Recently
introduced and emerging classes of glucose-lowering drugs
1. Drugs acting on the incretin system
Insulin secretagogues such as sulphonylureas cause insulin
release irre-spective of the prevailing glucose concentration. Enhancing
insulin secre-tion through a glucose-dependent mechanism is an attractive,
novel therapeutic approach that can circumvent some of the unwanted effects of sulphonylureas principally weight gain and hypoglycaemia.
This ap-proach would be expected to restore the defectivebcell insulin
secretion pathway without causing excessive hyperinsulinaemia and carry an intrinsically
lower risk of iatrogenic hypoglycaemia. In recent years, novel drugs have
become available that are designed to fulfill these aims.
2. Pathophysiology of the incretin system in type 2 diabetes
Gastrointestinal polypeptide hormones secreted in response to the inges-tion of
a meal augment insulin secretion; this is known as the incretin effect and is
held to account for up to 70% of postprandial insulin secre-tion (Figure 3.1).
The most important incretins are glucagon-like peptide (GLP)-1 and
glucose-dependent insulinotropic polypeptide (GIP). These hormones are secreted
by the L cells of the distal ileum and colon, and the K cells of the duodenum
and upper jejunum, respectively. Circulating levels rise within minutes of
eating, implying likely stimulation by neuroendocrine pathways. Incretin
hormones act by means of specific b-cell G-protein-coupled receptors to enhance
glucose-stimulated insulin secretion. The acute effect of GLP-1 on b-cells is
the stimulation of glucose-dependent insulin release; this is followed by
enhancement of insulin biosynthesis and stimulation of transcription of the
insulin gene.
The incretin effect is deficient in patients with type 2
diabetes, mainly because of reduced postprandial GLP-1 secretion (see Figure
3.1). Re-duced GLP-1 levels are accompanied by a reduced insulinotropic action
of GIP. The cause of these defects is presently unclear. GLP-1, but not GIP,slows
gastric emptying and also suppresses appetite, effects that are im-paired by
deficiency of the hormone in type 2 diabetes.
There is abundant experimental evidence that inappropriate
glucagon secretion plays a role in the development of hyperglycaemia in type 2 diabetes,
sustaining hepatic glucose production rates in the presence of relative insulin
deficiency; this defect in islet a-cell function is thought to reflect impaired
cellular glucose sensing. GLP-1 suppresses glucagon secretion during
hyperglycaemia. The counter regulatory secretion of glucagon in response to
hypoglycaemia, however, is preserved even in the presence of pharmacological
concentrations of GLP-1. Inappropriate glucagon secretion is reduced by the
incretin system
Studies in rodents and human islets indicate that GLP-1 can
promote
the expansion of b-cell mass. To date, however, there is no
convincing evidence that this effect is reproduced in humans with type 2
diabetes. In addition to isletbandacells the tissue distribution of the GLP-1
receptor includes the central and peripheral nervous system, kidney, lung and gastrointestinal
tract. GLP-1 receptors are also present in the myocardium where their
stimulation reduces ischaemic injury in animal models.
GLP-1 and GIP are subject to rapid degradation mainly by a
ubiqui-tous cell surface enzyme dipeptidyl peptidase (DPP)-4, which cleaves two
N-terminal amino acids thereby removing insulinotropic activity. The half-life
of GLP-1 in the circulation is less than 2min, and ~7min for GIP.
Numerous gastrointestinal hormones, cytokines and
chemopeptides are also substrates for DPP-4. The enzyme, which is a member of a
wider family, is also the CD26 T-cell-activating antigen found in nearly all
human tissues.Novel therapies that exploit the incretin effect of GLP-1 include
the orally activeDPP-4 inhibitors and the injectableGLPmimetics. The latter
fallinto two categories:
(1) derivatives of GLP-1modified to resist proteolysis and
(2) novel peptides that have metabolic actions similar to
GLP-1 and are intrinsically resistant to proteolysis. The GLP-1 receptor
agonists licensed in the UK are exenatide (twice-daily and once-weekly
formulations) and liraglutide. The place of these agents in treatment
algorithms is being explored.
3. Dipeptidyl peptidase 4 inhibitors
DPP-4 inhibitors, also known as gliptins, enhance the levels
of the intestinally secreted incretins GLP-1 andGIP through selective
inhibition of the enzyme DPP-4 (Figure 3.2). Drugs in this class are now being
incor-porated into management pathways for type 2 diabetes. Sitagliptin and vildagliptin
were introduced in the UK in 2007 and 2008, respectively.Saxagliptin is
available in the USA, and received marketing authorization in the European
Union in 2009. The drugs differ in their metabolism and safety profiles (Table
3.2). Sitagliptin is currently available in three fixed-dose combinations
withmetformin: 50/500mg, 50/850mg and 50/1000mg.
Vildagliptin is offered as fixed-dose combinations with
metformin:
50/850mg and 50/1000mg. In the USA, the Food and Drug
Adminis-tration (FDA) demanded additional clinical safety data before it could approve
vildagliptin. This followed evidence of skin lesions in a primate model and
issues of safety in patients with renal impairment.
