2. MANAGEMENT AND TREATMENT OF DIABETES MELLITUS 357
amputations, blindness,and end-stage renal disease occurs in diabetic patients.3
This chapter
will provide an in-depth account ofdifferent treatment options and latest advancement in
diabetes care. Managing diabetes complications and screening is a part ofcomprehensive
diabetes care , but cannot be covered in this chapter because of limited space.
MANAGEMENT OF DIABETES MELLITUS
The major objectives of proper diabetes management are to alleviate the symptoms,
achieve good glycemic control and prevent the micro and macrovascular damage. Data
from the United Kingdom Prospective Diabetes Study (UKPDS), DCCT and ADVANCE
studies demonstrated the substantial impact of good glycemic control on vascular
complications.r "It isestimated that a 1% decrease in HbA Ic results in significantreduction
in diabetes related deaths (21%) , reduction in microvascular complications (37%) and
reduction in myocardial Infarction (14%).
Diabetes Education
Diabetes education is the most important obligation on the part ofa clinician. Patients
and their families are the best persons to manage a disease that is affected so markedly
by daily fluctuations in environmental stress, exercise, diet and infections.' The teaching
should include explanations by the physician or educator of diabetes and its potential
acute and chronic complications and how they can be recognized early and prevented or
treated. Self-monitoring of blood glucose (SMBG) should be emphasized, especially in
Type I diabetes mellitus (T IDM) and insulin-requiring Type 2 diabetes mellitus (T2DM)
patients, and instructions must be given on proper testing and recording of the data.v?
Patients taking insulin should be taught how to adjust the insulin dose for the
carbohydrate content of a meal. Strenuous exercise can precipitate hypoglycemia and
patients must therefore be taught to reduce their insulin dosage in anticipation ofstrenuous
activity or to take supplemental carbohydrate.
The targets for blood glucose control in elderly patients should be flexible since they
have much higher risk of hypoglycemia if subjected to tighter glycemic control. Advice
on personal hygiene, including detailed instructions on foot and dental care, should
be provided. Finally, vigorous efforts should be made to persuade all diabetics to quit
smoking since large vessel peripheral vascular disease and debilitating retinopathy are
more common in diabetic smokers.
Medical Nutrition Therapy (MNT)
Medical nutrition therapy (MNT) is the process by which the nutrition prescription
is tailored for people with diabetes based upon medical, lifestyle, and personal factors. to
A well-balanced diet remains a cornerstone oftherapy.The American Diabetes Association
(ADA) recommends about 45-65% of total daily calories should be taken in the form
of carbohydrates, 25-35%, in the form offat (of which <7% are from saturated fat), and
10-35% in the form ofprotein.!':" Patients with TIDM orT2DM who take insulin should
be taught "carbohydrate counting," so they can administer their insulin bolus for each
meal based on its carbohydrate content. In obese individuals with diabetes, an additional
goal is weight reduction by calorie restriction.
3. 358 DIABETES
The current recommendations for both types ofdiabetes continue to limit cholesterol
to 300 mg daily, and individuals with LDL cholesterol more than 100 mg/dL should limit
dietary cholesterol to 200 mg/day .
High protein intake may cause progression ofkidney disease in patients with diabetic
nephropathy; for them, a reduction in protein intake to 0.8 kg/day (or about 10% oftotal
calories daily) is recommended. Diabetic patient should also be instructed to take daily
fibers in their diet. Fibers have good beneficial effects on cholesterol in the body.
Exercise
Exercise isbeing increasingly promoted as part ofthe therapeutic regimen for diabetes
mellitus. In addition to its cardiovascular benefits, exercise can also improve glycemic
control. The beneficial effect on glycemic control largely results from increased tissue
sensitivity to insulin .
Based on the literature ,ifcompletely sedentary and underactive individuals participate
in moderate physical activity 30 minutes a day, they would obtain at least a 30% reduction
in risk not only for T2DM but also for other chronic diseases such as coronary artery
disease, stroke and colon cancer. The American Heart Association and The American
Diabetes Association recommend at least 150minutes ofmoderate-intense aerobic activity
or at least 90 minutes of vigorous aerobic exercise per week." The activity should be
distributed over at least three days each week, with no more than two consecutive days
of inactivity.
Weight Loss
More than 80 percent of cases of T2DM can be attributed to obesity, which may
also account for many diabetes-related deaths. Despite the clear benefit of weight loss,
only a small percentage ofpatients with T2DM are able to attain and maintain substantial
weight IOSS.1 5 This difficulty results from limited success in long-term adherence to
calorie-restricted diets. However, impressive successes reported with intensive dietary
intervention.
Pharmacotherapy for weight loss may be effective in patients with T2DM, and
generally is associated with high dropout rates due to medication side effects and is not
recommended as primary therapy for diabetes. Orlistat, a pancreatic lipase inhibitor, is
the only FDA approved drug for the long term management ofobesity. Other weight loss
drugs such as rimonabant and sibutramine have been withdrawn from the market because
of increase suicidal thoughts and cardiovascular side effects, respectively.
Bariatric Surgery for Obesity
Bariatric surgery may be considered for adults with BMI >35 kg/m-, especially
if the diabetes or associated co-morbidities are difficult to control with lifestyle and
pharmacologic therapy. Gastric bariatric surgery results in the largest degree ofsustained
weight loss and improvements in blood glucose control and should be considered in
morbidly obese diabetics.f-" Bariatric surgery has been shown to lead to near- or complete
normalization of glycemia in more than 55-95% of patients with T2DM, depending on
the surgical procedure."
4. MANAGEMENT AND TREATMENT OF DIABETES MELLITUS
Table 1. Glycemic targets: Current recommendations
IDF
359
ADA
I-1bAlc %
Pre prandial glucose mg/dL
Post prandial glucose mg/dL
<6.5
<110
<140
<7.0
90-130
<180
Table 2. Lipids and blood pressure targets: Current recommendations
Total cholesterol mg/dL <200
Triglycerides mg/dL <150
LDL-C mg/dL <100
<70 with many CV risk factors
HDL-C mg/dL Man : >40
Woman: >50
Blood pressure mm I-1g <130/80
Cardiovascular Risk Factor Management
In addition to glycemic control, vigorous cardiac risk reduction includes smoking
cessation, use ofaspirin, secondary prevention, blood pressure control , and reduction in
serum lipids these should bethe top priority for all patients with diabetes (Tables I and 2).12
Vaccination
Influenza and pneumoniaare common, preventable infectious diseases associated with
high mortality and morbidity in the elderly and in people with chronic diseases. Diabetic
patients should receive influenza vaccination yearly and pneumococcal vaccination,
repeatingthe pneumococcal vaccination once after 65 years ofage ifthe initial vaccination
was prior to age 65.19,20
Psychological Assessment and Care
Psychological and social problems can impair the individual's or family's ability
to carry out diabetes care and may lead to compromised health status. Therefore, it is
important for the clinicians to assess psychosocial status in a timely and efficient manner
so that referral for appropriate services can be accomplished.v-"
PHARMACOLOGICAL TREATMENT OF DIABETES
Early institution ofpharmacological treatmentfor diabetes isassociated with improved
glycemic control over time and decreased long-term complications. Pharmacologic
therapy is often not initiated soon enough, resulting in poor glycemic control. After a
successful initial response to oral therapy, patients fail to maintain target HbAl c levels
«7 percent) at a rate of 5 to I0 percent per year." An analysis from the UKPDS found
that 50 percent of patients originally controlled with a single drug required the addition
5. 360 DIABET ES
First Lin e App roach
Lifestyle+Metformin Lifestyle+Metformin
+ +
Basal Insnlin Intensive Insnlin
At Diagnosis:
Lifestyle + Metformi n t
Lifestyle+Metformin
+
Sulfonylurea s
Step 3
Step 1 Step 2
Second Line App roach
Lifestyle+Metfo rm in Lifestyle+Metform in
+ +
Pioglitazone Pioglitazon e
-----+ Caution: Heart failure
r+ +
At Diagnosis: Sulfonylur eas
Lifestyle + Metformin f---
+Lifestyle+Metformin
/ 4 Lifestyle+Metformin
-----+ + +
GLP 1 agonist Basal Insulin I--
Step 1 Step 2 Step 3
Figure 1. Treatment flow sheet for Type 2 diabetes.
of a second drug after three years; by 9 years 75% of patients needed multiple therapies
to achieve the target HbA IC.
24Figure I illustrates a flow sheet of a consensus statement
from the American Diabetes Association (ADA) and the European Association for the
Study of Diabetes (EAS D) for the treatment of T2DM.25
Anti-Diabetic Drugs
They fall into two broad categories; oral and injectable.
