Diabetes mellitus is a common, chronic and progressive disease resulting in micro and macrovascular complications. Many classes of drugs are available for treatment but still the search for newer anti-hyperglycemic agents continues to combat significant adverse effect profile, loss of efficacy, progressive nature of disease and improve patient compliance. New emerging therapies in pipeline include drugs targeting various patho-physiologic mechanisms like incretin based therapies, sodium glucose co-transporter inhibitors, glucokinase inhibitors, 11b hydroxy steroid dehydrogenase inhibitors, drugs modulating fatty acid metabolism, selective PPARg receptor modulators and anti inflammatory agents. Aim of this review is to describe the emerging therapies for diabetes
mellitus.
2. a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 0 8 e1 1 2
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/apme
Review Article
Newer anti-hyperglycemic agents in type 2 diabetes
mellitus e Expanding the horizon
Savita Jain a,*, Nitin Gupta a, Radhika Jindal a, Tuhin Dubey a, Niti Agarwal b,
Asim Siddiqui b, S.K. Wangnoo c
a
DNB Fellow, Department of Endocrinology, Indraprastha Apollo Hospital, Sarita Vihar, New Delhi, India
Associate Consultant, Department of Endocrinology, Indraprastha Apollo Hospital, Sarita Vihar, New Delhi, India
c
Senior Consultant, Department of Endocrinology, Indraprastha Apollo Hospital, Sarita Vihar, New Delhi, India
b
article info
abstract
Article history:
Diabetes mellitus is a common, chronic and progressive disease resulting in micro and
Received 5 May 2013
macrovascular complications. Many classes of drugs are available for treatment but still
Accepted 16 May 2013
the search for newer anti-hyperglycemic agents continues to combat significant adverse
Available online 6 June 2013
effect profile, loss of efficacy, progressive nature of disease and improve patient
compliance. New emerging therapies in pipeline include drugs targeting various patho-
Keywords:
physiologic mechanisms like incretin based therapies, sodium glucose co-transporter
Type 2 diabetes mellitus
inhibitors, glucokinase inhibitors, 11b hydroxy steroid dehydrogenase inhibitors, drugs
Newer therapy
modulating fatty acid metabolism, selective PPARg receptor modulators and anti in-
Pathophysiology
flammatory agents. Aim of this review is to describe the emerging therapies for diabetes
mellitus.
Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved.
1.
Introduction
Diabetes mellitus is a chronic disease reaching epidemic
levels in both developed and developing countries. According
to WHO by 2030, there will be 366 million diabetic patients
worldwide and 80 million diabetics only in India. Significant
morbidity, mortality and cost are associated with this disease
due to progressive nature resulting in many micro and macrovascular complications. It requires continuous medical care
and self-management by the patient to prevent both acute
and chronic complications related to uncontrolled glycemic
status. Many classes of drugs are available for treatment of
diabetes mellitus like metformin, sulfonylureas, a-glucosidase inhibitors, glitazones, glinides and insulin. Newer drugs
like DPP4 inhibitors, GLP1 agonists, SGLT2 inhibitors, insulin
analogs have been added to this list during last few years.1
With these, clinical management of diabetes mellitus has
undergone a significant change. Despite availability of
numerous classes of drugs addressing different pathophysiologic mechanisms, search for new drugs continues to combat
adverse drug effects associated with available drugs (weight
gain, hypoglycemia, fluid retention, cardiovascular risk), efficacy, poor adherence due to need of injection or frequent
administration, cost or other factors and most importantly to
combat progressive decline in b cell function. In this review,
we discuss new emerging therapies for treatment of type 2
diabetes and other potential targets for development of new
drugs.
* Corresponding author.
E-mail addresses: dr.jain.savita@gmail.com, savitajain@yahoo.com (S. Jain).
0976-0016/$ e see front matter Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.apme.2013.05.013
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2.
