016;21(4):409-19.
DPP-4 Inhibitors
Monotherapy Efficacy
 Sitagliptin Placebo-Adjusted Mean
Reduction from Baseline HbA1C
Study Mean baseline Mean change from Placebo-corrected Description
HbA1C (%) baseline HbA1C (%) mean change in
HbA1C (%)
Sitagliptin 100 mg 8.0 -0.5 -0.6 HbA1C assessed at
once daily (N=193) (95% CI -0,8 to -0.4), week 18
p<0.001
Sitagliptin 100 mg 8.0 -0.6 -0.8 HbA1C assessed at
once daily (N=229) (95% CI -1,0 to -0.6), week 24
p<0.001

Januvia 25mg, 50mg, 100mg film-coated tablets. Summary of product characteristics, EU. Merck Sharp & Dohme. August 2017.
 Other DPP-4 Inhibitors Placebo-Adjusted
Mean Reduction from Baseline HbA1C
DPP-4 Inhibitors Placebo-Adjusted Trial Duration
Mean Reduction from
Baseline HbA1C

Saxagliptin 5 mg/day 0.63–0.83% 24 weeks

Linagliptin 5 mg/day 0.62–0.69% 24 weeks

Alogliptin 25 mg/day 0.48–0.61% 26 weeks

An update on the ‘gliptins’. Drug Ther Bull. 2016;54(12):138-41.

Efficacy of DPP-4 Inhibitors
Oral Combination
Karagianis et al. Dipeptidyl peptidase-4 inhibitors for treatment of type 2
diabetes mellitus in the clinical settings: systematic review and meta-analysis.
BMJ. 2012;344:e1369.
 Description
Systematic review

19 trials

13,881 participants
 Comparation Of

metformin + sulfonylurea

VS

metformin + DPP-4 inhibitors

VS

metformin + pioglitazone
 Results

metformin + sulfonylurea Statistically significant reduction in HbA1C for sulfonylurea

compared to DPP-4 inhibitors (WMD 0.07% favoring
sulfonylurea, 95% CI 0.02 to 0.13)
VS

metformin + DPP-4 inhibitors DPP-4 inhibitors had favorable body weight profile

WMD: Weighted-mean difference

 Results

metformin + pioglitazone No statistically significant difference in HbA 1C reduction

VS

metformin + DPP-4 inhibitors DPP-4 inhibitors had favorable body weight profile
Efficacy of DPP-4 Inhibitors
Oral Combination
Palmer S, et al. Comparison of clinical outcomes and adverse events
associated with glucose-lowering drugs in patients with type 2 diabetes.
JAMA. 2016.316:313-24.
 Description
2 meta-analyses

Dual therapy Triple therapy

(metformin + others) (metformin + sulfonylurea + others)

109 trials 29 trials

53,030 participants 10,598 participants
 Results

No significant difference in HbA1C reduction,

cardiovascular mortality, or all cause mortality
metformin + sulfonylurea
Treatment failures (lack of efficacy or need for rescue
VS treatment) were more common with DPP-4 inhibitors (OR
1.37, 95% CI 1.07 to 1.76)

metformin + DPP-4 inhibitors

Hypoglycemia events were less common in DPP-4
inhibitors (OR 0.12, 95% CI 0.10 to 0.16)
 Results

No statistically significant difference in HbA 1C reduction

metformin + thiazolidinedione
Treatment failures (lack of efficacy or need for rescue
VS treatment) were more common with DPP-4 inhibitors (OR
2.20, 95% CI 1.32 to 3.68)

metformin + DPP-4 inhibitors

Hypoglycemia events were not significantly different (OR
0.87, 95% CI 0.50 to 1.51)
DPP-4i Safety
Hypoglycemia
 Risk of Hypoglycemia
• DPP-4 inhibitors are generally safe in term of hypoglycemia risk.
• However, when combined with sulfonylurea or insulin, DPP-4
inhibitors combination therapy has increased risk of
hypoglycemia.
• Combined with DPP-4 inhibitors, dose of insulin or sulfonylurea
should be lowered to reduce the risk of hypoglycemia.

1. American Diabetes Association. Standards of medical care in diabetes – 2017. Diabetes Care. 2017;40(Supl 1)
2. American Association of Clinical Endocrinologist and American College of Endocrinology (AACE/ACE). Consensus statement by the american association of clinical endocrinologists and
american college of endocrinology on the comprehensive type 2 diabetes management algorithm – 2017 executive summary. Endocrin Pract. 2017;23(2):207-38.
3. American Diabetes Association. Standards of medical care in diabetes – 2017. Diabetes Care. 2017;40(Supl 1)
4. An update on the ‘gliptins’. Drug Ther Bull. 2016;54(12):138-41.
DPP-4i Safety
Acute Pancreatitis
 Risk of Acute Pancreatitis
• DPP-4 inhibitors have been associated with the risk of acute
pancreatitis.
• Therefore, patients using DPP-4 inhibitors should be informed
of acute pancreatitis symptoms, especially if there is a history of
acute pancreatitis.