Oral Anti-Diabetic Medications
A. Insulin secretagogues
1. Sulfonylureas
First generation sulfonylureas: includes tolbutamide, chlorpropamide
and acetohexamide
Second generation sulfonylureas: includes glimepiride, glibenclamide/
Glyburide, gliclazide and glipizide
2. Meglitinides includes repaglinide and nateglin ide
B. Insulin sensitizers
I. Biguanides: includes metformin and phenformin
2. Thiazolidinediones: includes pioglitazone and rosiglitazone
C. a -Glucosidase inhibitors: includes acarbose and migl itol
D. Dipeptidypeptidase IV inhibitors:includes sitagliptin,vidagliptinandsaxag liptin.
6. MANAGEMENT AND TREATMENT OF DIABETES MELLITUS
Injectable Anti-Diabetic Medications
361
A. Glucagon-like peptide I receptor agonist ( GLP-I analogue): includes exenatide
and liraglutide
B. Pramlintide (amylin analogue)
C. Insulin
I. Conventional insulin: includes regular and intermediate acting (NPH)
2. Insulin analogues
Ultra short acting: includes lispro, aspart and glulisine
Long acting analogues: includes glargine and detemir
Commonly Prescribed Oral Anti-Diabetic Medications (see Table 3)
There are different classes oforal anti-diabetic medications exerting clinical effects
via different mechanisms. These medications are commonly prescribed world wide and
have shown effectiveness while used alone or in combination.v-"
Table 3. Oral anti-diabetic drugs
Drug Potency Dail y Dosage Duration
Su Ifonylu reas
Glimepiride
Glibenclamide/
Glyburide
Gliclazide
Gliclazide MR*
Glipizide
Tolbutamide
Meglitinide
Repaglinide
Nateglinide
Biguanides
Metformin
Metformin XR**
1,2,3,4 mg
1,25, 2,5, 5 mg
80 mg
30,60 mg
5, 10 mg
500 mg
0,5, 1,2 mg
60-120 mg
250, 500, 850,
1000 mg
500 mg
1-8 mg once a day
1.25-20 mg single or two
divided dosages
80-320 mg two divided dos es
30-120 mg once a day
2.5-20 mg two divided doses
0.5-2 g in three divided doses
0,5-4 mg thrice a day
60-120 mg three times a day
1000-2500 mg two to three
divided doses
500-2000 mg once a day
Up to 24 hours
Up to 24 hours
Up to 12 hours
Up to 24 hours
6-12 hours
6-12 hours
3 hours
1.5 hours
6-12 hours
Up to 24 hours
15-45 mg onc e a day
4-8 mg once a day
Thiazolidinediones
Piogl itazon e 15, 30, 45 mg
Rosiglitazone 2,4,8 mg
a-Glucosidase inhibitors
Acarbose 50-100 mg 25-100 mg three times a day
Miglitol 25,50, 100 mg 25-100 mg th ree times a day
Dipeptidyl peptidase 4 (DPP-4) inhibitors
Sitalgliptin 25,50, 100 mg ***100 mg onc e a day
Vildagliptin 50 mg 50-100 mg/day
Saxagliptin 2,5 and 5 mg 2,5-5 mg once daily
Up to 24 hours
Up to 24 hou rs
4 hours
4 hou rs
24 hours
24 hours
24 hours
* Modified release; ** Extended release; *** 50 mg/day if creatinine clearance 30-50 mLimin and
25 mg/day ifclearance <30 mL/min.
7. 362 DIABETES
Following is the detail description ofthe use of different oral agents in T2DM with
their pharmacokinetic and pharmacodynamic properties .
Sulfonylureas
Sulfonylureas are most commonly prescribed and well tolerated oral hypoglycemic
drugs.They are moderately effective,lowering blood glucose concentrations by20 percent
and HbA Icby 1-2%. However,their effectiveness decreases overtime.AIthough the onset
ofthe glucose lowering effect ofsulfonylurea monotherapy is relatively rapid compared
with the thiazolidinediones (TZDs), maintenance of glycaemic targets over time is not
as good as monotherapy with a TZD or metformin. Generally sulfonylureas are safer
with in the group, use ofglyburide/glibenclamide has been shown to be associated with
higher mortality than other sulfonylureas."
Primary andSecondary Failure. The reported rate ofprimary failure ofsulfonylurea
therapy (i.e.,the inability to achieve a good or adequate glucose response) varies
from 5-30%. The rate of secondary failure in patients who have an initial response to
treatment with sulfonylureas ranges from 5-10% each year; after 10 years, only 50%
have satisfactory control.":"
Mechanism of'Action. Sulfonylureas exert clinical effects via receptors.Sulfonylurea's
receptor is a component of the ATP-dependent potassium channel in the pancreatic
~ cells. Binding leads to inhibition of these channels, which alters the resting potential
of the cell, leading to calcium influx and stimulation of insulin secretion. The net effect
is increased insulin secretion from ~ cells of pancreas. Thus, sulfonylureas are useful
only in patients with some ~-cell function.
Pharmacokinetics. Approximately 50% ofthe sulfonylurea dose is rapidly absorbed;
its level can be detected in serum one hour after administration. Ninety to 99% ofthe drug
is bound to plasma proteins, especially albumin. Binding ofsecond-generation agents is
limited to non-ionic sites; hence, they are less likely to interact with other medications
than are first-generation agents.
Glipizide, glyburide (glibenclamide), gliclazide, and glimepiride are so-called
second-generation sulfon ylureas. They have structural characteristics that allow them to
be given in much lower doses than the first-generation sulfonylureas. Nevertheless, the
different sulfonylureas are equally effective in lowering blood glucose concentrations.
There are,however,differences inabsorption and metabolism,as well as ineffectivedosage
(Table 3). Comparison of plasma half-lives is misleading, since the biological effect is
often much longer. For example, the hypoglycemic action ofglibenclamide can last for
more than 24 hours, due in part to the formation ofactive metabolites. Glibenclamide is
unique among all sulfonyureas in that it becomes sequestered in ~ cells. This may explain
its prolonged duration despite short plasma half life.
Chlorpropamide, glibenclamide and glimepiride can be given once daily because of
their long half-lives. They also cause greater suppression of overnight hepatic glucose
output, thereby lowering fasting blood glucose concentrations more. Sulfonylureas are
metabolized by the liver and excreted through kidneys and, in case ofsecond generation
sulfonylureas, partly excreted in the bile. Metabolites ofacetohexamide are more active
than othersulfonylureaswhos e metabolites are either inactive or partly active. Glimepiride
8. MANAGEMENT AND TREATMENT OF DIABETES MELLITUS 363
achieves blood glucose lowering with the lowest dose ofany sulfonylures,thus, increasing
its cost-effectiveness.
Side Effects. Hypoglycemia is the most common side effect and is more common
with long-acting sulfonylureadrugs such as chlorpropamide,glyburide/glibenclamide.32,33
Elderly patients are more prone to develop hypoglycemia; therefore, short acting
sulfonylureas are more preferable, such as gliclazide and glipizide.
One study has shown that patients receiving second generation sulfonylureas such
as glyburide, glipizide, or glimepiride at the time of myocardial infarction did not have
greater mortality rates than patients treated with insulin." Chlorpropamidehas a prolonged
biologic halflife and may cause severe hypoglycemia especially in elderly. Its other side
effects include alcohol-induced flushing and hyponatremia.
Factors Contributing Drug-Induced Hypoglycemia in Elderly. Drug-induced
hypoglycemia is most likely to occur in the following circumstances in older patients
and may be a limiting factor for use of these drugs in older adults:
After exercise or missed meals
Inadequate oral intake
Impaired renal functions
Impaired hepatic functions
Poor left ventricular function
Alcohol abuse
Drug therapy with salicylates, gemfibrozil, warfarin etc.
Weight gain may occur insome patients using sulfonylurea. Hypersensitivity reaction
to sulfonylureas may occur in the first 6-8 weeks oftherapy. It consists mainly ofallergic
skin reaction which progress rarely to erythema multiforme, exfoliative dermatitis, fever
and jaundice.
Contraindications. Sulfonylureas should not be given in severe liver disease, chronic
kidney diseases and porphyria. They should be avoided in pregnancy and lactation since
data are not sufficient to ensure safety of drugs in these conditions.":"
Meglitinides
Meglitinides are oral hypoglycemic agents derived from benzoic acid and chemically
unrelated to the sulfonylurea agents.
Repaglinide, which is rapidly absorbed after oral administration, reaches peak
plasma levels within I hour and is rapidly eliminated by oxidation and conjugation with
glucuronic acid in liver, therefore, can be given safely in renal failure because it has no
significant renal excretion.
Meglitinides stimulate insulin secretion like sulfonylureas but they bind to a different
site within the sulfonylurea receptor." They have a shorter circulating half-life than
the sulfonylureas and must be administered more frequently. Repaglinide is almost as
effective as metformin and decreasing HbA 1e levels by 1.5%. Nateglinide is somewhat
less effective in lowering HbA Ie than repaglinide when used as monotherapy or in
combination therapy."
9. 364 DIABETES
Side Effects . Side effects ofmeg litinides include weight gain and hypoglycemia. An
additional drawback to this drug is the dosing schedule since it must be taken with meals .
Biguanides
Metformin, phenformin and buformin are the derivatives of biguanides and have
glucose-lowering effects. Metformin is the commonly used biguanide and lowers HbA Ie
levels by 0.5_1 .0%.41,42Metformin is an effective monotherapy and may be an ideal drug
for overweight patients since it does not cause weight gain and has been seen to cause
modest amounts of weight loss when first administered.vv v" Diarrhea and abdominal
discomfort are the main side effects that can be alleviated by changes in diet and slow
increases in metformin dosage.
In the absence of contraindications, metformin is considered the first choice for
oral treatment of T2DM . American Diabetes Association (ADA) and the European
Association for the Study of Diabetes (EASD) proposed that metformin therapy (in the
absence of contraindications) be initiated, concurrent with lifestyle intervention, at the
time of diabetes diagnosis.
Mechanism . The mechanism of action of metformin is not entirely understood, but
its predominant effect is to suppress hepatic glucose production and to enhance insulin
sensitivity in peripheral tissues .v-" At cellular level metformin activates adenosine
monophosphate-activated protein kinase, which acts as an intracellular energy sensor
and has a critical role in regulating gluconeogenesis."
Pharmacokinetics. Metformin is partially absorbed from the gastrointestinal tract
and has a bioavailability of50-60%. The drug is stable, does not bind to plasma proteins,
and is not metabolized. It is excreted in the urine unchanged and has a plasma half-life
of 1.7 to 4.5 hours. Ofa given dose, 90% is cleared within 12 hours. Metformin does not
cause hypoglycemia if used as monotherapy. Absorption of vitamin B12 appears to be
reduced during long-term metformin therapy, but the serum vitamin B12 levels usually
remain in the normal range. However, periodic screening with serum vitamin B12levels
should be considered, especially in patients with symptoms of peripheral neuropathy.