Pathogenesis
b cells are the seat of pathophysiology of diabetes. b cell
dysfunction is an important pathophysiologic mechanism
underlying development of diabetes mellitus. There are nonmodifiable factors influencing b cell health like age and genetic predisposition. Also there are modifiable factors like
insulin resistance, lipotoxicity, glucotoxicity, incretin defect
and increase in islet amyloid polypeptide (IAPP). Along with b
cell dysfunction, insulin resistance in liver, muscle and adipose tissue accounts for development of impaired glucose
tolerance. There is increased gluconeogenesis from liver due
to hyperglucagonemia with increased sensitivity to glucagon,
lipotoxicity and glucotoxicity. Muscle is another major site for
insulin resistance characterized by multiple intramyocellular
defects like impaired glucose transport, phosphorylation,
glycogenesis and glucose oxidation. Diabetic patients have
increased lipolysis in adipose tissue thus causing release of
excessive free fatty acids into the circulation. These free fatty
acids are responsible for lipotoxicity in b cells, stimulate
gluconeogenesis from liver and cause insulin resistance. Also
there is increase in release of pro-inflammatory cytokines like
leptin and decrease in anti-inflammatory cytokines like adiponectin thus further exacerbating insulin resistance.2 Central adiposity with visceral fat deposition confers a higher risk
of developing diabetes mellitus. Drugs used earlier for diabetes targeted mainly these mechanisms for control of
hyperglycemia.
Other less important but established pathophysiologic
mechanisms include a cell dysfunction causing increased
glucagon release, enteroendocrine axis causing reduced
glucagon like peptide 1 (GLP1) secretion, kidney dysfunction
causing increased reabsorption of filtered glucose and
dysfunctional hypothalamic centers for appetite regulation in
brain. Newer drugs like DPP4 inhibitors, GLP1 agonists,
bromocriptine & SGLT2 inhibitors target these pathophysiologic mechanisms for anti-hyperglycemic effect. All these
features together form ominous octet responsible for the
development of diabetes mellitus.
Recently some other factors have been implicated and
concept of dirty dozen was proposed. Other four factors
include increased dopamine in brain, vitamin D deficiency,
testosterone deficiency and dysfunction of local renin angiotensin system in b cells.
Two other factors that have been proposed are increased
iron stores causing insulin resistance and b cell damage and
gut derived serotonin that activates hormone sensitive lipase
and thus increases lipolysis in adipose tissue.2
Many new drugs are under development targeting these
mechanisms.
3.
Drugs
3.1.
Incretins
3.1.1.
DPP4 inhibitors
DPP4 inhibitors are a class of orally active drugs that enhance
incretin system activity by blocking GLP1 degradation. GLP1 is
109
a major incretin hormone responsible for glucose dependent
increase in insulin secretion after meals, but its duration of
action is shortened by DPP4 (Dipeptidyl peptidase 4) enzyme.
Increased activity of DPP4 has been seen in diabetic patients.
Thus DPP4 inhibitors are an attractive target as antihyperglycemic drug. AnNumber of DPP4 inhibitors have
become available in last decade like sitagliptin, linagliptin,
alogliptin, vildagliptin and saxagliptin. Others that are in
various phases of trial include dutogliptin and gemigliptin.
As a class, DPP4 inhibitors have been shown to reduce
HbA1C by 0.75%. Benefits over older drugs include very low
risk of hypoglycemia, weight neutrality, oral administration,
cardiovascular safety and most importantly improving b cell
health.
Short-term studies have shown good tolerability. Adverse
effects reported in different studies are minor and include
pruritus, diarrhea, nausea, dizziness and diaphoresis.
3.1.2.
GLP1 agonists
GLP1 agonists increase insulin secretion in response to oral
glucose ingestion, induce satiety by slowing gastric emptying,
suppresses appetite, inhibit glucagon secretion and also have
been proposed to cause b cell neogenesis and protection from
cytokine and free fatty acid induced injury. Endogenous GLP1
released from intestinal L cells has a short half-life of
4e11 min. To overcome this, GLP1 analogs resistant to
degradation by DPP4 have been devised. Various drugs available are exanatide and liraglutide. Drugs under development
are albiglutide (awaiting FDA approval), lixisenatide and
semaglutide.
Potential benefits of these agents include control of postprandial hyperglycemia, less hypoglycaemia, satiety induction and thus promoting weight loss and most importantly
disease modifying effect by causing b cell neogenesis. Major
disadvantage is the need of injecting these drugs once or twice
a day. To overcome this, exanatide extended release has
recently been available. It is administered as once a week dose
at any time of the day without regard to meal.
Other minor adverse effects associated with the use of
GLP1 agonists are nausea, fullness, bloating and vomiting (to
overcome these, slow escalation of dose is done), nasopharyngitis, headache and extremity pain. Rarely pancreatitis and
hypersensitivity reactions have been reported.
3.1.3.