1. American Diabetes Association. Standards of medical care in diabetes – 2017. Diabetes Care. 2017;40(Supl 1)
2. American Association of Clinical Endocrinologist and American College of Endocrinology (AACE/ACE). Consensus statement by the american association of clinical endocrinologists and
american college of endocrinology on the comprehensive type 2 diabetes management algorithm – 2017 executive summary. Endocrin Pract. 2017;23(2):207-38.
3. American Diabetes Association. Standards of medical care in diabetes – 2017. Diabetes Care. 2017;40(Supl 1)
4. An update on the ‘gliptins’. Drug Ther Bull. 2016;54(12):138-41.
DPP-4i Safety
Pregnancy
 Pregnancy
• Use of alogliptin, linagliptin, saxagliptin, sitagliptin, and
vildagliptin in pregnant patients has not been studied.
• Therefore, the use of DPP-4 inhibitors should be avoided in
pregnant patients.

1. An update on the ‘gliptins’. Drug Ther Bull. 2016;54(12):138-41.

2. Three new drugs for type 2 diabetes. Drug Ther Bull. 2008;46(7):49-52.
DPP-4i Safety
Hepatic Impairment
 Saxagliptin, Sitagliptin, Alogliptin
Mild or moderate hepatic impairment : no dose adjustment needed.
Severe hepatic impairment : not recommended.

Linagliptin
Lack of clinical experience use in patients with hepatic impairment.

Vildagliptin
Should not be used in hepatic impairment, including in patients with pretreatment ALT and
AST more than 3 times the upper limit of normal.
Child-Pugh Score:
Class A = 5 – 6 points (mild liver disease)
1. An update on the ‘gliptins’. Drug Ther Bull. 2016;54(12):138-41. Class B = 7 – 9 points (moderate liver disease)
2. Three new drugs for type 2 diabetes. Drug Ther Bull. 2008;46(7):49-52. Class C = 10 – 15 points (severe liver disease)
DPP-4i Safety
Renal Impairment
 Saxagliptin
Moderate or severe renal impairment : half dose (2.5 mg) should be used.
End-stage renal disease : should not be used.

Linagliptin
Moderate renal impairment : half dose (12.5 mg) should be used.
Severe renal impairment or end-stage renal disease : quarter dose (6.25 mg) should be used.

Alogliptin
Renal impairment : no dose adjustment required.
1. An update on the ‘gliptins’. Drug Ther Bull. 2016;54(12):138-41.
2. Three new drugs for type 2 diabetes. Drug Ther Bull. 2008;46(7):49-52.
Moderate renal impairment: creatinine clearance 30-50 mL/min
Severe renal impairment: creatinine clearance <30 mL/min
End-stage renal disease: requiring dialysis
 Sitagliptin
Moderate renal impairment : half dose (50 mg).
Severe renal impairment and end-stage renal disease : quarter dose (25 mg)

Vildagliptin
Moderate/severe renal impairment or end-stage renal impairment: half dose (50 mg).

Moderate renal impairment: creatinine clearance 30-50 mL/min

1. An update on the ‘gliptins’. Drug Ther Bull. 2016;54(12):138-41. Severe renal impairment: creatinine clearance <30 mL/min
2. Three new drugs for type 2 diabetes. Drug Ther Bull. 2008;46(7):49-52. End-stage renal disease: requiring dialysis
DPP-4i Safety
Cardiovascular
 SAVOR-TIMI 53
Saxagliptin
Double-blind placebo controlled trial
HbA1C 6.5 – 12% (mean 8.0%)
and
History of cardiovascular disease (≥40 years and a prior
history of coronary, cerebrovascular, or peripheral vascular
16,492 patients, with event)

or
Multiple risk factors for cardiovascular disease (male ≥55
years or female ≥60 years + either dyslipidemia or
hypertension, or active smoking)

Scirica B, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Eng J Med. 2013;369:1317-26
 SAVOR-TIMI 53
Saxagliptin
2.1 years of median follow-up

Occurred in 7.3% with saxagliptin

Primary endpoint
(composite of cardiovascular Hazard ratio [HR] 1.00, 95%
death, non-fatal myocardial CI 0.89 to 1.12; p<0.001 for
infarction, or non-fatal stroke) non-inferiority
Occurred in 7.2% with placebo

Scirica B, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Eng J Med. 2013;369:1317-26
 SAVOR-TIMI 53
Saxagliptin

Significantly higher rate of

hospitalization for 3.5% vs 2.8%; HR 1.27, 95%
CI 1.07 to 1.51
heart failure

Scirica B, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Eng J Med. 2013;369:1317-26
 EXAMINE
Alogliptin
Double-blind placebo controlled non-inferiority trial

HbA1C 6.5 – 11% (or 7.0 – 11.0% if the regimen included insulin)

5,380 patients, with and

Acute myocardial infarction or unstable angina requiring

hospitalization within the last 15 – 90 days.