Contraindications. Renal dysfunction (serum creatinine> 1.5 mg/dL in man and
>1.4mg/dL inwomen or creatinine clearance <30 mL/min) isconsidered acontraindication
to metformin use because it may increase the risk of lactic acidosis, an extremely rare
(less than I case per 100,000 treated patients) but potentially fatal complication."
Its use should be avoided in acute medical conditions like ketoacidosis, sepsis ,
hepatitis, respiratory failure , heart failure. It should be withdrawn one day prior to giving
radio contrast agent or general anesthesiaand restart when renal function returns to normal
or at least three days after giving these agents.
Thiazolidinediones (TZDs)
Pioglitazone and rosiglitazones are two drugs ofthis class , effective as monotherapy
and in combination with sulfonylureas or metformin or insulin. When used as
monotherapy, these drugs lower HbA Ic by about 0.5-1.4%.49 TZDs can be used in
10. MANAGEMENT AND TREATMENT OF DIABETES MELLITUS 365
combination with oral anti-diabetic drugs and insulin." When used in combination with
insulin, they can result in a 30-50% reduction in insulin dosage, and som e patients can
come off insulin completely."
Mechanism ofAction. The thiazolidinediones increase insulin sensitivity by acting
on adipose tissues, muscle and liver to increase glucose utilization and decrease glucose
production.P-" The mechanism by which the thiazolidinediones exert their effect is not
fully understood. It is postulated that they bind a nuclear receptor called peroxisome
proliferator-activated receptor gamma (PPAR-y) and affect the expression of a number
ofgenes.>'>' Observed effects ofthiazolidinediones include increased glucose transporter
expression (GLUT I and GLUT 4), decreased free fatty acid levels, decreased hepatic
glucose output, increased adiponectin and decreased release of resistin from adipocytes,
and increased differentiation of pre-adipocytes into adipocytes.
This class of drugs has also been shown to lower blood pressure and decrease
vascular inflammation in vitro." Rosiglitazone and pioglitazone have similar effects on
glycaemic control, but their effects on serum lipid concentrations are different. Most
randomized trials found that pioglitazone produces a more favorable lipid profile and
card iovascular safety.53,56-58
Cardiovascular Safety. Several meta-analyses have suggested a 30-40% relative
increase in risk for myocardial infarction with rosiglitazone.v" Although subsequent
studies have cast doubt on this finding; the FDA required the manufacturer to include a
boxed warning about the potential risk ofheart attacks on the drug label. A meta-analysis
ofclinicaltrials with pioglitazone did not show a similarfinding.Many physicians, because
of these findings, have stopped prescribing rosiglitazone and instead use pioglitazone,
if indicated.
Side Effects. Adverse effects ofTZDs include weight gain, edema, a possible increase
in alanine aminotransferase levels (AL T), anaemia due to hemodilution and farcture risk
at atypical sites. Recently increased risk of bladder cancer has also been reported after
one year of piogl itazone therapy.63,64
Contraindications. TZDs are contraindicated in patients with advanced forms of
congestive heart failure . Due to reported cases of liver failure and liver toxicity caused by
the increase inALT levels,TZDs should be avoided in patients with abnormal liver function.
They should also be avoided in pregnancy and lactation since no safety data available.
a-Glucosidase Inhibitors
Acarbose and miglitol are the drugs included in this group. A fundamental difference
between acarbose and miglitol is in their absorption. Acarbose has the molecular mass
and structural features of a tetrasaccharide, and very little (about 2%) crosses the
microvillar membrane. Miglitol, however, has a structural similarity with glucose and
is absorbable.
Clinical studies with these agents have demonstrated a reduction in postprandial
glucose elevations in both T 10M and T2DM.65,66In older patients with T2DM, acarbose
may also increase insulin sensitivity."?
11. 366 DIABETES
Mechanism ofAction. Alpha-glucosidase inhibitors (AGls) work by blocking the
enzyme in the small intestine that breaks down complex carbohydrates, a-glucosidase.
By blocking this enzyme these drugs prevent starches from being absorbed into the
bloodstream and in doing so lower blood glucose levels. AGls are the only drug class
used to treat T2DM that does not specifically target the pathology of the disease.
Because AGls work in the digestive tract , they are more effective at lowering
postprandial glucose levels than fasting plasma glucose levels. AGls are less effective
at lowering HbA Ic levels than biguan ides or sulfonylureas." >" a-glucosidase inhibitors
are associated with weight loss and less hypoglycemia.
Side Effects. Flatulence is the principal adverse effect, seen in more than two third
ofpatients." This is caused by undigested carbohydrate reaching the lower bowel , where
gases are produced by bacterial flora. In 3% ofcases, troublesome diarrhea occurs. This
gastrointestinal discomfort tends to discourage excessive carbohydrate consumption
and promotes improved compliance of T2DM patients with their diet prescriptions.
A slight rise in hepatic aminotransferases has also been noted. Acarbose should be
avoided in inflammatory bowel disease, severe renal and hepatic impairment, pregnancy
and lactation.
Dipeptidyl Peptidase IV Inhibitors (DPP-IV inhibitors)
Dipeptidyl peptidase IV(DPP-IV)isanenzyme expressed onthesurface ofmostcellsand
deactivatesglucagon-likepeptide-l (GLP-I). Therefore, DPP-IV inhibition could potentially
augment the effects of endogenous GLP-1. GLP-I exerts its main effect by stimulating
glucose-dependent insulin release from the pancreatic islets. It restores both first phase and
second phaseinsulinresponsetoglucose.lthasalsobeenshowntoslowgastricemptying, inhibit
inappropriate post meal glucagon release, and reduce food intake."
DPP IV inhibitors, unlike other GLP-I based therapies, can be administered orally.
Metformin has been shown to modestly enhance GLP-I secretion, making it an attractive
option for combination therapy with DPP-IV inhibitors." DPP IV inhibitors are weight
neutral and generally do not cause hypoglycemia. Currently available DPP IV inhibitors
are sitagliptine, vildagliptin and saxagliptin.
Sitagliptin. This drug is effective in lowering glucose when used alone and in
combination with metformin and pioglitazone and sulfonylureas in T2DM.73-76Dose of
sitagliptin should be reduced to 50 mg/day if creatinine clearance is 30-50 mUmin and
25 mg/day if clearance <30 mUmin. In various clinical trials, improvements in HbA 1c
ranged from 0.5-1.4%.74
Adverse Effects. The main adverse effects ofsitagliptin appears to be a predisposition
to nasopharyngitis or upper respiratory tract infection, a small increase in neutrophi Icount
of-200 cells/me. Aanaphylaxis, angioedema, and exfoliative skin conditions including
Stevens-Johnson syndrome have also been reported. There have also been reports of
pancreatitis (88 cases including 2 cases of hemorrhagic or necrotizing pancreatitis).
Saxagliptin. Saxagliptin is approved as a monotherapy for the treatment of T2DM
or in combination with sulfonylurea, metformin, or a thiazolidinedione.":" The dose is
2.5 mg or 5 mg once a day. The 2.5-mg dose should be used in patients with calculated
creatinine clearance <50 mUmin. The drug is weight neutral.
12. MANAGEMENT AND TREATMENT OF DIABETES MELLITUS 367
Adverse Effects. The main adverse effects are upper respiratory tract infection,
nasopharyngitis, headache, and urinary tract infection. There is also small reversible
dose-dependent reduction in absolute lymphocyte count, which remains within normal
limits . Hypersensitivity reactions, such as urticaria and facial edema, occurred in
1.5% of patients taking the drug.
Vildagliptin. Like the other DPP-4 inhibitors, vildagliptin lowers HbA Ie by about
0.5-1% when added to the therapeutic regimen of patients with T2DM .80
-
83
The dose is
50 mg once or twice daily.
Adverse Effects. Adverse reactions include upper respiratory tract infections,
nasopharyngitis, dizziness and headache. Rare cases of hepatic dysfunction, including
hepatitis, have been reported. Liver function testing is recommended quarterly during
the first year of use and periodically thereafter.
Injectable Anti-Diabetic Drugs
GLP-I Analogues
GLP-I is rapidly degraded by dipeptidyl peptidase 4 (DPP-4) and cleared rapidly by
the kidney rendering their half-lives to only 1-2 minutes. The native peptide, therefore,
cannot be used therapeutically and GLP-I receptoragonists are made to escape degradation.
Two GLP-I receptor agonists, exenatide and Iiraglutide are currently available for clinical
use for T2DM.
Exenatide. Exenatide is a synthetic exendin-4. Exendin-4 is a naturally occurring
component of the Gila monster saliva." It is resistant to DPP-IV degradation and
therefore exhibits a prolonged half-life." It is approved for the treatment of T2DM as
monotherapy or in combination with oral agents. Exenatide binds to the GLP-I receptor
and exerts same effects like GLP-I and has been shown to promote ~-cell regeneration
and differentiation in animal models.86
,87 Exenatide is not currently approved for use
with insulin therapy
In clinical trials, adding exenatide therapy to patients with T2DM already taking
metformin, or sulfonylurea, or a thiazolidindione, further lowered the HbA Ie value by
0.4-0.6%. These patients also experienced a weight loss of3-6 pounds.P-"
Side Effects. Nausea is the major side effect affecting over 40% of the patients.
The nausea was dose-dependent and declined with time . In post marketing surveillance
pancreatitis has been reported." Patients taking exenatide should be advised to seek
immediate medical care ifthey experience unexplained persistent severe abdominal pain.
Other side effects include renal impairment, acute renal failure , and delayed absorption
of the drugs . Low-titer antibodies against exenatide develop in over one-third (38%) of
patients, but of no clinical significance. High-titer antibodies develop in approximately
6% of patients, and in about half ofthese cases, an attenuation ofglycemic response has
been seen.?'