GPR40 agonists
G-protein coupled receptor is present on b cells and are
responsible for increased glucose dependent insulin secretion. It normally gets activated by fatty acids. GPR40 activation
has been shown to be potential therapeutic target to improve
insulin secretion and glucose tolerance.3 A novel GPR40
agonist TAK-875 has recently been shown to produce clinical
and statistically significant improvement in glycemic control
in type 2 diabetic subjects who were not controlled on diet and
exercise alone.4 Efficacy in HbA1C has been shown to be
equivalent to glimepride at higher doses, with lower propensity to cause hypoglycaemia and overall good tolerability.
Doses tested range from 6.25 mg to 200 mg, >50 mg produce
reduction in HbA1C equivalent to 1 mg glimepride. Adverse
effect attributable to drug was nasopharyngitis, mild hypoglycaemic episodes and weight gain (lesser than glimepride).
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Another agent JTT-851 is under trial for safety, tolerability and
efficacy.5
3.1.4.
GPR119 agonist
GPR119 is a lipid-sensing G protein coupled receptor (GPCR)
present on enteroendocrine cells in the gut that regulate
incretin secretion & have direct effects on insulin secretion in
pancreatic b cells. GPR-119 agonists currently under development include SAR-260093/MBX-2982 (Metabolex) in phase 2
trial, GSK-1292263 in phase 2 trial and PSN-821 in phase 2
trials.6 They have been shown to be weight negative and have
less risk of hypoglycemic episodes. Another important
advantage is oral availability. It has been proposed that coadministration of GPR119 and DPP4 inhibitors (mechanism
to protect secreted GLP-1) may offer dual benefit of providing
improved glycemic control with weight loss (as observed with
GLP-1 mimetics).
3.2.
SGLT2 inhibitors
Sodium glucose co-transporters (SGLT) are located in the
proximal tubules of the kidney and are responsible for renal
glucose reabsorption from proximal tubules. SGLT2 accounts
for 90% of this reabsorption. SGLT2 inhibitors are another
novel class of drugs with potential of improving hyperglycemia. These drugs lower glycemia by causing glucosuria and
thus do not require functioning b cells. As a class they have
modest efficacy in lowering HbA1C, do not cause hypoglycemia and have a potential use in type 1 diabetes also. Along
with glycemic control these drugs are weight negative (due to
calorie loss in urine), mild reduction in blood pressure due to
chronic osmotic dieresis and associated with lower risk of
hypoglycemia. Various drugs in this category include Dapagliflozin, Canagliflozin, Remogliflozin, Empagliflozin, Ipragliflozin, Luseogliflozin and Topogliflozin. Canagliflozin has
recently been approved for clinical use (though cardiovascular safety profile still pending). Adverse effects include urinary tract infections (due to glucosuria providing a good
medium for bacterial growth), nausea, constipation, diarrhea,
concern for potential renal toxicity (short term studies have
not shown any renal toxicity) and small risk of bladder and
breast cancer.5,7 These agents do not have any effect on lipid
profile, but long term cardiovascular safety data is still not
available.
3.3.
Glucokinase activators
Glucokinase is an enzyme present in b and a cells of pancreas
and plays an important role in glucose homeostasis. Glucokinase activation acts as glucose sensor and affects coupling
factors ATP and ADP thus depolarizing the cell, resulting in
calcium influx and stimulated insulin release. It also activates
the GABA shunt, producing gamma-hydroxybutyrate that
functions as an important paracrine inhibitor of glucagon
secretion. Further insulin itself along with GABA may inhibit
glucose-mediated alpha cell suppression. Glucokinase activator drugs thus have the potential as an anti-diabetic drugs.8
Glucokinase activation acts as a prominent regulator of hepatic intermediary and energy metabolic pathways like
glycogen synthesis, amino acid (alanine, aspartate, glutamate,
glycine and serine), lactate and urea production. Potential
detrimental effects include enhanced lipogenesis and associated hepatosteatosis and hyperlipidemia. Also this class has
propensity to cause hypoglycemia and glucolipotoxicity on b
cell survival and function.5 Trials for two drugs MK0941
(Merck) and piragliatin (Roche) were terminated prematurely.
To avoid hypoglycemia, hepatospecific compound TTP399 has
been devised by modification by introducing charged side
chains changing permeability characteristics. Preclinical trials
have proven efficacy and apparently no hepatotoxicity and
mild hypoglycemic effect, but this drug has not been extensively tested.5
3.4.