In 2011, the FDA and EMA approved linagliptin, which has a
primarily non-renal route of elimination. Linagliptin has been approved for combination
with insulin as well as in combination with certain oral glucose-lowering
agents. Other DPP-4 inhibitors are in development, including alo-gliptin, for
which the results of further safety and efficacy studies are awaited.
3.1 Pharmacokinetics
Sitagliptin, vildagliptin and saxagliptin are selective, competitive,
reversible inhibitors of DPP-4. Sitagliptin is non-covalently bound to DPP-4,where
as vildagliptin and saxagliptin bind covalently. Selectivity of action has been
an important consideration in the development of these drugs.
For sitagliptin, no inhibition of DPP-8 and DPP-9, gene
members of the S9b family of dipeptidyl peptidases, is anticipated at exposures
required for glucose lowering in humans.Sitagliptin–This has high
bioavailability (~90%) and a plasma half-life of 8–14h; Tmaxis 1–4h. Plasma
protein binding is relatively low at approxi-mately 40%. A small proportion of
the drug is hepatically metabolised by CYP3A4 and CYP2C6. Approximately 80% of
sitagliptin is eliminated unchanged in the urine through renal tubular secretion.
A single dose of 100mg sitagliptin achieves near complete inhibition of DPP-4
activity for approximately 12h, with>95% inhibition up to 24h Vildagliptin–This
has a shorter plasma half-life: 1.5–4.5h. Tmaxis less than 2h. Bioavailability
is approximately 85%. The majority of vildagliptin (~70%) undergoes
predominantly renal metabolism to inactive metabolites with a negligible
contribution from CYP450 isoforms; most (~85%) is eliminated in the urine. A
dose of 50–100mg vildagliptin will provide al-most complete inhibition of DPP-4
for approximately 12h and approxi-mately 40% inhibition at 24h. Plasma protein
binding is less than 10%.
Saxagliptin–Maximal inhibition of DPP-4 occurs 2–3h after
oral ad-ministration; the suppression of DPP-4 activity extends to 24h. Saxagliptin
is eliminated by both renal and hepatic pathways. Hepatic meta-bolism creates a
hydroxylated metabolite that has approximately 50% of the activity of the
parent compound. There is evidence of active renal excretion of the parent
compound. Circulating levels of saxagliptin and its metabolite are increased by
renal impairment.In vitro serum protein binding is 30% or less in humans.
3.2 Clinical applications
In principle, DPP-4 inhibitors can be used as monotherapy in
patients with type 2 diabetes who have responded inadequately to lifestyle
measures. This is not, however, permitted in all countries. At present, DPP-4
inhibitors tend to be preferred as second or third-line therapy in patients
inadequately con-trolled by metformin, a sulphonylurea, or a thiazolidinedione.
Theoretically,they could be used with any other class of oral agent or insulin,
as their mode of action on the b-cell is different to that of sulphonylureas
and meglitinides; moreover, their ability to reduce glucagon levels may provide
a useful adjunct to insulin therapy even when there is major b-cell
dysfunction. In the UK sitaglipitin is approved for addition to a stable dose
of insulin, with or without metformin.
Improvements in b-cell function reflect the mode of action of the drugs and are
dependent onb-cell reserves. The absence of weight-promoting actions makes the
DPP-4 inhibitors especially suitable for overweight and obese patients. The low
intrinsic risk of hypoglycaemia when used in conjunction with non-insulin-releasing
agents makes them suitable for higher-risk groups. These include individuals
who are already approach-ing glycaemic targets, or have unpredictable meal
patterns.Sitagliptin 100mg is required once a day and can be taken with or without
food; vildagliptin 50mg is usually taken twice a day. Lower do-sages are
recommended if combined with a sulphonylurea. In the UK the licence for
sitagliptin includes monotherapy if metformin cannot be used; in combination
with a sulphonylurea; in combination with a thiazolidinedione (pioglitazone);
in combination with metformin plus sulphonylurea; and in combination with metformin
plus thiazolidinedione.Sitagliptin is also approved in the UK as add-on to
insulin, or insulin and metformin.Recently introduced glucose-lowering drugs Saxagliptin
is usually taken once a day in a dose of 5mg. The dose of saxagliptin should be
reduced to 2.5 mg once daily and used with caution in patients with moderate or
severe renal impairment (i.e. creatinine clearance ‡30 to<50 ml/min).
Saxagliptin is not recommended for pa-tients with end-stage renal disease
requiring haemodialysis. The UK licence includes use with metformin, a
sulphonylurea if metformin is in-appropriate, and with a thiazolidinedione; in
all these situations diet and exercise will have been deemed to be providing
inadequate glycaemic control Vildagliptin is licensed in the UK for use as dual
oral therapy in com-bination with metformin, in patients with insufficient
glycaemic control despite the maximal tolerated dose of monotherapy with
metformin; with a sulphonylurea, in patients with insufficient glycaemic control
despite the maximal tolerated dose of a sulphonylurea and for whom metformin is
in-appropriate due to contraindications or intolerance; and a
thiazolidinedione,in patients with insufficient glycaemic control. In 2012
approval was rec-ommended for use of vildagliptin in combination with insulin
by the EMA.