Exenatide is dispensed as two fixed-dose pens (5 ug and 10 ug). It is administered
subcutaneouslytwice daily immediately before orwithin one hourofmorning and evening
meals." Patients should be prescribed the 5 f.-lg pen for the first month and, if tolerated,
the dose can then be increased to 10 ug twice a day. The drug is not recommended in
patients with glomerular filtration rate <30 mUmin.
13. 368 DIABETES
Liraglutide. Liraglutide is albumin bound with a half-life ofapproximately 12hours,
allowing the drug to be injected once a day. It is available for use as monotherapy as an
adjunct to diet and exercise or in combination with oral agents in adults with T2DM. It
is not considered a first-line therapy.v-" HbAl c decline is in the range of0.6-1.5%. The
patients may have sustained weight loss of 1-6 pounds.
Side Effects. Frequent side effects are nausea and vomiting and found in 28% and
10% of users respectively. There is also an increased incidence of diarrhea. In clinical
trials, there were seven cases ofpancreatitis in the liraglutide treated group with one case
in the comparison group.
Liraglutide stimulates C-cell neoplasia and causes medullary thyroid carcinoma
in rats. Human C-cells express very few GLP I-receptors, and the relevance to human
therapy is unclear; however, because of the animal data, the drug should not be used
in patients with personal or family history of medullary thyroid carcinoma or multiple
endocrine neoplasia (MEN 2).95
The dosing is initiated at 0.6 mg daily , increased after I week to 1.2 mg daily. If
needed, an additional increase in dose to 1.8 mg is recommended for optimal glycemic
control. No dose adjustment is recommended in renal failure.
Pramlintide
This drug is a synthetic analogue ofislet amyloid polypeptide or amylin. When given
subcutaneously, pramlintide delays gastric emptying, suppresses glucagon secretion, and
decreases appetite. It is approved for use both in TI DM and in insulin-treated T2DM.96
,97
Nausea is the major side effect but hypoglycemia can occur specially in T IDM and it is
recommended that the short-acting or premixed insulin doses be reduced by 50% when
the drug is started.
In patients with T IDM, the initial dose ofpramlintide is 15 ug before each meal and
titrated up by IS ug increments to a maintenance dose of30 ug. In patients with T2DM,
the starting dose is 60 ug pre meals increased to 120 ug in 3 to 7 days .
Insulin
Insulin is indicated for all types of diabetes. Initiation of insulin therapy is often
delayed, owing to physician or patient reluctance and fear of injection, thus exposing
patients to the physiological consequences of prolonged hyperglycemia.
Insulin is a reasonable choice for initial therapy in patients who present with
symptomatic or poorly controlled diabetes, and is the preferred second-line medication
for patients with HbA Ie> 8.5% or with symptoms of hyperglycemia despite initial
therapy with metformin and life-style intervention. The ADA/EASD have developed a
flow diagram for initiating and titrating insulin in the management ofT2DM.25
Pharmacokinetics. Insulin is secreted in a pulsatile manner; pulses occur under basal
conditions and in response to meals.98 Basal insulin secretion represents approximately 50%
of24-hour insulin production, with the remainder accounted for by prandial excursions.
Half-life ofintravenous insulin appears to be 5-10 minutes in normal persons. The liver is
the major site ofinsulin clearance, accounting for ~5 0% ofthe total ; the kidney accounts
for ~3 0%, and skeletal muscle account for most of the rest."
Insulin pharmacokinetics is complicated by many factors that alter insulin absorption
from the subcutaneous site.
14. MANAGEMENT AND TREATMENT OF DIABETES MELLITUS
Table 4. Conventional insulin 's pharmacokinetics
369
Types
Regular
NPH
Premixed 30/70
Onset Peak
30-60 min 2 hr
2-4 hr 4-6 hr
Follows combined pharmacokinetics
Duration
4-6 hr
12-18 hr
Factors Causing Increased Insulin Absorption
Low doses of insulin.
Diluted insulin solution.
Increased subcutaneous blood flow (exercise, massage, heat) .
Local tissue injury.
Abdominal injection and intramuscular injection.
Factors Causing Decreased Insulin Absorption
Concentrated insulin solution.
Decreased subcutaneous blood flow (shock, cold, standing).
Lipohypertrophy.
Intradermal injection, and injection into limbs (at rest).
Conventional Insulin
Regular Insulin. Regular insulin is short-acting soluble crystalline zinc insulin
whose effect appears within 30 minutes after subcutaneous injection and lasts 4-6 hours
(Table 4). Intravenous infusions ofregular insulin are particularly useful in the treatment
of diabetic ketoacidosis, hyperglycemic hyperosmolar state, critically ill patient and
during the perioperative management of diabetics.100
NPH (Neutral Protamine Hagedorn) Insulin. Isan intermediate-acting insulin whose
onset ofaction is delayed by combining 2 parts soluble crystalline zinc insulin with I part
protamine zinc insulin . Its onset ofaction is delayed to 2-4 hours, and its peak response is
generally reached in about 4-6 hours .'?' (Table 4). Because its duration ofaction is often
<24 hours (with a range of 10-20 hours), most patients require at least two injections
daily to maintain a sustained insulin effect.
Rapidly-Acting Insulin Analogues (see also Tables 5 and 6)
Insulin Lispro. Insulin lispro is an insulin analogue produced by recombinant
technology, wherein two amino acids near the carboxyl terminal of the f)-chain have
been reversed in position; proline at position B28 has been moved to B29 and lysine
moved from B29 to B28.
Insulin Aspart. This insulin is a single substitution of proline by aspartic acid at
position B28.
Insulin Glulisine. This insulin differs from human insulin in that the amino acid
asparagine at position B3 is replaced by lysine and the lysine in position B29 by
glutamic acid.
Alterations of the amino acids sequences in these analogues result in formation of
monomers when injected subcutaneously in contrast to regular human insulin, whose
hexamers require considerably more time to dissociate and absorbed.Pv'?'
15. 370 DIABETES
Table 5. Pharmacokinetics of analogues
Type s Onset Peak Duration
Rapidly acting
Lispro
Aspart
Glulisine
5-15 min
5-15 min
5-15 min
60min
60 min
60min
2 hr
2 hr
2 hr
Premixed Lispro 25%, Neutral Protamine Lispro 75% ( Humalog Mix 25)
Lispro 50%, Neutral Protamine Lispro 50% ( Humalog Mix 50)
Aspart 30%, Protamine Aspart 70% (Novo Mix 30)
These follow combined pharmacokinetics of ultra short acting
and NPH insulin
Long acting
Glargine
Detemir
2-4 hr
2-4 hr
None
None
24 hr
20-24 hr
Table 6. Compares some features of conventional and analogue insulin types
Conventional Analogues
Less physiologic time action profile More physiologic time action profile
Strong affinity for self dissociation Easy dissociation
Unpredictable hypoglycemia Less hypoglycemia
Low cost High cost
Long-Acting Insulin Analogues
Insulin Glargine. Insulin glargine is an insulin analogue in which the asparagine at
position 21 ofthe A chain in the human insulin molecule is replaced by glycine and two
arginines are added to the carboxyl terminal of the B chain.'?' The arginines raise the
isoelectric point of the molecule closer to neutral, making it more soluble in an acidic
environment. Insulin glargine is a clear insulin which, when injected into the neutral pH
environment ofthe subcutaneous tissue, forms microprecipitates that slowly release the
insulin into the circulation. It lasts for about 24 hours without any pronounced peaks and
is given once a day to provide basal coverage.
Insulin glargine has got a six fold greater affinity for IGF-I receptor compared
with the human insulin. There has also been a report that insulin glargine had increased
mitogenicity compared with human insulin in a human cell line. The significance ofthese
observations is not yet clear. lOS
Insulin Detemir.lnsulin detemir isan insulin analogue inwhich the tyrosine at position
30 of the j3-chain has been removed and a 14-C fatty acid chain is attached to the lysine
at position 29 by acylation. The fatty acid chain makes the molecule more lipophilic than
native insulin and the addition of zinc stabilizes the molecule and leads to formation of
hexamers. After injection, self-association at the injection site and albumin binding in the
circulation via the fatty acid side chain, leads to slower distribution to peripheral target
tissues and prolonged duration of action.!"
It is recommended that the insulin be injected once or twice a day to achieve a
stable basal coverage. This insulin has been reported to have lower within-subject
pharmacodynamic variability compared with NPH insulin and insulin glargine.
16. MANAGEMENT AND TREATMENT OF DIABETES MELLITUS
GENERAL PRINCIPLES OF INSULIN THERAPY
371
The need for insulin depends upon the balance between insulin secretion and insulin
resistance. All patients with TI OM need long term insulin treatment and many patients
with T20M will require insulin as their ~-cell function declines over time.
Therapy should begin with diet, weight reduction, and exercise, which can frequently
induce normoglycemia if compliance is optimal. For many patients with T20M, a basal
supplement is often adequate for good glycemic control as endogenous insulin secretion
will control the postprandial excursions. Some patients with T20M may require additional
premeal boluses, similar toTI OM.
The use of premixed insulin is not recommended for patients with TIOM since
these offer little glycemic advantage compared with adequately titrated basal and bolus
insulin. Many patients with T20M can use premixed preparations with reasonable effect.
Theterm "intensive insulin therapy" has been used to describe complex regimens that
separate basal insulin delivery with superimposed doses of short or rapid-acting insulin
three or more times daily . Intensive regimens more nearly approximate normal insulin
physiology. While intensive regimens were initially used for patients with TI OM, they
are used for patients with T20M as well.
Basal Insulin
Although intermediate-acting NPH insulin has been used commonly at bedtime
to supplement oral hypoglycemic drug therapy, longer acting insulin, such as insulin
glargine and detem ir,added to oral agents are equally effective for reducing HbA Icvalues
and may cause less nocturnal hypoglycemia.t'"! " Meta-analyses oftrials in patients with
T20M comparing once-daily insulin glargine or detemir to once- or twice-daily NPH
insulin report similarglycemic controIbetween groups. However,the rates ofsymptomatic
overall and nocturnal hypoglycemia were lower in patients treated with either insulin
glargine or detemir compared with NPH .