Combined a and g PPAR agonists (the glitazars)
PPARg receptors are nuclear receptors directly affecting peripheral insulin resistance and PPAR-a receptors- modulate
lipids especially triglycerides. So compounds having combined PPAR-a &g agonist activity (glitazars) were developed to
incorporate both insulin sensitizing and lipid lowering activity. These drugs are classified as thiazolidinedione variants
that include DRF-2189 & KRP-297 and nonthiazolidinedione
variants including JTT-501, BMS-298585 (muraglitazar), AZ242 (tesaglitazar) and NN-622 (ragaglitazar).1 These drugs
had favorable side effect profile in relation to cardiac hypertrophy, less weight gain and beneficial for triglyceride levels
and visceral adiposity. Other advantages found in animal
models were antiproliferative properties, angiotensin 2
antagonism, antioxidant effects, reduction of blood pressure,
correction of endothelial dysfunction and amelioration of
cardiac fibrosis associated with HT & MI. But clinical trials
revealed development of excessive peripheral edema, volume
overload and heart failure. Other detrimental effects were
bone marrow hematopoietic changes, soft tissue neoplasms
in rodents (Ragaglitazar) and hepatotoxicity.
3.5.
SPPARM’s
PPARg agonists with partial agonistic activity (SPPARM), also
known as selective PPARg receptor modulators. SPPARM’s
bind to PPARg in a different manner from full agonists and
recruit different coactivators, thus retaining insulin sensitizing effect with little side effects. Compounds under development in this class include INT-131, PN2034 (Wellstat) and
mitoglitazone.1
3.6.
11b hydroxy steroid dehydrogenase 1 inhibitors
11b hydroxy steroid dehydrogenase (11b HSD1) catalyses
activation of cortisone to cortisol in liver, adipose tissue,
pancreas and brain. Cortisol acts as an insulin antagonist,
promotes gluconeogenesis and reduces glycogenesis. Compounds in this novel class include INCB-13739, JTT-654,
AZD4017, DIO902 and RG4929.5,9 These agents are undergoing
phase 2 or 1 clinical trials. Preliminary data has shown good
tolerability, HbA1c reduction similar to DPP4 inhibitors,
modest weight loss, reduction in blood pressure & improvement in cholesterol profile without causing hypoglycemia.
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3.7.
Protein tyrosine phosphatase 1B inhibitors
3.11.
111
Anti-inflammatory therapies
Protein tyrosine phosphatase (PTP) is a negative regulator of
insulin signaling via dephosphorylation of insulin receptor
and insulin receptor substrate-1 and leptin signaling by
dephosphorylation of JAK and STAT3 in hypothalamic
neuron. Thus protein tyrosine phosphatase 1B inhibition is
another potential target for anti-hyperglycemic action.10
These agents have dual benefit of control of hyperglycemia
and weight loss. But lack of selectivity over other similar PTPs
and cell permeability are obstacles in development of these
agents. Presently studies are underway for this class of drugs.
Diabetes is a state of chronic low-grade inflammation. Inflammatory markers like interleukin-1b (IL-1b), Nuclear factor
kB and chemokines have been implicated in the pathogenesis
of type 2 diabetes. Monoclonal antibodies against IL-1b, anakinra and canakinubab are in clinical phase 2 studies. Recombinant IL-1 receptor antagonist Xoma052 is also under
study. Two compounds Triolex and VGX-1027 modulating NFkB are in clinical phase 1 studies. Chemokine receptor (CCR2)
antagonists BMS-741672 and CCX-140 are also in clinical
phase 2 studies.5
3.8.
4.
Regulators of fatty acid metabolism
Fatty acid metabolism is an important pathophysiologic link
in development of insulin resistance and glucose intolerance.
Drugs targeting fatty acid metabolic pathways are an attractive target for development of anti-hyperglycemic drugs.
Steroyl Co-A desaturase (SCD) and diacylglycerol acyltransferase (DGAT) are potential targets for drugs under
development. SCD catalyses the rate limiting step in synthesis
of monounsaturated fatty acids. Isoform SCD1 inhibition
(found in liver and adipose tissue) decreases lipogenesis and
increases fatty acid oxidation thus improving multiple metabolic parameters. But SCD1 inhibition is associated with
reduced production of triglycerides, cholesterol and wax esters required for normal function of eyelid and skin also. To
overcome this, liver-targeted approach has been employed by
including acetic or carboxylic acid group in the inhibitors.
