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Insulin and Other Glucose-Lowering Drugs
I. OVERVIEW
The pancreas is both an endocrine gland that produces the peptide hormones insulin,
glucagon, and somatostatin and an exocrine gland that produces digestive enzymes. The
peptide hormones are secreted from cells located in the islets of Langerhans (β cells
produce insulin, α cells produce glucagon, and δ cells produce somatostatin).
Hyperinsulinemia cause severe hypoglycemia. Diabetes mellitus can cause serious
hyperglycemia. If this condition is left untreated, retinopathy, nephropathy, neuropathy,
and cardiovascular complications may result. Administration of insulin preparations or
other injectable or oral glucoselowering agents can prevent morbidity and reduce
mortality associated with diabetes
II. DIABETES MELLITUS
Diabetes is not a single disease. Rather, it is a heterogeneous group of syndromes
characterized by an elevation of blood glucose caused by a relative or absolute deficiency
of insulin. The American Diabetes Association (ADA) recognizes four clinical
classifications of diabetes: type 1 diabetes (formerly, insulindependent diabetes mellitus),
type 2 diabetes (formerly, non-insulindependent diabetes mellitus), gestational diabetes,
and diabetes due to other causes (for example, genetic defects or medications).
Gestational diabetes is defined as carbohydrate intolerance with onset or first recognition
during pregnancy. It is important to maintain adequate glycemic control during
pregnancy, because uncontrolled gestational diabetes can lead to fetal macrosomia
(abnormally large body) and shoulder dystocia (difficult delivery), as well as neonatal
hypoglycemia. Diet, exercise, and/ or insulin administration are effective in this
condition.
A.
Type 1 diabetes
Type 1 diabetic shows classic symptoms of insulin deficiency (polydipsia, polyphagia,
polyuria, and weight loss). Type 1 diabetics require exogenous insulin to avoid the
catabolic state that results from and is characterized by hyperglycemia and life-
threatening ketoacidosis.
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1.
Cause of type 1 diabetes: The development and progression of neuropathy,
nephropathy, and retinopathy are directly related to the extent of glycemic control
(measured as blood levels of glucose and/or hemoglobin A1c [HbA1c]).3
2.
Treatment: A person with type 1 diabetes must rely on exogenous (injected)
insulin to control hyperglycemia, avoid ketoacidosis, and maintain acceptable levels of
glycosylated hemoglobin (HbA1c). The goal in administering insulin to those with type 1
diabetes is to maintain blood glucose concentrations as close to normal as possible and to
avoid long-term complications. Continuous subcutaneous insulin infusion (also called the
insulin pump) is another method of insulin delivery. Other methods of insulin delivery,
such as trans- dermal, buccal, and intranasal, are currently under investigation.
B.
Type 2 diabetes
Most diabetic patients have type 2 disease. Type 2 diabetes is influenced by genetic
factors, aging, obesity, and peripheral insulin resistance, rather than by autoimmune
processes or viruses
1.
Cause: In type 2 diabetes, the pancreas retains some β-cell function, but variable
insulin secretion is insufficient to maintain glucose homeostasis. Type 2 diabetes is
frequently accompanied by the lack of sensitivity of target organs to either endogenous or
exogenous insulin. This resistance to insulin is considered to be a major cause of this type
of diabetes.
2.
Treatment: The goal in treating type 2 diabetes is to maintain blood glucose
concentrations within normal limits and to prevent the development of long-term
complications of the disease. Weight reduction, exercise, and dietary modification
decrease insulin resistance and correct the hyperglycemia of type 2 diabetes in some
patients. However, most patients are dependent on pharmacologic intervention with oral
glucose-lowering agents. As the disease progresses, β-cell function declines and insulin
therapy is often required to achieve satisfactory serum glucose levels.
III. INSULIN AND ITS ANALOGS
Insulin is a polypeptide hormone consisting of two peptide chains that are connected by
disulfide bonds. It is synthesized as a precursor (proinsulin) that undergoes proteolytic
cleavage to form insulin and C-peptide. Measurement of circulating C-peptide provides a
better index of insulin levels.
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A.