Bolus Insulin
For patients with T20M, a basal supplement is often adequate for good glycaemic
control, but for others premeal boluses are needed as they are in T 10M.
The newer rapid-acting analogue insulin may have a minor glycemic advantage over
short-acting (regular) insulin in patients with TI OM, but not in patients with T20M.
No significant differences were seen in serum HbA Ic concentrations or the number of
hypoglycemic episodes between short acting and analogs. However, the ability to inject
the rapid-acting insulin immediately before meals, as opposed to the 30 to 45 minutes
before the meal recommended for short-acting insulin, may provide improved convenience
for patients.109
Setting Insulin Dosages
Basal Insulin
If a bedtime dose of NPH, detemir or glargine insulin is being added to oral
hypoglycemic drug therapy, it is recommended to start at 10 units or 0.2 units per kg.
17. 372 DIABETES
Fasting blood glucose (FBG) should be measured every day. An increase of2 to 4 units in
the bedtime insulin dose should be made approximately every 3 days ifthe mean fasting
plasma glucose is more than 130 mg/dl..!'?
Bolus Insulin
A typical starting dose is approximately 4 to 6 units. The dose can be increased
by 2 to 3 units every three days until the postprandial blood glucose target is achieved.
A more complex method for adjusting premeal insulin is to match insulin delivery
to the anticipated glucose excursion with meals. With this approach (called carbohydrate
counting), insulin-to-carbohydrate ratios are determined based upon an individual's
usual insulin requirements and carbohydrate intake.II I
Side Effects of Insulin Therapy
Hypoglycemia
Hypoglycemia is the most frequently occurring side effect of insulin treatment."
The common causes of hypoglycemia include missed meals or erratic meal timing,
excessive insulin dosage, and unplanned exercise. Renal impairment, cortisol deficiency,
hypothyroidism and alcohol intoxication should also be considered as the potential causes
of hypoglycem ia.
Post Hypoglycemic Hypergly cemia (Somogyi effect) . Many years ago, Somogyi
postulated that over-treatment with insulin produces late night hypoglycemia, which is
followed by fasting hyperglycem ia caused by activation ofcounter regulatory hormones.
Unexplained Fasting Hyp erglycemia (Dawn phenomenon) . The dawn phenomenon
occurs in persons with and without diabetes. In the early morning hours , a transient state
of insulin resistance occurs that may be partially due to nocturnal secretion of growth
hormone and cortisol. In persons without diabetes, this early morning insulin resistance
is limited by compensatory insulin secretion, but in patients with T1OM, troublesome
hyperglycemia can occur.
Weight Gain and Edema
Sodium and fluid retention is a common occurrence after insulin therapy. Insulin 's
sodium-retaining effect on the kidney could be the best explanation for this phenomenon.
Another contributor could be glucagon, which is known to have natriuretic effect. Plasma
glucagon levels are increased in uncontrolled diabetes, and a fall in glucagon with insulin
treatment could contribute to the sodium retention.
Insulin Allergy
The problem of insulin allergy has been greatly reduced by the introduction and
widespread use of human insulin. There have been case reports of successful use of
insulin lispro in those rare patients who have a generalized allergy to human insulin or
insulin resistance due to a high titer of insulin antibodies.l'?
18. MANAGEMENT AND TREATMENT OF DIABETES MELLITUS
Lipoatrophy
373
Lipoatrophy is characterized by a loss ofsubcutaneous fat at insulin injection sites.
This phenomenon is rarely seen since then purified human insulin is being used . The
cause of this complication is unknown but is suspected to be immunologic.
Lipohypertrophy
Lipohypertrophy is a non- immune phenomenon,consistingofa localized hypertrophy
of subcutaneous fat that develops from repeated injections of insulin into a highly
circumscribed area and resolves spontaneously with the use ofother insulin injection sites.
Orthostatic Hypotension
Normally, insulin stimulates the cardiovascular sympathetic nervous system. In the
presence of autonomic neuropathy, however, insulin has a direct vasodilator effect on
the vascular bed that can lead to hypotension.
NEW ADVANCEMENTS IN DIABETES MANAGEMENT
Cure from diabetes remains an elusive dream so far. The greatest success in diabetes
research has been inthe treatmentofdiabetes, with Iittle progress toward a cure . Following
is the brief discussion regarding the latest advancements and research towards diabetes
treatment and cure.
Artificial Pancreas
An artificial pancreas system combines a continuous glucose monitor and an insulin
pump and uses a sophisticated algorithm to calculate the appropriate amount ofinsulin to
deliver based on the real-time glucose readings. Using an artificial pancreas system can
significantly reduce the risk of hypoglycemia, a major concern for children and adults
with TI DM. In a small study conducted in TI DM, results showed the artificial pancreas
kept blood glucose levels in the normal range for 60% of the time, compared with 40%
for the continuous subcutaneous insulin infusion.'!'
Islet Cell Regeneration Therapy
In human pancreas, it now seems clear that there is a slow rate of 13-cell turnover
whereby 13 cells replicate and new islets are formed , probably from exocrine duct cells
through the process of neogenesis. In the future, islet cell replacement or regeneration
therapy may thus offer therapeutic benefit and potentially a cure to people with diabetes.
Islet cell regenerative therapy could be achieved by in situ regeneration or implantation of
cells previously derived in vitro.I 14 Both approaches are being explored, and their ultimate
success will depend on the ability to recapitulate key events in the normal development of
the endocrine pancreas to derive fully differentiated islet cells that are functionally normal.
However, these approaches are at an early stage ofpreclinical development and should not
be offered to patients until shown to be safe as well as more efficacious than existingtherapy.
19. 374
Islet Cell Transplantation
DIABETES
Islet cell transplantation isthe transplantation ofisolated islets from a donor pancreas
to a recipient. It is an experimental treatment for TI DM patients; the islets begin to
produce insulin and actively regulating the level of glucose in the blood. The purified
islets usually are infused into the patient's liver via the portal vein. Since body perceive
islets tissues as foreign body , therefore, the patient needs to undergo treatment with
immunosuppressants.
Recentstudies have shown that islettransplantation has progressedto the pointthat58%
ofthe patients in one study were insulin independent one year after the operation. lI S Two
ofthe most important limitations are the currently inadequate means for preventing islet
rejection, and the limited supply ofislets for transplantation. Current immunosuppressive
regimens are capable of preventing islet failure for months to years, but the agents used
in these treatments are expensive and may increase the risk for specific malignancies
and opportunistic infections.
Pancreas Transplantation
Pancreas transplantation continues to evolve as a strategy in the management of
diabetes mellitus. In most cases, pancreas transplantation is performed on individuals with
T IDM with end-stage renal disease. The majority ofpancreas transplantations (>90%) are
simultaneous pancreas-kidney transplantations.I'" In the absence ofindications for kidney
transplantation, pancreas transplantation should only be considered a therapy in patients
who exhibit a history of frequent hypoglycemia, ketoacidosis, clinical and emotional
problems with exogenous insulin therapy that are so severe as to be incapacitating and
consistent failure of insulin-based management to prevent acute complications.'!" The
prognosis after pancreas transplantation is very good. One year after transplantation more
than 95% of all patients are still alive and 80-85% of all pancreases are still functional.
After transplantation patients need lifelong immunosuppression which increases the risk
of infection and malignancy.
Gene Therapy
Gene therapy can be used to manufacture insulin. In this modality viral vector
containing the insulin sequence, is digested and delivers its genes to the upper intestines.
By delivering [3-cell DNA to the intestine cells in the duodenum, a few intestine
cells will turn into [3 cells, and subsequently adult stem cells will develop into [3 cells.
This makes the supply of [3 cells in the duodenum self replenishing, and the [3 cells will
produce insulin in proportional response to carbohydrates consumed. Gene therapy might
eventually be used to cure the cause of'p-cell destruction, thereby curing the new diabetes
patient before the [3-cell destruction is complete and irreversible.'!"
Sodium-Glucose Co-Transporter Inhibitors (SGLT2)
Sodium-glucose co-transporter 2 [SGLT2 (Dapagliflozin, Sergliflozin)] expressed
in the proximal renal tubules accounts for about 90% of the re-absorption of glucose
from tubular fluid. SGLT2 is almost exclusively expressed in the proximal renal tubules.
Preclinical studies with selective SLGT2 inhibitors show dose-dependent glucosuria
20. MANAGEMENT AND TREATMENT OF DIABETES MELLITUS 375
and lowering of blood glucose in models of T2DM . Preliminary clinical studies of up
to 3-month duration show dose-dependent lowering of glycosylated hemoglobin up to
0.9% along with modest weight loss.'!"
Side effects include an increase in genital fungal infection, increased urine volume ,
and evidence ofvolume depletion consistentwith mild diuretic effect. SGLT2 inhibitors are
showing promise as a useful addition to the current therapeutic options in TIDM. Results
ofongoing Phase 11 clinical trials are awaited and will determine whether the risk-benefit
ratio will allow approval of this new class of drug for the management ofTIDM.
Colesevelam
Colesevelam is a bile acid sequestrant that lowers LDL cholesterol in patients with
primary hypercholesterolemia. Colesevelam modestly reduces HbA lc levels 0.3 to 0.4 %
in patients with T2DM inadequately treated with oral agents or insulin.'?" Colesevelam's
mechanism ofaction to improve glycemic control is uncertain. One possibility is that bile
acid sequestrants act in the gastrointestinal tract to reduce glucose absorption.
Piragliatin (Glucokinase Activator)
Glucokinase plays a key role in glucose homeostasis. Glucokinase activators can
lower glucose levels in both animal and human T2DM. In a study, Piragliatin caused a
dose-dependent reduction ofglucose levels in both fasting and fed states.'?' In the fasting
state, piragliatin caused a dose-dependent increase in ~-cell function, a fall in endogenous
glucose output, and a rise in glucose use. In the fed state, the primary effects ofpiragIiatin
were on ~-cell function .