White W, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Eng J Med. 2013;369:1327-35.
 EXAMINE
Alogliptin
18 months of follow-up

Occurred in 11.3% with alogliptin

Primary endpoint
(composite of cardiovascular HR 0.96, 95% CI upper
death, non-fatal myocardial boundary 1.16; p<0.001 for
infarction, or non-fatal stroke) non-inferiority
Occurred in 11.8% with placebo

White W, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Eng J Med. 2013;369:1327-35.
 EXAMINE
Alogliptin

Not significantly higher rate of

hospitalization for 3.9% vs 3.3%; HR 1.19, 95%
CI 0.90 to 1.58**
heart failure*

* Hospitalization for heart failure was not a formal outcome in the trial, but the data reviewed by
FDA.
** Despite not statistically significant, FDA still added a warning of potential increased risk of
heart failure to the label of alogliptin.

White W, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Eng J Med. 2013;369:1327-35.
 TECOS
Sitagliptin
Double-blind placebo controlled non-inferiority trial

HbA1C 6.5 – 8.0% (mean 7.2%)

14,735 patients, with and

History of major coronary disease, ischemic cerebrovascular

disease, or atherosclerotic peripheral arterial disease

Green J, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Eng J Med. 2015;373:232-42.
 TECOS
Sitagliptin
3 years median of follow-up

Occurred in 11.4% with sitagliptin

Primary endpoint
(composite of cardiovascular HR 0.98, 95% CI 0.89 to
death, non-fatal myocardial 1.09; p<0.001 for non-
infarction, non-fatal stroke, or inferiority
hospitalization for unstable Occurred in 11.6% with placebo
angina)

Green J, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Eng J Med. 2015;373:232-42.
 TECOS
Sitagliptin

No increased risk of
hospitalization for 3.1%; HR 1.00, 95% CI 0.83
to 1.20
heart failure

Green J, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Eng J Med. 2015;373:232-42.
 Risk of Hospitalization for Heart
Failure
• Because of limited safety data, caution should be exercised
when saxagliptin and alogliptin are used in patients with New
York Heart Association (NYHA) functional class III and IV heart
failure.
• Patients who are taking saxagliptin should be informed of heart
failure symptoms, especially patients who have known risk
factors for hospitalization due to heart failure (e.g. previous
history of heart failure).

1. Scirica B, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Eng J Med. 2013;369:1317-26
2. White W, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Eng J Med. 2013;369:1327-35.
3. Green J, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Eng J Med. 2015;373:232-42.
 Ongoing Clinical Trials
• CAROLINA: study of linagliptin cardiovascular safety profile,
estimated to end in 2019.
• CARMELINA: study of linagliptin cardiovascular safety profile,
estimated to end in 2018.

Cahn A, Cernea S, Raz I. An update on DPP-4 inhibitors in the management of type 2 diabetes. Expert Opin Emerg Drugs. 2016;21(4):409-19.
Fixed-Drugs Combination
VS
Separate Drugs
 Fixed Dose Combination (FDC)
• Fixed dose combination (FDC) drug is formulation of multiple
oral antidiabetics into a single form.
• FDC advantages: increase patient adherence and avoid
confusion.
• FDC disadvantages: difficulty in dose titration, increase number
of adverse drug reaction, and affecting bioavailability of agents.

1. Vijayakumar TM, Jayram J, Cheekireddy VM, Himaja D, Teja YD, Narayanasamy D. Safety, efficacy, and bioavailability of fixed-dose combinations in type 2 diabetes mellitus: a systematic
updated review. Cur Ther Res Clin Exp. 2017;84(2017):4-9.
2. Cahn A, Cernea S, Raz I. An update on DPP-4 inhibitors in the management of type 2 diabetes. Expert Opin Emerg Drugs. 2016;21(4):409-19.
Conclusion
Conclusions
• All DPP-4 inhibitors exhibit similar efficacies.
• As monotherapy or add-on therapy, DPP-4 inhibitor is superior
than placebo, but does not superior compared to another oral
antidiabetic.
• However, it generally safe in regard to hypoglycemia and body
weight side effects. Most DPP-4 inhibitors also safe to be used
in renal and hepatic impairment conditions.
• Therefore, DPP-4 inhibitors are an excellent choice as an add-on
to metformin in dual or triple therapy.
Conclusions
• Furthermore, fixed drug combination may become a desirable
choice compared to separate drug to improve patient’s
adherence.
• However, both clinician and patient should exercise cautions
when using DPP-4 inhibitors due to its increased risk of
pancreatitis (all) and worsened heart failure (saxagliptin and
alogliptin only).
Thank You