Insulin secretion
Insulin secretion is regulated not only by blood glucose levels but also by certain amino
acids, other hormones, and autonomic mediators. Secretion is most commonly triggered
by high blood glucose, which is taken up by the glucose transporter into the β cells of the
pancreas. There, it is phosphorylated by glucokinase, which acts as a glucose sensor. The
products of glucose metabolism enter the mitochondrial respiratory chain and generate
adenosine triphosphate (ATP). The rise in ATP levels causes a block of K+ channels,
leading to membrane depolarization and an influx of Ca2+. The increase in intracellular
Ca2+ causes pulsatile insulin exocytosis. The sulfonylureas and glinides owe their
hypoglycemic effect to the inhibition of K+ channels.
B. Sources of insulin
Human insulin is produced by recombinant DNA technology using special strains of
Escherichia coli or yeast that have been genetically altered to contain the gene for human
insulin. Modifications of the amino acid sequence of human insulin have produced
insulins with different pharmacokinetic properties. For example, three such insulins,
lispro, aspart, and glulisine, have a faster onset and shorter duration of action than regular
insulin, because they do not aggregate or form complexes. On the other hand, glargine
and detemir are long-acting insulins and show prolonged, flat levels of the hormone
following injection.
C. Insulin administration
Because insulin is a polypeptide, it is degraded in the gastrointestinal tract if taken orally.
Therefore, it is generally administered by subcutaneous injection. [Note: In a
hyperglycemic emergency, regular insulin is injected intravenously (IV).] Insulin
preparations vary primarily in their onset of activity and in duration of activity. This is
due to differences in the amino acid sequences of the polypeptides. Dose, site of
injection, blood supply, temperature, and physical activity can affect the duration of
action of the various preparations. Insulin is inactivated by insulin-degrading enzyme
(also called insulin protease ), which is found mainly in the liver and kidney.
D. Adverse reactions to insulin
The symptoms of hypoglycemia are the most serious and common adverse reactions to an
excessive dose of insulin. Longterm diabetic patients commonly do not produce adequate
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amounts of the counter-regulatory hormones (glucagon, epinephrine, cortisol, and growth
hormone), which normally provide an effective defense against hypoglycemia. Other
adverse reactions include weight gain, lipodystrophy (less common with human insulin),
allergic reactions, and local injection site reactions.
IV. INSULIN PREPARATIONS AND TREATMENT
A.
Rapid-acting and short-acting insulin preparations
Four preparations fall into this category: regular insulin, insulin lispro, insulin aspart, and
insulin glulisine. Regular insulin is a short-acting, soluble, crystalline zinc insulin.
Regular insulin is usually given subcutaneously (or IV in emergencies), and it rapidly
lowers blood glucose. Regular insulin, insulin lispro, and insulin aspart are pregnancy
category B, and insulin glulisine is pregnancy category C. Because of their rapid onset
and short duration of action, the lispro, aspart, and glulisine forms are classified as rapid-
acting insulins. These agents offer more flexible treatment regimens and may lower the
risk of hypoglycemia. Insulin lispro differs from regular insulin in that lysine and proline
at positions 28 and 29 in the B chain are reversed. This results in more rapid absorption
after subcutaneous injection than is seen with regular insulin. Consequently, insulin lispro
acts more rapidly. Peak levels of insulin lispro are seen at 30 to 90 minutes after
injection, as compared with 50 to 120 minutes for regular insulin. Insulin lispro also has a
shorter duration of activity. Insulin aspart and insulin glulisine have pharmacokinetic and
pharmacodynamic properties similar to those of insulin lispro. They are administered to
mimic the prandial (mealtime) release of insulin, and they are usually not used alone but
with a longer-acting insulin to ensure proper glucose control. Like regular insulin, they
are administered subcutaneously.
B.
Intermediate-acting insulin
Neutral protamine Hagedorn (NPH) insulin is a suspension of crystalline zinc insulin
combined at neutral pH with the positively charged polypeptide protamine. [Note:
Another name for this preparation is insulin isophane.] Its duration of action is
intermediate because of the delayed absorption from its conjugation with protamine,
forming a less-soluble complex. NPH insulin should only be given subcutaneously (never
IV) and is useful in treating all forms of diabetes except diabetic ketoacidosis and
emergency hyperglycemia. It is used for basal control and is usually given along with
rapid- or short-acting insulin for mealtime control. [Note: A similar compound called
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neutral protamine lispro (NPL) insulin has been prepared that is used only in combination
with insulin lispro.]
C.
Long-acting insulin preparations
1.