Oral Insulin!"
Insulin isa protein,which isdigested inthe stomach and gut and inorderto be effective
at controlling blood sugar, cannot be taken orally in its current form. Investigators have
attempted to devise ways ofmoving enough intact insulin from the gut to the portal vein
to have a measurable effect on blood sugar.
Oral-Lyn isan oral spray formulation ofhuman insulin indicated forthetreatment
ofTlDM and T2DM. Having secured regulatory approval in 2005 for clinical
use ofOral-Lyn in T2DM in Ecuador, ongoing Phase 11 clinical trials are being
conducted in North America and many European countries.
Oral insulin analogue (NN 1952). Trial has already initiated on December 2009 .
The aim ofthe trial is to investigate the safety, tolerance, pharmacokinetics and
pharmacodynamics in people with TI DM and T2DM. Results from the trial,
which is planned to enroll about 80 people, are expected to be reported in the
first half of 20 II.
VIAtab isan oral formulation ofinsulin designed to be administered sublingually.
This therapy is a tablet that dissolves in minutes when placed under the tongue.
In a Phase I study, VIAtab delivered insulin to the blood stream quickly and
resembled the first-phase insulin release spike found in healthy individuals.
Oral insulin capsule (ORMD-080 I). Results substantiated the safety and
tolerability of ORMD-080 I and demonstrate that oral insulin has a relevant
clinical impact at the tested dose .
21. 376
CONCLUSION
DIABETES
Treatment of patients with any type of diabetes requires a comprehensive approach
including education, normalization ofglycemia, minimization ofcardiovascularand other
long-term risk factors , and avoidance ofdrugs that can aggravate abnormalities ofinsulin
or lipid metabolism. The core objective of diabetes management is to prevent acute and
long term diabetes complications. Current treatment modalities focus on increasing insulin
secretion, responsiveness, or both, or decreasing the rate of carbohydrate absorption,
and mimeting incretin effects. Monotherapy with metformin is considered a drug offirst
choice for all T2DM (especially obese), ifno contraindication.
Insulin is indicated for all types of diabetes, is the first choice in acute diabetes
complications and critically ill patients. Diet and exercise are an essential component of
diabetes management and significantly affect the glycemic control. Majority of TIDM
patients fail to achieve glycemic control on life style modification alone and require
oral combination therapy with or without insulin . Obesity is very common in T2DM
and contributes greatly to insulin resistance, therefore, weight reduction and exercise
should be greatly emphasized in obese T2DM patients. In addition, a strong partnership
between the patient and the treating physician is ofparamount importance inthe successful
management of diabetes.
Some T2DM eventually fail to respond to oral medications and must proceed to
insulin therapy. GLP I analogues and DPP IV inhibitors are relatively new addition to
oral therapy and a reasonable option in obese T2DM patients, while TZDs , the insulin
sensitizers, should be used very carefully in those patients with poor left ventricular
function, and in those who are prone to develop soteoporosis.
Current therapeutic modalities are unable to cure diabetes, but we hope for a better
future for diabetic as new advancements and technologies are coming to cure diabetes.
REFERENCES
I. Steven RG.Emergingepidemic:diabetes inolderadults:demography,economicimpact,and pathophysiology.
Diabetes Spectrum 2006; 19:221-228.
2. Norris SL, Zhang X, Avenell A et al. Long-term effectiveness of lifestyle and behavioral weight loss
intervention s in adults with type 2 diabetes: a meta-analysis. Am J Med 2004; 117:762.
3. Mokdad AH, Ford ES, Bowman BA et al. Prevalence of obesity, diabetes, and obesity-related health risk
factors. JAMA 2003; 289():76-79.
4. Effect of intensive blood-glucose control with metformin on complications in overweight patients with
type 2 diabetes (UKPDS 34). Lancet 1998; 352(9131):854-865.
5. Patel A et al. ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in
patients with type 2 diabetes . N Engl J Med 2008; 358(24):2560-2572.
6. White NH, Danis RP, Davis MD et al. Long-term renal outcomes of patients with type I diabetes mellitus
and microalbuminuria: an analysis of the Diabetes Control and Complications Trial/Epidemiology of
Diabetes Interventions and Complications cohort. Arch Intern Med 2011; 171(5):412-420.
7. Funnell MM, Brown TL, Childs BP et al. National standards for diabetes self-management education .
Diabetes Care 2007; 30:1630.
8. Karter AJ, Parker MM, Moffet Hh et al. Longitudinal study of new and prevalent use of self-monitoring of
blood glucose. Diabetes Care 2006; 29(8):1757-1763.
9. Goldstein DE, Little RR, Lorenz RA et al. Tests of glycemia in diabetes. Diabetes Care 2004; 27:1761.
10. Miller CK, Edwards L, Kissling G et al. Nutrition education improves metabolic outcomes among older
adults with diabetes mellitus. Prev Med 2002; 34(2):252-259.
II . Bantle Jl>, Wylie-Rosett J, Albright AL et al. Nutrition recommend ations and interventions for diabetes:
a position statement of the American Diabetes Association. Diabetes Care 2008; 31 Suppl I:S61.
12. Standards of medical care in diabetes. Diabetes Care 2010; 33 Suppl LS I .
22. MANAGEMENT AND TREATMENT OF DIABETES MELLITUS 377
13. Masharani U. Diabetes mellitus & hypoglycemia. In: McPhee SJ, Papadakis MA, eds. Current Medical
Diagnosis and Treatment 2010. McGraw-Hill : New York City, 2010:I079-1122.
14. Buse JB, Ginsberg HN, Bakris GL et al. Primary prevention of cardiovascular diseases in people with
diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes
Association. Circulation 2007; 115(): 114-126.
15. Klein S, Burke LE, Bray GA et al. Clinical implication s of obesity with specific focus on cardiovascular
disease:a statement for professiona ls from the American Heart AssociationCouncil on Nutrition, Physical
Activity and Metabolism. Circulation 2004; 110( 8):2952-2967.
16. Lawson ML, Kirk S, Mitchell T et al. One-year outcomes of Roux-en-Y gastric bypass for morbidly obese
adolescents. J Pediatr Surg 2006; 41():137-143.
17. O'Brien PE, Sawyer SM, Laurie C et al. Laparoscopic adjustable gastric banding in severely obese
adolescents: a randomized trial. JAMA 20 I0; 303(6):519-526.
18. Buchwald H, Estok R, Fahrbach K et al. Weight and type 2 diabetes after bariatric surgery. Am J Med
2009; 122:248-256.
19. Colquhoun AJ, Nicholson KG, Botha JL et al. Effectiveness of influenza vaccine in reducing hospital
admissions in people with diabetes. Epidemiol lnfect 1997; 119:335-341.
20. Bridges CB, Fukuda K, Uyeki TM et al. Prevention and control of influenza. Recommendations of the
Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2002; 51:1-31.
21. Fisher L, SkaffMM, Mullan JT et al. Clinical depression versus distress among patients with type 2 diabetes:
not just a question of semantics. Diabetes Care 2007; 30:542-548 .
22. Ismail K, Winkley K, Rabe-Hesketh S. Systematic review and meta-analysis of randomized controlled
trials of psychological interventions to improve glycaemic control in patients with type 2 diabetes. Lancet
2004; 363:1589.
23. Turner RC, Cull CA, Frighi V et al. Intensive blood-glucose control with sulphonylureas or insulin
compared with convention al treatment and risk ofcomplications in patients with type 2 diabetes. Lancet
1998; 352(9131):837-853.
24. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus:
progressive requirement for multiple therapies (UKPDS 49). JAMA 1999; 281(2 1):2005-2012.
25. Nathan DM, Buse JB, Davidson MB et al. Medical Management of Hyperglycemia in Type 2 Diabetes:
A Consensu s Algorithm for the Initiation and Adjustment of Therapy : A consensus statement of the
American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care
2009; 32:193.
26. Monami M, Lamanna C, Marchionni N et al. Comparison of different drugs as add-on treatments to
metformin in type 2 diabetes: Diabetes Res Clin Pract 2008; 79:196.
27. Bolen S, Feldman, L Vassy J et al. Comparative Effectiveness and Safety ofOral Medications for Type 2
Diabetes Mellitus. Ann Intern Med 2007; 147:386.
28. Zeller M, Danchin N, Simon D et al. Impact of type of pre-admission sulfonylureas on mortality and
cardiovascular outcomes in diabetic patients with acute myocardial infarction. J Clin Endocrinol Metab
20 I0; 95( 1):4993-5002.
29. Eurich DT, Simpson SH, Majumdar SR et al. Secondary failure rates associated with metformin and
sulfonylurea therapy for type 2 diabetes. Pharmacotherapy 2005; 25:810-816.
30. Groop LC, Pelkonen R, Koskimies S et al. Secondary failure to treatment with oral antidiabetic agents in
non-insulin-dependent diabetes. Diabetes Care 1986; 9:129-133.
31. Matthews DR, Cull CA, Stratton 1M et al. UKPDS 26: sulphonylurea failure in non-insulin dependent
diabetic patients over six years. Diabet Med 1998; 15:297-303.
32. Tessier D, Dawson K, Tetrault JP, Bravo G et al. Glibenclamide vs gliclazide in type 2 diabetes of the
elderly. Diabet Med 1994; 11(10):974-980.
33. Holstein A, Plaschke A, Egberts EH. Lower incidence of severe hypoglycaemia in patients with type 2
diabetes treated with glimepiride versus glibenclamide. Diabetes Metab Res Rev 200 I; 17(6):467-473.
34. Arruda-Olson AM, Patch RK et al. Effect ofsecond-generation sulfonylureas on survival in patients with
diabetes mellitus after myocardial infarction. Mayo Clin Proc 2009; 84( I):28-33.