DGAT catalyses the final step in triglyceride synthesis. DGAT1
inhibition has been shown in preliminary studies to benefit
diabetes, obesity, dyslipidemia and metabolic syndrome. Potential adverse effect associated is alopecia due to retinoid
toxicity. DGAT1 inhibitors being evaluated are AZD7687,
PF4620110 and LCQ908. AZD7687 has been found to reduce
postprandial triglyceride increase. Adverse effects reported in
preliminary study are nausea, vomiting and diarrhea.11
3.9.
Fibroblast growth factor 21 agonist
Fibroblast growth factor 21 is a hormonal regulator with the
potential to treat a variety of metabolic abnormalities like
diabetes mellitus, obesity and cardiovascular disease. It activates glucose uptake on adipocytes and reduces triglyceride
also. Currently a drug LP10152 is undergoing trial as antihyperglycemic drug.
3.10.
Glycogen phosphorylase inhibitor
Glycogen phosphorylase catalyses the breakdown of glycogen
to glucose 1 phosphate in liver. Inhibits breakdown of
glycogen and thus decrease hepatic glucose output. Glycogen
phosphorylase inhibitors thus serve as a promising treatment
strategy for hyperglycemia.12 An agent GSK1362885 is undergoing phase 1 trial presently.5
Conclusion
Better understanding of pathophysiologic mechanisms underlying diabetes, has opened gateway for development of
many new drugs for treating hyperglycemia. Many such drugs
are in pipeline, proven to be efficacious in preliminary studies
and may be available in coming few years. It is expected that
availability of new drugs will provide choices for treating
these patients better with lesser adverse effects.
Conflicts of interest
All authors have none to declare.
references
1. Uwaifo Gabriel I, Ratner Robert E. Novel pharmacologic
agents for type 2 diabetes. Endocrinol Metab Clin N Am.
2005;34:155e197.
2. Kalra S. Recent advances in pathophysiology of diabetes:
beyond the dirty dozen. J Pakistan Med Assoc. February
2013;63(2):277e280.
3. Nagasumi Kae, Esaki Ritsuko, Iwachidow Kimihiko, et al.
Overexpression of GPR40 in pancreatic b-cells augments
glucose-stimulated insulin secretion and improves glucose
tolerance in normal and diabetic mice. Diabetes. May
2009;58:1067e1076.
4. Kaku K, Araki T, Yoshinaka R. Randomized double- blind,
dose ranging study of TAK-875, a novel GPR40 agonist in
Japanese patients with inadequately controlled type 2
diabetes. Diabetes Care. 2013 Feb;36(2):245e250.
5. Cheon Hyae Gyeong. Latest research and development trends
in non-insulin anti-diabetics. Arch Pharm Res.
2013;36:145e153.
6. Xiaoyun Zhu, Wenglong Huang and Hai Qian. GPR119
agonists: a novel strategy for type 2 diabetes treatment.
Diabetes mellitus e insights and perspectives. Chapter 4.
7. Edward C, Chao, Henry Robert R. SGLT2 inhibition e a novel
strategy for diabetes treatment. Nat Rev Drug Discov AOP,
published online 28 May 2010.
8. Matschinsky Franz M. GKA’s for diabetes therapy: why no
clinically useful drug after two decades of trying? Trends
Pharmacol Sci. February 2013;34(2):90e99.
9. Ge R, Huyang Y, Liang G, Li X. 11b hydroxysteroid
dehydrogenase type 1 inhibitors as promising therapeutic
6. 112
a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 0 8 e1 1 2
drugs for diabetes: status and development. Curr Med Chem.
2010;17(5):412e422.
10. Popoy D. Novel protein tyrosine phosphatase 1B inhibitors:
interaction requirements for improved intracellular
efficacy in type 2 diabetes mellitus and obesity control.
Biochem Biophys Res Commun. 2011 Jul 8;410(3):377e378.
11. Denison H, Nilsson C, Kujacic M, et al. Proof of mechanism for the
DGAT1 inhibitor AZD7687: results from a first-time-in-human
single-dose study. Diabetes Obes Metab. Feb 2013;15(2):136e143.
12. Baker David J, Timmons James A, Greenhaff Paul L. Glycogen
phosphorylase inhibition in type 2 diabetes therapy. Diabetes.
August 2005;54:2453e2459.
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