The Role of DPP-4 Inhibitors in Management of Type 2 Diabetes

Strategies for Diabetes Management: The Efficacy and Safety of Oral

Combination Therapies

Starting Antidiabetic Combination Therapy

Antidiabetic should be given in combination in two conditions. First, failure to achieve glycemic
target with monotherapy (for dual therapy) or dual therapy (for triple therapy) within a given
period, which is 3 months. Next, if initial HbA1C is high. The cut-off for starting initial combination
therapy remain a debate. See Table 1 to see the minimum cut-off to start initial combination
therapy for dual therapy and triple therapy in various guidelines.1-3

Table 1. Minimum cut-off for initial combination therapy in various guidelines1-3

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 : Indonesian Endocrinology Association
AACE/ACE : American Association of Clinical Endocrinologist/American College of Endocrinology
ADA : American Diabetes Association

DPP-4 Inhibitors
Normally, an enzyme called dipeptidyl peptidase-4 (DPP-4) is responsible for destroying a group
of gastrointestinal hormones called incretins. Incretins help stimulate insulin production when
needed (e.g. after meals) and reduce glucagon production by the liver when insulin is not needed
(e.g. when digesting food). Incretins also slow down digestion and decrease appetite. By
administering DPP-4 inhibitor, incretins will not be destroyed. Therefore, its beneficial effect can
be maintained.

There are several DPP-4 inhibitors that are available. See Table 2 for further information.4

Table 2. Available DPP-4 inhibitors4

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

Efficacy of DPP-4 Inhibitors as Monotherapy

As monotherapy, there is similarity between each DPP-4 inhibitor (see Table 3). Overall, DPP-4
inhibitors exhibit good efficacy in reducing HbA1C compared to placebo.5,6

Table 3. Efficacy of sitagliptin6

Study Mean Mean change Placebo-corrected Description

baseline from baseline mean change in
HbA1C (%) HbA1C (%) HbA1C (%)
Sitagliptin 100 8.0 -0.5 -0.6 HbA1C
mg once daily (95% CI -0,8 to - assessed at
(N=193) 0.4), p<0.001 week 18
Sitagliptin 100 8.0 -0.6 -0.8 HbA1C
mg once daily (95% CI -1,0 to - assessed at
(N=229) 0.6), p<0.001 week 24

Table 4. Efficacy of other DPP-4 inhibitors5

DPP-4 Inhibitors Placebo-Adjusted Mean Reduction from Baseline Trial

HbA1C Duration
Saxagliptin 5 0.63–0.83% 24 weeks
mg/day
Linagliptin 5 0.62–0.69% 24 weeks
mg/day
Alogliptin 25 0.48–0.61% 26 weeks
mg/day

Efficacy of DPP-4 Inhibitors as Oral Combination Therapy

There are two interesting systematic reviews and meta-analyses of DPP-4 inhibitors. The first one
is a systematic review by Karagianis et al which included 19 trials, consisted of 13,881 participants,
comparing sulfonylurea, pioglitazone (thiazolidinedione), and DPP-4 inhibitor as add-on to
metformin. Compared to combination of metformin and sulfonylurea, DPP-4 inhibitors dual
therapy with metformin had favorable body weight profile. However, sulfonylurea combination
therapy showed statistically significant reduction in HbA1C compared to DPP-4 inhibitor
combination therapy (weighted mean difference 0.07% favoring sulfonylurea, 95% CI 0.02 to 0.13).
When compared to pioglitazone combination with metformin, DPP-4 inhibitors still had favorable
body weight profile. There was no statistically significant difference in HbA1C reduction between
both combinations.7

The second systematic review is a study done by Palmer et al. They separated the study into two
meta-analyses; one for dual therapy, one for triple therapy. The dual therapy meta-analysis
included 109 trials and 53,030 participants. As dual therapy, DPP-4 inhibitor was added to
metformin and compared to sulfonylurea as an add-on to metformin. The results showed that
there was no significant difference in HbA1C reduction, cardiovascular mortality, and all-cause
mortality between both dual therapy. Treatment failures (defined as lack of efficacy or need for
rescue treatment) were more common with DPP-4 inhibitor (OR 1.37, 95% CI 1.07-1.76).
Hypoglycemia events were less common with DPP-4 inhibitor (OR 0.12, 95% CI 0.10-0.16).8