The glucose-dependent action of these agents reduces the
risk of ex-cessive reductions in blood glucose, unless combined with a
sulphonylurea.There is thus no dose titration. Monitoring of fasting and
postprandial glycaemia aids assessment of response. If hypoglycaemia occurs
when a DPP-4 inhibitor is combined with a sulphonylurea, reducing the dose of
the sulphonylurea or withdrawal of the DPP-4 inhibitor is recommended.
3.3 Cautions and contraindications
Sitagliptin is mainly eliminated unchanged in the urine. In
the USA,a reduced dose is recommended for patients with moderate renal
in-sufficiency, i.e. creatinine clearance of 30ml/min or more to less than 50ml/min;
for patients with severe renal insufficiency or with end-stage renal disease
requiring haemodialysis or peritoneal dialysis, a dose of 25mg once a day
should be considered. Sitagliptin does not appear to affect P450 isoforms; this
allows its use in patients with minor to moderate impair-ment of liver
function, provided renal function is adequate. The levels of saxagliptin and
its active metabolite are reduced in patients with impaired hepatic function.
The dose of saxagliptin should be reduced to 2.5 mg once daily in patients with
moderate or severe renal impairment. In view of the renal metabolism and
elimination of vildagliptin, its use is not re-commended in patients with
moderate or severe renal impairment. The primarily non-renal route of
elimination of linagliptin means that no dose reduction is required in patients
with renal impairment. Some cases of reversible elevations in alanine aminotransferase
or aspartate aminotransferase have been observed in patients receiving
vildagliptin. Clinical chemistry assessment of liver function is recommended
before starting treatment, at 3-month intervals in the first year, and
periodically there-after. A marked rise in liver enzymes, e.g. alanine
aminotransferase or aspartate aminotransferase more than three times the upper
limit of the normal range, or other signs of hepatic impairment contraindicate
con-tinued treatment. No significant drug interactions have been noted with sitagliptin,
vildagliptin, or saxagliptin. DPP-4 inhibitors should be avoided in women
planning conception and during pregnancy.Saxagliptin is being evaluated in a
cardiovascular outcomes study to fulfill a US FDA post marketing requirement.
No evidence of cardiovascular risk has emerged to date. A pooled analysis of
phase IIb and III trials suggested a trend towards a reduction in
cardiovascular events compared with placebo or active comparators.
3.4 Efficacy
Sitagliptin–In clinical trials, the administration of
100mg/day sitagliptin as monotherapy or add-on therapy to other oral agents
typically reduced glycated haemoglobin (HbA1c) from a baseline of approximately
8% by approximately 0.7 percentage points after 24–52 weeks. Individuals with
higher baseline HbA1c levels have shown reductions in HbA1c greater than 1%;
this observation, i.e. greater glucose lowering with higher baselineHbA1c levels,
is not unique to this class of agents. Fasting plasma glucose concentrations
were reduced by approximately 1.0–1.5mmol/l, and postprandial glucose levels measured
2h after a standard mixed meal were usually reduced by approximately 3mmol/l.
Sitagliptin did not cause a clinically significant increase in the incidence of
hypoglycaemia; the combination of sitagliptin plus metformin was associated with
fewer espisodes of hypoglycaemia than a combination of glipizide plus metformin
at similar levels of HbA1creduction. Sitagliptin did not increase body weight
compared with placebo in clinical trials.
Vildagliptin–In trials, a single daily dose of 50–100mg/day
vildagliptin showed similar efficacy and tolerability to sitagliptin when used
as monotherapy or as add-on therapy to metformin or a thiazolidinedione.
The dose of vildagliptin should be 50mg once a day when
combined with a sulphonylurea. Several trials with vildagliptin produced
slightly greater reductions in HbA1c but
these tended to be associated with slightly higher average baseline HbA1c levels,
i.e. greater than 8.5%. There was no in-crease in hypoglycaemia or changes in mean
body weight with vildagliptin.
Saxaglipitin–In clinical trials, a dose of 5mg a day either
as monotherapy,or in combination with metformin, a sulphonylurea, or a
thiazolidinedione produced mean placebo-subtracted reductions in HbA1c in the range
of approximately 0.60–0.65%. No excess of hypoglycaemia or weight gain was
observed in phase III trials compared with placebo.
3.5 Adverse effects
To date no serious adverse effects have been reported.
Unlike GLP-1 agonists, upper gastrointestinal side-effects are not a feature of
DPP-4 therapy. In clinical trials generally of 6–12 months’ duration,
tolerability and adverse events were broadly similar to placebo or the
comparator drug,athough there have been reports of higher rates of
nasopharyngitis and upper respiratory tract infections. The a fore mentioned
increases in liver enzymes observed with the 100mg dose of vildagliptin does
not appear to be relevant to the 50mg dose that is marketed