35. Langer 0 , Conway DL, Berkus MD et al. A comparison ofglyburide and insulin in women with gestational
diabetes mellitus. N Engl J Med 2000; 343(16): 1134-1 138.
36. Langer 0 , Yogev Y, Xenakis EM et al. Insulin and glyburide therapy: dosage, severity level ofgestational
diabetes, and pregnancy outcome. Am J Obstet Gynecol 2005; 192():134-139.
37. Conway DL, Gonzales 0 , Skiver D. Use of glyburide for the treatment of gestational diabetes: the San
Antonio experience. J Matern Fetal Neonatal Med 2004; 15:51.
38. Rochon M,Rand L, Roth Let al. GIyburideforth emanagement ofgestationaldiabetes: risk factorspredictive
of failure and associated pregnancy outcomes. Am J Obstet Gynecol 2006; 195:1090.
39. Fuhlendorff J, Rorsman P, Kofod H et al. Stimulation of insulin release by repaglinide and glibenclamide
involves both common and distinct processes. Diabetes 1998; 47(3):345-351.
23. 378 DIABETES
40. Moses R, Siobodniuk R, Boyages S et al. Effect of repaglinide addition to metformin monoth erapy on
glycem ic control in patients with type 2 diabetes. Diabetes Care 1999; 22(1) :II :9-24.
41. DeFronzo RA, Goodman AM. Efficacy of metformin in patient s with non-insulin-dependent diabetes
mellitus. N Engl 1 Med 1995; 333(9):541-549.
42. Bailey C.I, Turner RC. Metformin. N Engl 1 Med 1996; 334:574.
43. Effect of intensive blood-glucose control with metformin on complic ations in overweight patients with
type 2 diabetes (UKPDS 34). Lancet 1998; 352(9131):854-865.
44. UKPDS13: Relativeefficacyofrandomly allocated diet,sulphon ylurea, insulin,ormetformin in patients with
newly diagnosed non-insulin dependent diabete s followed for three years. BMl 1995; 310(6972):83-88.
45. Stumvoll M, Nurjhan N, Perriello G et al. Metabolic effects ofmetformin in non-insulin-dependent diabete s
mellitus. N Engl .I Med 1995; 333(9):550-554.
46. Bailey C.I, Turner RC. Metformin. N Engl 1 Med 1996; 334:574.
47. Zhou G, Myers R, Li Y, Chen Y et al. Role ofAMP-activated protein kinase in mechanism of metformin
action..1 Clin Invest200 I; 108(8):1167-1174. http://reference.medscape.comlmedline/abstract/20702526.
48. Kasia Jl., Clifford lB, Silvio EI. Use ofMetformin in the Setting ofMild-to-Moderate Renal Insufficiency.
Diabetes Care 20 I I; 34:1431-1436.
49. Schernthaner G,Matthews DR, Charbonnel Bet al. .IClin Endocrinol Metab 2004 ; 89(12) :6068-6076.
50. Kipnes MS, Krosnick A, Rendell MS et al. Pioglitazone hydrochloride in combination with sulfonylurea
therapy improves glycemic control in patients with type 2 diabete s mellitus. Am 1 Med 200 I; 111:1O.
5 1. Schwartz S, Raskin P, Fonseca V et al. Effect oftroglitazone in insulin-treated patients with type II diabete s
mellitus. Troglitazone and Exogenous Insulin Study Group . N Engl .l Med 1998; 338( 13):861-866.
52. Iwamoto Y, Kosaka K, Kuzuya T et al. Effects of troglitazone: a new hypog lycem ic agent in patients with
NIDDM poorly controlled by diet therapy . Diabetes Care 1996; 19(2):151-156.
53. Yki-Jarvinen H. Thiazolidinediones. N Engl 1 Med 2004; 351:1106.
54. Vidal-Puig A.I, Considine RV, .Iimenez-Linan M et al. Peroxisome proliferator-activated receptor gene
expression in humantissues. Effectsofobesity, weight loss, and regulation by insulin and glucocorticoids.
1 Clin Invest 1997; 99( 10):2416-2422.
55. GervoisP, Fruchart.lC, Staels B. Drug Insight: mechanismsofaction and therapeutic applications for agonists
of peroxisome proliferator-activated receptors. Nat Clin Pract Endocrinol Metab 2007; 3(2):145-156.
56. Chiquette E, Ramirez G, Defronzo R. TI A meta-analysis comparing the effect ofthiazolidinediones on
cardiovascular risk factors. Arch Intern Med 2004 ; 164(19):2097-2 I04.
57. Goldberg RB, Kendall DM, Deeg MA et al. A comparison oflipid and glycemic effects ofpioglitazone and
rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care 2005; 28(7): 1547-1554.
58. Winkelmayer WC, SetoguchiS, Levin Ret al. Comparisonofcardiovascularoutcome sinelderly patients with
diabetes who initiated rosiglitazon e vs pioglitazone therapy. Arch Intern Med 2008; 168(21):2368 -2375.
59. Nissen SE, Wolski K. Effect of Rosiglitazone on the Risk of Myocard ial Infarction and Death from
Cardiovascular Causes. N Engl 1 Med 2007; 356:2457-2471. http://www.n ejm.org/toc/nejm/356/24/.
60. Rosen C.I. The Rosiglitazone Story: Lessons from an FDA Advisory Committee Meeting. N Engl.l Med
2007 ; 357:844-846. http://www .nejm.org/toc/nejm/357/9/.
61. Singh S, Loke YK, Furberg CD.Long-term risk ofcardiovascular events with rosiglitazone:ameta-analysis.
lAMA 2007; 298(10) :1189-1195.
62. Winkelmayer WC, SetoguchiS, Levin Ret al. Comparisonofcardiovascular outcome sinelderly patients with
diabetes who initiated rosiglitazone vs pioglitazone therapy. Arch Intern Med 2008; 168(21):2368 -2375.
63. Lewis.lD, FerraraA , PengT etal. RiskofBladder Cancer Among Diabetic PatientsTreated With Pioglitazone:
Interim report of a longitudinal cohort study. Diabetes Care 20 II ; 34:9I6-922.
64. SOl, Vector One": Total Patient Tracker (TPT). 2010-2010. Data extracted 10.
65. Hollander P, Pi-Sunyer X, Coniff RF. Acarbose in the treatment of type I diabetes. Diabetes Care 1997;
20(3):248-253 .
66. McCulloch DK, Kurtz AS , Tattersall RB. A new approach to the treatment of nocturnal hypoglycemia
using alpha-glucosidase inhibition. Diabetes Care 1983; 6(5):483 -487.
67. Meneilly GS, Ryan EA, Radziuk .Iet al. Effect of acarbose on insulin sensitivity in elderly patients with
diabetes. Diabetes Care 2000 ; 23(8) :1162-1167.
68. Hoffmann .I, Spengler M. Efficacy of 24-week monoth erapy with acarbose, glibenclamide, or placebo in
NIDDM patients. Diabetes Care 1994; 17(6):561-566.
69. Holman RR, Cull CA, Turner RC. A randomi zed double-blind trial of acarbose in type 2 diabetes shows
improved glycemic control over 3 years. Diabetes Care 1999; 22(6) :960-964 .
70. Chiasson Jl. , Josse RG, Hunt lA et al. The efficacy of acarbose in the treatment of patients with
non-insu lin-dependent diabetes mellitus. A multicenter controlled clinical trial. Ann Intern Med 1994;
121(12):928-935.
71. Demuth I-IU, Mclntosh CH, Pederso n RA. Type 2 diabetes-therapy with dipeptid yl peptidase IV inhibitors .
Biochim Biophys Acta 2005 ; 1751(1):33-44.
24. MANAGEMENT AND TREATMENT OF DIABETES MELLITUS 379
72. Mannu cci E, Ognibene A, Cremasco F et al. Effect of metformin on glucagon-like peptide I (GLP-I) and
leptin levels in obese nond iabetic subjects. Diabetes Care 2001 ; 24(3):489-494.
73. Raz I, Hanefeld M, Xu L et al. Efficacy and safety of the dipeptidyl peptid ase-4 inhibitor sitagliptin as
monotherapy in patients with type 2 diabetes mellitus. Diabetologia 2006 ; 49( 1):2564-2571.
74. Charbonnel B, Karasik A, Liu Jet al. Efficacy and safety of the dipeptidyl peptid ase-4 inhibitor sitagliptin
added to ongo ing metformin therapy in patients with type 2 diabetes inadequately controlled with
metformin alone. Diabetes Care 2006 ; 29(12) :2638-2643.
75. RosenstockJ, Brazg R,Andryuk PJet al. Efficacy and safetyofthe dipeptid yl peptidase-4 inhibitor sitagliptin
added to ongo ing pioglitazone therapy in patient s with type 2 diabetes.ClinTher 2006; 28( I0):1556-1568 .
76. Hermansen K, Kipnes M, Luo E et al. Efficacy and safety ofthe dipeptidyl peptidase-4 inhibitor, sitagliptin,
in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride
and metformin. Diabete s Obes Metab 2007; 9(5):733-745.
77. Rosenstock J, Sankoh S, ListJF.Glucose-Iowering activity ofthe dipeptidyl peptidase-4 inhibitor saxagliptin
in drug-naive patients with type 2 diabetes. Diabetes Obes Metab 2008 ; 10(5):376-386.
78. DeFronzo RA, Hissa MN, Garber AJ et al. The efficacy and safety ofsaxagliptin when added to metformin
therap y in patients with inadequately controlled type 2 diabetes with metformin alone. Diabetes Care
2009 ; 32(9):1649-1655.
79. Chacra AR, Tan GH, Apanovitch A et al. Saxagliptin added to a submaximal dose of sulphonylurea
improve s glycaemic control compared with uptitration of sulphonylurea in patients with type 2 diabetes:
a randomi zed controlled trial. Int J Clin Pract 2009 ; 63(9) :1395-1406 .