Insulin glargine: It is slower in onset than NPH insulin and has a flat, prolonged
hypoglycemic effect with no peak. Like the other insulins, it must be given
subcutaneously.
2.
Insulin detemir: Insulin detemir has a fatty-acid side chain. This addition enhances
association to albumin. Slow dissociation from albumin results in long-acting properties
similar to those of insulin glargine. Neither insulin detemir nor insulin glargine should be
mixed in the same syringe with other insulins, because doing so may alter the
pharmacodynamic and pharmacokinetic properties.
D.
Insulin combinations
Various premixed combinations of human insulins, such as 70-percent NPH insulin plus
30-percent regular insulin, 50 percent of each of these, and 75-percent NPL insulin plus
25-percent insulin lispro, are also available.
E.
Standard treatment versus intensive treatment
For patients with diabetes mellitus who require insulin therapy, standard treatment
involves injection of insulin twice daily. In contrast, intensive treatment seeks to
normalize blood glucose through more frequent injections of insulin (three or more times
daily in response to monitoring blood glucose levels). The ADA recommends a target
mean blood glucose level of 154 mg/dL or less for patients with diabetes, and this is more
likely to be achieved with intensive treatment. The frequency of hypoglycemic episodes,
coma, and seizures due to excessive insulin is higher with intensive treatment regimens.
Nonetheless, patients on intensive therapy show a significant reduction in such long-term
complications of diabetes as retinopathy, nephropathy, and neuropathy compared to
patients receiving standard care. Intensive therapy has not been shown to significantly
reduce the macrovascular complications of diabetes.
V. SYNTHETIC AMYLIN ANALOG
Pramlintide is a synthetic amylin analog that is indicated as an adjunct to mealtime
insulin therapy in patients with type 1 and type 2 diabetes. By acting as an
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amylinomimetic, pramlintide delays gastric emptying, decreases postprandial glucagon
secretion, and improves satiety. Pramlintide is administered by subcutaneous injection
and should be injected immediately prior to meals. When pramlintide is initiated, the
dose of rapid- or short-acting insulin should be decreased by 50 percent prior to meals to
avoid a risk of severe hypoglycemia. Pramlintide may not be mixed in the same syringe
with any insulin preparation. Adverse effects are mainly gastrointestinal and consist of
nausea, anorexia, and vomiting.
VI. ORAL AGENTS: INSULIN SECRETAGOGUES
These agents are useful in the treatment of patients who have type 2 diabetes but who
cannot be managed by diet alone. Patients who have developed diabetes after age 40 and
have had diabetes less than 5 years are those most likely to respond well to oral glucose-
lowering agents. Patients with long-standing disease may require a combination of
glucose-lowering drugs with or without insulin to control their hyperglycemia.
A.
Sulfonylureas
These agents are classified as insulin secretagogues, because they promote insulin release
from the β cells of the pancreas. The primary drugs used today are the second-generation
drugs glyburide, glipizide, and glimepiride.
1.
Mechanism of action: The mechanism of action includes 1) stimulation of insulin
release from the β cells of the pancreas by blocking the ATP-sensitive K+ channels,
resulting in depolarization and Ca2+ influx; 2) reduction in hepatic glucose production;
and 3) increase in peripheral insulin sensitivity.
2. Pharmacokinetics and fate: Given orally, these drugs bind to serum proteins, are
metabolized by the liver, and are excreted by the liver or kidney. The duration of action
ranges from 12 to 24 hours.
3. Adverse effects: Weight gain, hyperinsulinemia, and hypoglycemia. These drugs
should be used with caution in patients with hepatic or renal insufficiency, because
delayed excretion of the drug and resulting accumulation may cause hypoglycemia. Renal
impairment is a particular problem in the case of those agents that are metabolized to
active compounds such as glyburide. Glyburide has minimal transfer across the placenta
and may be a reasonably safe alternative to insulin therapy for diabetes in pregnancy.
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B. Glinides
This class of agents includes repaglinide and nateglinide. Although they are not
sulfonylureas, they have common actions.
1. Mechanism of action: Like the sulfonylureas, their action is dependent on functioning
pancreatic β cells. They bind to a distinct site on the sulfonylurea receptor of ATP-
sensitive potassium channels, thereby initiating a series of reactions culminating in the
release of insulin. However, in contrast to the sulfonylureas, the glinides have a rapid
onset and a short duration of action. They are particularly effective in the early release of
insulin that occurs after a meal and are categorized as postprandial glucose regulators.
