1) The document summarizes newer oral antidiabetic drugs for type 2 diabetes mellitus, including incretin-based therapies like DPP-4 inhibitors and GLP-1 analogues, and SGLT-2 inhibitors. 2) DPP-4 inhibitors work by inhibiting the DPP-4 enzyme, increasing incretin hormone activity. SGLT-2 inhibitors work by inhibiting the SGLT-2 transporter in the kidney, reducing glucose reabsorption and increasing urinary glucose excretion. 3) The document also discusses other potential drug classes still under research, such as GPR-40 agonists, glucokinase activators, and glucagon receptor antagonists.

1. 1
Newer Oral Antidiabetic Drugs
Authors
 Prof. Dr. C. R. Anand Moses MD,FRCP,
Head and Chief Diabetologist,
Moses Diabetes and Medical Centre, Chennai.
Former Director,
Institute of Diabetology,
Madras Medical College & Rajiv Gandhi Government General Hospital,
Chennai.
 Dr. S. Charles Bronson MBBS, D.Diab. (MMC),MRi
Diabetologist,
Institute of Diabetology,
Stanley Medical College and Hospital,
Chennai.

2. 2
Introduction
Oral antidiabetic drugs (OAD) form the mainstay of treatment for type 2 diabetes mellitus
(T2DM). Metformin is considered as the first line OAD unless it is contraindicated or is not
tolerated by the patient. When adequate glycaemic control is not achieved by a single drug alone,
combination therapy is necessary [1]
In recent years, the knowledge on the pathophysiology of T2DM and hence, the therapeutic
opportunities have increased considerably. Drugs which target different aspects of the
pathophysiology are increasingly being employed in treatment and new drugs are being developed.
The time-tested OADs
These are the OADs which have been in clinical usage for a good number of years and for
which considerable research evidence, clinical experience and safety data are available.
Sulphonylureas
 Glibenclamide
 Glipizide
 Gliclazide
 Glimepiride
Biguanides
 Metformin
Thiazolidinediones
 Pioglitazone
Alpha-glucosidase inhibitors
 Acarbose, voglibose

3. 3
Meglitinide analogues
 Repaglinide
 Nateglinide
The newer OADs
1) Incretin-based therapies:
In their landmark paper in 1906, Moore, Edie and Abram showed that the “internal”
secretion of the pancreas is stimulated by a hormonal substance produced in the duodenum and
that in the absence of this excitatory stimulation, glycosuria ensues. [2, 3]. Glucagon-like peptide
-1 (GLP-1) and glucose dependent insulinotropic peptide (GIP) are the two incretins which are
secreted in the gut in response to a meal. They act on their receptors on the pancreatic beta cell
and potentiate the secretion of insulin. These incretins are inactivated by the enzyme dipeptidyl
peptidase-4 (DPP-4) [2].
Both GLP-1 and GIP enhance insulin secretion from the beta cells (insulinotropic effect).
GLP-1 suppresses glucagon secretion in a glucose-dependent manner. This is not seen with GIP-
1. GLP-1 and not GIP delays gastric emptying in humans. All these contribute to the glucose
lowering effect. Further, the incretins have other pleiotropic effects also. [4]
The insulinotropic effect of GIP is minimized and is almost lost is T2DM. In contrast to
this, the effect of GLP-1 is better preserved in T2DM patients. [4].
Incretin based therapies for diabetes are DPP-4 inhibitors and GLP-1 analogues.
DPP-4 inhibitors
DPP-4 inhibitors are also known as “gliptins”.
The various drugs under this class are

4. 4
- Sitagliptin
- Vildagliptin
- Saxagliptin
- Linagliptin
- Alogliptin
Pharmacokinetics:
Gliptins are given orally, as a tablet.
The pharamacokinetic properties of the various gliptins are briefly discussed in Table-1. [5]
Pharmacodynamics:
Mechanism of action:
These drugs inhibit the intestinal brush border enzyme DPP-4 which inactivates the incretins.
Thus, they increase the activity of the incretin hormones.
Effects:
DPP-4 inhibitors enhance insulin secretion from the beta cells and suppress glucagon
secretion. They are weight neutral. DPP-4inhibitors decrease beta cell apoptosis and improve beta-
cell mass. [6]
Adverse effects:
DPP-4 inhibitors are generally well tolerated.
Adverse effects include- upper respiratory infections, nasopharyngitis, headache,
hypersensitivity reactions, angioedema, pancreatitis [7], arthritis and arthralgia [8].