Meanwhile, as triple therapy, DPP-4 inhibitor was compared to thiazolidinedione as third add-on
to combination of metformin and sulfonylurea. The results showed that there was no significant
difference in HbA1C reduction between both triple therapy. Treatment failures were more
common with DPP-4 inhibitor (OR 2.20, 95% CI 1.32-3.68). Hypoglycemia events were not
significantly different (OR 0.87, 95% CI 0.50-1.51).8

DPP-4 Inhibitor Safety

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.5

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.5

Cardiovascular Safety
Until now, there are three big clinical trials which have assessed the cardiovascular safety profile
of DPP-4 inhibitors: SAVOR-TIMI 53 for saxagliptin, EXAMINE for alogliptin, and TECOS for
sitagliptin. All three of those studies showed that there was no difference in primary endpoint
(composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke, between
saxagliptin, alogliptin, and sitagliptin, compared to placebo. While those results mean than those
three are safe for cardiovascular endpoint, it also means that there is no benefit of those drugs
use for cardiovascular endpoint.9-11
It is important to highlight that SAVOR-TIMI 53 study found that saxagliptin use was associated
with significantly higher rate of hospitalization for heart failure compared to placebo (3.5% vs
2.8%; hazard ratio 1.27, 95% CI 1.07-1.51). Alogliptin was not associated with significantly higher
rate of hospitalization for heart failure (3.9% vs 3.3%; hazard ratio 1.19, 95% CI 0.90-1.58), but
Food and Drug Administration (FDA) still added a warning of potential increased risk of heart
failure to alogliptin’s label.5,9-11

Renal Impairment
Except for saxagliptin, most DPP-4 inhibitors are safe to be used even in severe renal
impairment.5,12

Table 5. DPP-4 inhibitors safety in renal impairment5,12

DPP-4 Renal Impairment

Inhibitors Moderate Severe End-stage
Saxagliptin Half dose (2.5 mg) Not recommended Not recommended
Alogliptin No dose adjustment No dose adjustment No dose adjustment
needed needed needed
Sitagliptin Half dose (50 mg) Quarter dose (25 mg) Quarter dose (25 mg)
Linagliptin Half dose (12.5 mg) Quarter dose (6.25 mg) Quarter dose (6.25 mg)
Vildagliptin Half dose (50 mg) Half dose (50 mg) Half dose (50 mg)
Renal impairment
Moderate renal impairment : creatinine clearance 30-50 mL/min
Severe renal impairment : creatinine clearance <30 mL/min
End-stage renal disease : requiring dialysis

Hepatic Impairment
DPP-4 inhibitors are generally safe to be used in patients with mild and moderate hepatic
impairment, except for linagliptin and vildagliptin. DPP-4 inhibitors should not be used in severe
hepatic impairment.5,12

Table 6. DPP-4 inhibitors safety in hepatic impairment5,12

DPP-4 Hepatic Impairment

Inhibitors Mild Moderate Severe
Saxagliptin No dose adjustment No dose adjustment Not recommended
needed needed
Alogliptin No dose adjustment No dose adjustment Not recommended
needed needed
Sitagliptin No dose adjustment No dose adjustment Not recommended
needed needed
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)
Class B = 7 – 9 points (moderate liver disease)
Class C = 10 – 15 points (severe liver disease)

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.5,12

Fixed-Dose Combination or Separate Drugs?

Fixed dose combination (FDC) drug is formulation of multiple oral antidiabetics into a single form.
It has advantages and disadvantages compared to separate drugs. FDC advantages are increased
patient adherence and avoiding confusion. It also disadvantages, which are difficulty in dose
titration, increase number of adverse drug reaction, and affecting bioavailability of agents.13

Conclusion
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 regarding 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.

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).

Keywords
dipeptidyl peptidase-4; DPP-4 inhibitor; efficacy; oral combination therapy; safety; acute
pancreatitis; hypoglycemia; heart failure; cardiovascular safety; saxagliptin; alogliptin

References
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