2. Pharmacokinetics and fate: These drugs are well absorbed orally. Both glinides are
metabolized to inactive products by cytochrome P450 3A4 in the liver and are excreted
through the bile.
3. Adverse effects: Although these drugs can cause hypoglycemia, the incidence of this
adverse effect appears to be lower than that with the sulfonylureas. Repaglinide has been
reported to cause severe hypoglycemia in patients who are also taking the lipid-lowering
drug gemfibrozil, and concurrent use is contraindicated. Weight gain is less of a problem
with the glinides than with the sulfonylureas. These agents must be used with caution in
patients with hepatic impairment.
VII. ORAL AGENTS: INSULIN SENSITIZERS
Two classes of oral agents, the biguanides and thiazolidinediones, improve insulin action.
These agents lower blood sugar by improving target-cell response to insulin without
increasing pancreatic insulin secretion.
A. Biguanides
Metformin, is classed as an insulin sensitizer. It increases glucose uptake and use by
target tissues, thereby decreasing insulin resistance. Metformin differs from the
sulfonylureas in that it does not promote insulin secretion. Therefore, the risk of
hypoglycemia is far less than that with sulfonylurea agents.
1. Mechanism of action: The main mechanism of action of metformin is reduction of
hepatic glucose output, largely by inhibiting hepatic gluconeogenesis. Metformin also
slows intestinal absorption of sugars and improves peripheral glucose uptake and
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utilization. An important property of this drug is its ability to modestly reduce
hyperlipidemia. Metformin as the drug of choice for newly diagnosed type 2 diabetics.
Metformin may be used alone or in combination with one of the other agents as well as
with insulin.
2. Pharmacokinetics and fate: Metformin is well absorbed orally, is not bound to serum
proteins, and is not metabolized. Excretion is via the urine.
3. Adverse effects: These are largely gastrointestinal. Metformin is contraindicated in
diabetic patients with renal and/or hepatic disease and in those with diabetic ketoacidosis.
It should be discontinued in cases of acute myocardial infarction, exacerbation of
congestive heart failure, and severe infection. Metformin should be used with caution in
patients older than age 80 years and in those with a history of congestive heart failure or
alcohol abuse. Metformin should be temporarily discontinued in patients undergoing -
iagnosis d requiring IV radiographic contrast agents. Rarely, potentially fatal lactic
acidosis has occurred. Long-term use may interfere with vitamin B12 absorption.
4.
Other uses: In addition to the treatment of type 2 diabetes, metformin is effective
in the treatment of polycystic ovary disease. Its ability to lower insulin resistance in these
women can result in ovulation and, therefore, possibly pregnancy.
B.
Thiazolidinediones (glitazones)
Another group of agents that are insulin sensitizers are the thiazolidinediones (TZDs),
also called the glitazones. Although insulin is required for their action, these drugs do not
promote its release from the pancreatic β cells, so hyperinsulinemia is not a risk.
Troglitazone was the first of these to be approved for the treatment of type 2 diabetes but
was withdrawn after a number of deaths from hepatotoxicity were reported. The two
members of this class currently available are pioglitazone and rosiglitazone.
VIII. ORAL AGENTS: α-GLUCOSIDASE INHIBITORS
Acarbose and miglitol are orally active drugs used for the treatment of patients with type
2 diabetes.
A.
Mechanism of action
These drugs are taken at the beginning of meals. They act by delaying the digestion of
carbohydrates, thereby resulting in lower post- randial p glucose levels. Both drugs exert
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their effects by reversibly inhibiting membrane-bound α-glucosidase in the intestinal
brush border. This enzyme is responsible for the hydrolysis of oligosaccharides to
glucose and other sugars. [Note: Acarbose also inhibits pancreatic α-amylase, thereby
interfering with the breakdown of starch to oligosaccharides.] Consequently, the
postprandial rise of blood glucose is blunted. Unlike other oral glucose-lowering agents,
these drugs neither stimulate insulin release nor increase insulin action in target tissues.
B.
Pharmacokinetics and fate
Acarbose is poorly absorbed. It is metabolized primarily by intestinal bacteria, and some
of the metabolites are absorbed and excreted into the urine. On the other hand, miglitol is
very well absorbed but has no systemic effects. It is excreted unchanged by the kidney.