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Role in the management of T2DM:
DPP-4 inhibitors are employed in combination therapy or as monotherapy in the treatment
of T2DM. The HbA1c lowering efficacy of DPP-4 inhibitors is about 0.6 – 0.8 % [9].
The DPP-4 inhibitors, except Linagliptin, need dose adjustment in renal impairment (Table
2). [10 - 15]
When vildagliptin is to be initiated in a patient, liver function tests should be performed
prior to initiation and should be monitored at three months’ interval during the first year and
annually thereafter. During the course of treatment, if there is a persistent elevation of
aminotransferases to three times or more of the upper limit of normal, vildagliptin should be
withdrawn. Following normalization of liver function testes later, vildagliptin should not be
restarted in these patients. Vildagliptin is not recommended in patients with hepatic impairment
and in those with aminotransferases level of greater than 2.5 times the upper limit of normal. [12]
For saxagliptin and linagliptin, no dose adjustment is needed in hepatic impairment. [13,
14] Regarding sitagliptin and alogliptin, no dose adjustment is necessary in mild and moderate
hepatic impairment. However, they have not been studied sufficiently and hence not recommended
in severe hepatic impairment. [11, 15]
DPP-4 inhibitors are classified as Pregnancy class B drugs. It is not known if they are
secreted in human milk. Hence, they are not recommended for use in nursing mothers. The safety
and effectiveness of DPP-4 inhibitors in the pediatric population of less than 18 years, have not
been established. [11 - 15]
In the ‘SAVOR-TIMI 53’ trial, saxagliptin was significantly associated with a 27%
increased risk of hospitalizations due to heart failure. [16]
Newer gliptins
 Teneligliptin – available in India.
 Omarigliptin – a once weekly DPP-4 inhibitor, under research [17]

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GLP-1 analogues
The GLP-1 analogues like exenatide and liraglutide are subcutaneous injections.
A new oral formulation of the GLP-1 analogue semaglutide has shown promising results
in HbA1c lowering and is under investigation. [18]
2) Sodium glucose co-transporter - 2 (SGLT-2) inhibitors
This group of drugs inhibit the sodium glucose co-transporter-2 (SGLT-2) present in the
proximal convoluted tubule of the nephron, thereby decreasing the reabsorption of glucose.
The drugs in this class include canagliflozin, dapagliflozin and empagliflozin.
Pharmacokinetics:
The SGLT-2 inhibitors are oral preparations. They can be taken without regard to meals.
They are usually taken in the morning, before breakfast. There is no interaction with food.
Canagliflozin-
 Dose – 100 – 300 mg; once daily
 Half- life - 10.3 to 13 hours
Dapagliflozin
 Dose – 5 – 10 mg; once daily
 Half-life – 12.9 hours
Empagliflozin
 Dose – 50 mg; once daily
 Half-life – 10 -19 hours [19]

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Pharmacodynamics:
Mechanism of action
Physiologically, most of the glucose which is freely filtered in the glomerulus is reabsorbed
back into the circulation through the SGLT-2 transport protein present in the proximal convoluted
tubule of the nephron. In patients with diabetes, the renal threshold for glucose is also increased,
probably due to the upregulation of SGLT-2. Inhibitors of SGLT-2 reduce the reabsorption of
glucose in the kidney, increase the excretion of glucose in urine and thereby decrease the plasma
glucose levels. [Figure 1] [20]
Effects
Treatment with SGLT-2 inhibitors cause reduction in blood glucose. Reduction in body weight
and blood pressure also occurs. The SGLT-2 inhibitors have a low risk of causing hypoglycaemia.
[20]
Adverse effects:
 Genital and urinary tract infections [20]
 Osmotic-diuresis related adverse events like polyuria [20]
 Hypoglycaemia especially when combined with insulin or sulphonyl urea. [20]
 Increase in total, LDL and HDL cholesterol [21]
 Euglycemic ketosis [22]
 Hyperkalemia, especially in patients with moderate renal impairment and in those taking
potassium sparing diuretics and drugs that act on the renin-angiotensin-aldosterone system
(canagliflozin) [20]
 Volume-related adverse effects like postural dizziness (canagliflozin) [20]
 Small decrease in the eGFR which was acute (canagliflozin) [20]
 Hypersensitivity reactions

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Role in the management of T2DM
SGLT-2 inhibitors are indicated in combination therapy or as monotherapy in the treatment
of T2DM. [1] The HbA1c lowering efficacy of SGLT2 inhibitors is about 0.5-0.8 %. [23]
SGLT 2 inhibitors are classified as ‘pregnancy category C’ drugs. It is not known whether
they are secreted in human milk. Hence they are not to be used while breastfeeding. Their safety
and effectiveness in the age group of less than 18 years have not been clearly established. [24]
Based on the available studies, it is observed that canagliflozin had less glycemic control
efficacy in patients with moderate renal impairment with increased adverse events [24, 25] The
response to canagliflozin decreases with increasing level of renal impairment. [24] The efficacy
and safety of canagliflozin have not been established in those with severe renal impairment, ESRD
and those patients on dialysis.[25] Dapagliflozin is contraindicated in those with moderate to
severe renal impairment and ESRD [26]. With worsening renal function, the glucose lowering
effect of empagliflozin decreases and the risks of renal impairment and adverse effects increase.
[27]
For Canagliflozin, no dosage adjustment is necessary in patients with mild or moderate
hepatic impairment. It is not recommended in those with severe renal impairment. [25] As per the
evidence available, no dosage adjustment is needed for dapagliflozin in patients with mild,
moderate and severe hepatic impairment. [26] Empagliflozin can be used in patients with hepatic
impairment. [27].
In the EMPA-REG study, patients who received empagliflozin in addition to standard care,
had reduced rates of death from cardiovascular causes, all-cause mortality and hospitalization due
to cardiac failure, when compared to placebo. [28]
Upcoming SGLT-2 inhibitors:
 Sotagliflozin, a dual SGLT-1 and SGLT-2 inhibitor [29]