80. Pratley RE, Jau ffret-Kamel S, Galbreath E et al. Twelve-week monotherapy with the DPP-4 inhibito r
vildagliptin improve s glycemic control in subjects with type 2 diabetes. Horm Metab Res 2006 ;
38(6):423-428.
81. Pi-Sunyer FX, SchweizerA,Mills Detal. Efficacy and tolerabi lityofvildagliptin monotherapy indrug-naive
patients with type 2 diabetes . Diabetes Res Clin Pract 2007; 76():132-138.
82. Fonseca V, Schweizer A, Albrecht D et al. Addition ofvildaglipti n to insulin improves glycaemic contro l
in type 2 diabete s. Diabetologia 2007; 50(6): 1148-1155.
83. Bosi E, Camisasca RP, Collober C et al. Effects ofvildagliptin on glucose control over 24 weeks in patients
with type 2 diabete s inadequ ately controlled with metformin. Diabetes Care 2007; 30(4) :890-895.
84. Eng J, Kleinm an WA, Singh L et al. Isolation and characterization of exendin-4, an exendin-3 analogue,
from Heloderma suspectum venom. Further evidence fo r an exendi n receptor on dispersed acini from
guinea pig pancreas. J Bioi Chern 1992; 267( I I):7402-7405.
85. Parkes DG, Pittner R, Jodka C et al. Insulinotrop ic actions ofexend in-4 and glucagon-like peptide-I in vivo
and in vitro. Metabolism 2001; 50(5) :583-589.
86. Kolterman OG, Buse JB, Fineman MS et al.Synthetic exendin-4 (exenatide) significantly reducespostprandial
and fasting plasmaglucosc in subjects with type 2diabetes.JClin Endocrinol Metab 2003;88(7):3082-3089.
87. Xu G, Stoffers DA, Habener JF et al. Exendin-4 stimulates both beta-cell replication and neogenesis,
resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes 1999;
48( 12):2270-2276 .
88. Kendall DM, Riddle MC, Rosenstock J et al. Effects of exenatide (exendin-4) on glycemic control over
30 weeks in patients with type 2 diabetes treated with metformin and a sulfonyl urea. Diabetes Care
2005 ; 28(5): 1083- 109 1.
89. Zinman B, Hoogwerf BJ, Duran GS etal.Theeffect ofadding exenatide to athiazolidinedione in suboptimally
controll ed type 2 diabetes: a randomized trial. Ann Intern Med 2007; 146(7):477-485.
90. www .fda.gov/CDER/Drug/lnfoSheets/HCP/exenatide2008HCP.htm. Accessed 2008.
91. Stephen JM, Maxine AP. Diabetes mellitus and hypoglycemia. Current Medical Diagno sis and Treatment
20 10; 1079- 1121.
92. Linnebje rg H, Kothare PA, Skrivanek Z et al. Exenatide: effect of injection time on postprandial glucose
in patients with Type 2 diabetes. Diabet Med 2006; 23(3):240-245.
93. Vilsboll T, Zdravkovic M, Le-Thi T et al. Liraglutide, a long-acting human glucagon-like peptide-I analog,
given as monotherapy significantly improv es glycemic control and lowers body weight without risk of
hypoglycemia in patients with type 2 diabetes. Diabetes Care 2007; 30:1608.
94. Zinman B, Gerich J, Buse JB et al. Efficacy and safety of the human glucagon-like peptide-I analog
Iiraglutid e in combi nation with metformin and thiazolid inedione in patients with type 2 diabetes. Diabetes
Care 2009; 32(7): 1224-1230.
95. Bjerre Knudsen L, Madsen LW, Andersen S et al. Glucagon-like Peptide-I receptor agonists activate rodent
thyroid C-cells causing calcitonin releaseand C-cell proliferation. Endocrinology 20 I0; 151(4):1473-1486.
96. Ratner RE, Dickey R, Fineman M et al. Amylin replacement with pram lintide as an adjunctto insulin therapy
improv es long-term glycaemic and weight control in Type I diabetes mellitus: one year, randomized
controlled trial. Diabet Med 2004; 21( I):1204-1212 .
25. 380 DIABET ES
97 . Hollan der PA, Levy 1', Fineman MS et al. Pramlintide as an adjunct to insulin therapy improves long-term
glycemic and weight control in patients with type 2 diabetes: a I-year randomized controlled trial.
Diabetes Care 2003 ; 26(3):784-790 .
98. Polonsky KS, Given BD, Van Cauter E.Twenty-fo ur-hour profiles and pulsatile patterns ofinsulin secre tion
in normal and obese subject s. J Clin Invest 1988; 81(2):442-448.
99 . Binder C, Lauritzen T, FaberO, Pramming S. Insulin pharmacokinet ics. Diabetes Care 1984 ; 7(2) :188-199.
100. Kitabchi AE, Umpierrez GE, Murphy MB et al. Management of hyperglycemic crises in patients with
diabetes (Techn ical Review) . Diabetes Care. 200 1; 24: 131-153.
101. Greenspan FS, Gardner DG. Basi c and Clinical Endocrinology. Sixth edition 2001 ; 66 1-668.
102. Barnett AH, Owen s DR. Insuli n analogues. Lancet 199 7; 349:47.
103. Singh SR, Ahmad F, Lal A et al. Efficacy and safety of insul in analog ues for the managem ent of diabe tes
mell itus: a meta-analysis. CMAJ 200 9; 180:385.
104. Heinem ann L, Linkeschova R, Rave K et al. Time-action profile of the long-acting insulin analog
insulin glargine (HOE901) in comparison with those ofNPH insul in and placebo. Diabetes Care 2000;
23(5):644-649.
105. Home I'D, Lagarenne P. Combined randomi zed controlled trial expe rience of malignanc ies in studies
using insul in glargi ne. Diabe tologia 200 9; 52(12):2499-506.
106. Havelund S, Plum A, Ribel U et al. The mechanism of protraction of insulin detemi r, a long-acting,
acylated analog of hum an insulin. Pharm Res 2004; 21: 1498.
107. Philis-Tsimikas A, Charpentier G, Clauson I' et al. Comparison of once-daily insulin detem ir with NP H
insulin added to a reg imen of oral antidiabetic drugs in poorly contro lled type 2 diabetes. Clin Ther
2006; 28(10):1569-1581.
108. Riddle MC, Rosenstock J, Gerich 1. The treat-to-target trial: randomize d addition of glargi ne or hum an
NPH insulin to oral thera py of typ e 2 diabetic patients. Diabetes Care 2003; 26(11 ):3080-30 86.
109. Plank J, Siebenhofer A, Berghold A et al. Systematic review and meta-analysis of short-acting insulin
analogues in patien ts with diabetes mell itus. Arch Intern Med 2005; 165(12):1337-1344.
110. Nat han DM, Buse JB , Davidson MB et al. Management ofhype rglycemia in type 2 diabetes: a consensus
algorithm for the initiation and adj ustmentoft herapy. A consensus statement from the American Diabetes
Association and the European Association for the Study of Diabetes. Diabete s Care 2006 ; 29:1963.
11I. Bergenstal RM, John son M, Powers MA et al. Adj ust to target in type 2 diabetes: comparison of a simple
algorithm with carbohydrate counting for adj ustment of me altime insulin glulisine. Dia betes Care 2008;
3 I(7):1305-1 310.
112. Castera V, Dutour-Meyer A, Koepp el M et al. Systemic allergy to human insulin and its rapid and long
acting analogs: successful treatm ent by continuous subcutaneous insulin lispro infusion. Diabetes Metab
200 5; 3 1:39 1-400.
113. van Bon AC, Brouwer TB, von Basum G et al. Future Acceptance of an Art ificial Pancreas in Adults with
Type I Diabetes. Diabetes Technol Ther 20 11; 13(7):73 1-736.
114. Nagaya M, Katsuta H, Kaneto H ct al. Adult mouse intrahepatic biliary epithelial cells indu ced in vitro
to beco me insulin-producing cells. J Endocrinol 2009 ; 20 1:37-47.
115. Alejandro R, Barton FB, Hering BJ et al. Update from the Co llaborative Islet Transplant Registry.
Transplant ation 2008; 86 :I783-1788.
116. Ojo AO, Meier-Kriesche HU, Hanson JA et al. The impact of simultaneo us pancreas-ki dney transplantation
on long-term patient survival. Tran splant ation 200 I; 7 1:82-90.
117. Larsen. Pancreas transplantation : indications and consequences.Endocr Rev 2004; 25:919-946.
118. Lee HC, Kim SJ, Kim KS etal. Rem ission in models oftype I diabetes by gene therapy using asingle-chain
insuli n analogue. Nature 2000; 408 :483-4 88.
119. Rahmo une H, Thompson PW, Ward JM et al. Glucos e transporters in hum an renal proxim al tubular cells
isolated from the urine of patient s with non-in sulin dependent diabetes . Diabetes 2005 ; 54:3427 -3434.
120. Handelsman Y,Goldberg RB,Garvey WT et al.Colesc velam hydrochloride to treat hypercholesterolemiaand
improve glycemia in prediabetes: arandomized,prospective study.Endocr Pract20 10; 16(4):6 17-628. http://
reference.medscape.com/m edline/abstract/20634 I76.
121. Bonadonna RC, Heise T, Arbet-Engel et al. Piragliatin (R04389620), a novel gluco kinase activator,
lowers plasma glucose both in the postabsorptive state and after a glucose challenge in patients with
type 2 diabetes mellitus: a mechani stic study . J Clin Endocrinol Metab 20 10; 95(1 1):502 8-5036. http://
reference.medscape.com/m edl ine/abstract/20739378.
122. http://en.wikipedia.orgiwiki/ln sulin_th erapy#cite_note-24.