C.
Adverse effects
The major side effects are flatulence, diarrhea, and abdominal cramping. Patients with
inflammatory bowel disease, colonic ulceration, or intestinal obstruction should not use
these drugs.
IX. ORAL AGENTS: DIPEPTIDYL PEPTIDASE-IV INHIBITORS
Sitagliptin and saxagliptin are orally active dipeptidyl peptidase-IV (DPP-IV) inhibitors
used for the treatment of patients with type 2 diabetes. Other agents in this category are
currently in development.
A.
Mechanism of action
These drugs inhibit the enzyme DPP-IV, which is responsible for the inactivation of
incretin hormones. Prolonging the activity of incretin hormones results in increased
insulin release in response to meals and a reduction in inappropriate secretion of
glucagon. DPP-IV inhibitors may be used as monotherapy or in combination with a
sulfonylurea, metformin, glitazones, or insulin.
B.
Pharmacokinetics and fate
The DPP-IV inhibitors are well absorbed after oral administration. Food does not affect
the extent of absorption. The majority of sitagliptin is excreted unchanged in the urine.
Saxagliptin is metabolized via CYP450 3A4/5 to an active metabolite. The primary route
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of elimination for saxagliptin and the metabolite is renal. Dosage adjustments for both
DPPIV inhibitors are recommended for patients with renal dysfunction.
C.
Adverse effects
In general, DPP-IV inhibitors are well tolerated, with the most common adverse effects
being nasopharyngitis and headache. Rates of hypoglycemia are comparable to those with
placebo when these agents are used as monotherapy or in combination with metformin or
pioglitazone. Pancreatitis has occurred with use of sitagliptin. Strong inhibitors of
CYP450 3A4/5, such as nelfinavir, atazanavir, ketoconazole, and clarithromycin, may
increase levels of saxagliptin. Therefore, reduced doses of saxagliptin should be used.
X. INCRETIN MIMETICS
Oral glucose results in a higher secretion of insulin than occurs when an equal load of
glucose is given IV. This effect is referred to as the “incretin effect” and is markedly
reduced in type 2 diabetes. The incretin effect occurs because the gut releases incretin
hormones, notably GLP-1 and glucosedependent insulinotropic polypeptide, in response
to a meal. Incretin hormones are responsible for 60 to 70 percent of postprandial insulin
secretion. Exenatide [EX-e-nah-tide] and liraglutide [LIR-a-GLOO-tide] are injectable
incretin mimetics used for the treatment of patients with type 2 diabetes. These agents
may be used as adjunct therapy in patients who have failed to achieve adequate glycemic
control on a sulfonylurea, metformin, a glitazone, or a combination thereof.
A.
Mechanism of action
The incretin mimetics are analogs of GLP-1 that exert their activity by acting as GLP-1
receptor agonists. These agents not only improve glucose-dependent insulin secretion but
also slow gastric emptying time, decrease food intake, decrease postprandial glucagon
secretion, and promote β-cell proliferation. Consequently, weight gain and postprandial
hyperglycemia are reduced, and HbA1c levels decline.
B.
Pharmacokinetics and fate
Being polypeptides, exenatide and liraglutide must be administered subcutaneously.
Liraglutide is highly protein bound and has a long halflife, allowing for once-daily dosing
without regard to meals. Exenatide is eliminated mainly via glomerular filtration and has
a much shorter halflife. Because of its short duration of action, exenatide should be
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injected twice daily within 60 minutes prior to morning and evening meals. A once-
weekly preparation is under investigation. Exenatide should be avoided in patients with
severe renal impairment.
C.
Adverse effects
Similar to pramlintide, the main adverse effects of the incretin mimetics consist of
nausea, vomiting, diarrhea, and constipation. Because of the peptide nature of incretin
mimetics, patients may form antibodies to these agents. In most cases the antibodies do
not result in reduced efficacy of the drug or increased adverse effects. Exenatide and
liraglutide have been associated with pancreatitis. Patients should be advised to
discontinue these agents and contact their healthcare provider immediately if they
experience severe abdominal pain. Liraglutide causes thyroid C-cell tumors in rodents.
However, it is unknown if it causes these tumors or thyroid carcinoma in humans.