9. 9
 Ertugliflozin [30]
 Ipragliflozin [31]
 Tofogliflozin [32]
 Remogliflozin [33]
3) OADs under research and in the pipeline
GPR-40 agonists
A cell surface receptor called ‘free fatty acid receptor-1’, also known as ‘G protein coupled
receptor-40’ (GPR-40) is expressed in the pancreatic beta cells. Agonists at this receptor increase
insulin secretion. These agents are being investigated. [17]
Metformin- Delayed release
The glucose lowering action of metformin is partly due to its effect on the entero-endocrine
cells in the small intestine to release hormones like GLP-1 and peptide YY (PYY). Metformin-
delayed release, termed NewMet is a formulation which is not absorbed in the small intestine and
has its action mainly in the lower bowel segment. It is found to be more effective in lowering
HbA1c than extended release metformin. [17]
Mitochondrial targets of thiazolidinediones
Recent studies have shown that the glucose lowering effect of thiazolidinediones can be
separated from their action on the peroxisome proliferator-activated receptor- γ. Drugs under
investigation target a novel complex, the ‘mitochondrial target of thiazolidinediones’ (mTOT)
which seems to modulate the entry of pyruvate into the mitochondrion and the oxidation of
pyruvate. The agents under research have been shown to have HbA1c lowering efficacy similar to
that of pioglitazone, with lesser fluid retention. [17]

10. 10
Glucagon receptor antagonists
This class of agents were investigated and they showed HbA1c lowering effect. However,
elevation in liver aminotransferases was observed. [17]
Glucokinase activators
A lot of studies were conducted on this class of drugs. Glucose lowering effect was
observed initially. However, the efficacy waned over time. Still, this group is being investigated
for developments, because of the central role the enzyme glucokinase plays in glucose metabolism.
[17]
Other potentially promising OADs under research
These include modulators of gut microbiota, bile acid sequestrants, glycogen synthase
activators, glycogen phosphorylase inhibitors, etc. [17].
Conclusion
T2DM is a modern day scourge which affects millions worldwide. However, as a result of
untiring research throughout the world, newer anti-diabetic agents are continuously being
developed. This enables the clinician to have a multi-pronged approach to the management of
T2DM, which in turn would improve the quality of life and longevity of the patient.

11. 11
Table 1
Pharmacokinetics of gliptins [5]
Dose Half-life (t ½) DPP-4
inhibition
Drug
interactions
Sitagliptin 100 mg O.D. 8-24 hours Max ~ 97% -
Vildagliptin 50 mg B.D. 1 ½ to 4 ½ hours Max ~ 95% -
Saxagliptin 5 mg O.D. 2-4 hours (parent)
3-7 hours
(metabolite)
Max ~ 80% Caution with
drugs
metabolized by
the CYP3A4/5
system
Linagliptin 5 mg O.D. 10-40 hours Max ~ 80% -
Alogliptin 25 mg O.D. 12-21 hours Max ~ 90% -
DPP-4 - Dipeptidyl peptidase 4
Adapted from Gupta V, Kalra S [5]. Used under the Creative Commons license CC-BY-NC-SA
https://creativecommons.org/licenses/by-nc-sa/4.0/

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Table 2
Use of DPP-4 inhibitors in patients with CKD [10 –15]
Renal
excretion
eGFR
> 60 ml/min
eGFR
30-59 ml/min
eGFR
< 30 ml/min
Haemodialysis
Sitagliptin Predominant 100 mg 50 mg 25 mg 25 mg – with
caution
Vildagliptin Intermediate 100 mg as two
divided doses
50 mg 50 mg 50 mg - with
caution
Saxagliptin Predominant 5 mg 2.5 mg 2.5 mg -with
caution
2.5 mg -with
caution
Linagliptin Low 5 mg 5 mg 5 mg 5 mg – with
caution
Alogliptin Predominant 25 mg 12.5 mg 6.25 mg 6.25 mg – with
caution
Adapted from Eleonora Russo et al [10]. Used under the Creative Commons license: CC BY-NC
4.0 https://creativecommons.org/licenses/by-nc/4.0/
eGFR- estimated glomerular filtration rate
Note - most of the DPP-4 inhibitors have been studied only in the setting of hemodialysis and
not in peritoneal dialysis.

13. 13
Figures
Figure 1
Reabsorption of glucose via SGLT-2 and the action of SGLT-2 inhibitors. [20]
Reproduced from the article by Eva M. Vivian [20]. Used under the Creative Commons license- CC BY
NC ND 3.0. https://creativecommons.org/licenses/by-nc-nd/3.0/

14. 14
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