Insulin resistance and insulin secretion impairment is often shown
in diabetes mellitus type 2 (DM2). Exaggerate insulin secretion, obesity,
hypertension and hyperlipidemia are the earliest changes in DM2.
The aim of our study was to evaluate the effectiveness of orlistat in
treatment of DM2 patients in University hospital Plzen. It was recruited
87 DM2 patients with metabolic syndrome in the retrospective study during
24 months. Data from 64 patients were analysed. The inclusive criteria
were obesity with low glycemic control (31%), hyperlipidemia (25%),
hypertension(33%) and cardiovascular ischemic disease (1%). 56,2% patients
was treated with insulin. We assessed glycemic, and blood pressure control,
and the use and doses of insulin, antihypertensive, oral agents and
hypolipidemic drugs at the start and after 3 and 6 months.
The mean time of orlistat therapy was 9 months (1-24M). The treatment
was terminated in 53%patients because of low effectiveness (53%), diarrhoea
(35%), and high expenses for the patients (12%). Results are shown in
the table. The doses of drugs were decreased in 20%patients in 3 months,
and in 28% in 6 months period. One or more drugs were terminated in
42%patients after 3 months, and in 50% after 6 months.
Orlistat was shown to be effective in more than 50%patients. The moderate
weight loss was accompanied by improvement of glycemic control and metabolic
treatment doses reduction.
Results HbA1C (%) 8,8+/-1,64 8,21+/-1,9 P<0.05 7.8+/-1.56 P<0.05
[2000-PO] Orlistat the New Oral Antidiabetic Agent ZDENEK RUŠAVÝ,
JIRÍ MUDRA, SILVIE LACIGOVÁ, ANDREA VÍTOVÁ,
DANIELA CECHUROVÁ, ZDENEK JANKOVEC. Plzen, Plzen, Czech Republic.
New TZD Shows Glucose and Lipid Control in
Type 2 Diabetes
Drops FBG by 46mg/dL, Balaglitazone, a novel thiazolidinedione, improves
glucose and lipid control in patients with type 2 diabetes, researchers
reported here in a poster presentation at the ADA 63rd Annual Meeting.
"This new agent showed efficacy for dose-dependent reductions
in glucose and lipid markers," said investigator Dragomir Koev,
PhD, head of the diabetes clinic at the Clinical Center of Endocrinology
and Gerontology, Medical University-Sofia, in Bulgaria. "It looks
like a potent potential treatment for type 2 diabetes.
Balaglitazone (DRF 2593; NN2344) is an insulin sensitizer that acts
as a partial PPAR (peroxisome proliferator-activated receptor) gamma
agonist.
The investigators enrolled 199 patients with type 2 diabetes in a 10-week,
randomized, double-blind, placebo-controlled, dose-finding study. They
administered balaglitazone 5 mg to 42 subjects, 10 mg to 38 subjects,
and 20 mg to 38 subjects, as well as open-label pioglitazone 45 mg to
42 subjects and placebo to 39 subjects.
The primary end point was change in fasting plasma glucose.
Examination of the data indicated that balaglitazone therapy resulted
in dose-dependent reductions in levels of fasting plasma glucose, haemoglobin
A1c (HbA1c), very low density lipoprotein (VLDL), free fatty acids,
and triglycerides, as well and a dose-dependent increase in high-density
lipoprotein (HDL).
Mean decreases in fasting plasma glucose were 1.03 for balaglitazone
5 mg (P<0.05), 1.72 for balaglitazone 10 mg (P<0.01), 2.54 for
balaglitazone 20 mg (P<0.01), and 1.91 for pioglitazone (P<0.01).
Among the 90% of subjects that completed the study, three experienced
serious adverse events (one each in the placebo group, the 5 mg balaglitazone
group, and the 20 mg group). One patient in the 5 mg balaglitazone group
and one in the pioglitazone group developed edema.
"Increases in [creatine kinase], [lactate dehydrogenase], and
urea were observed following both pioglitazone and balaglitazone treatment,"
the researchers said.
No major safety concerns were evident from adverse events, laboratory
values, physical exam, slit lamp exam and electrocardiograms. Total
and LDL cholesterol levels were non-significantly increased with both
pioglitazone and balaglitazone treatment.
The researchers concluded that balaglitazone might be "a promising
treatment for type 2 diabetes."
[Study title: Balaglitazone, a New Thiazolidinedione, Improves Glucose
and Lipid Control in Patients with Type 2 Diabetes. Abstract 530]
Rosiglitazone Improves Insulin Sensitivity,
Glucose Control and Inflamation.
They enrolled 29 subjects with IR and a steady-state plasma glucose
level greater than 180 mg/dL after a 3-hour insulin suppression test.
Fifteen of the subjects had Gp A (glucose production) with fasting plama
glucose level lower than 126 mg/dL. Fourteen had a Gp B (basal glucose
production) level of 126 and 150 mg/dL.
The investigators also measured at baseline and after 3 months of rosiglitazone
therapy the levels of fasting C-reactive protein, interleukin-6, plasminogen
activator inhibitor-1 (PAI-1), ICAM-1 (intercellular adhesion molecule-1),
VCAM-1 (vascular cell adhesion molecule 1), as well as the levels of
E-, L-, and P-selectin, which are three membrane-attached calcium-dependent
lectins that initiate rolling adhesion of leukocytes on the vascular
wall by binding to cell-surface carbohydrate ligands.
They compared changes in the markers to changes in steady-state plasma
glucose, binding proteins, fasting plasma glucose, insulin, free fatty
acids, and lipids.
The study showed that rosiglitazone produced a decrease in fasting
plasma glucose by 8% to 23% and a decrease in C-reactive protein by
38% to 55%. This suggests cardiovascular benefit, said Dr. Chu.
The results also showed that rosiglitazone therapy led to lower steady-state
plasma glucose and fasting plasma glucose, respectively, in Gp A (242
to 184 mg/dL; 105 to 97 mg/dL) and Gp B (255 to 164 mg/dL; 142 to 119
mg/dL) (all P<0.01). In both Gps A and B, 3 markers fell after rosiglitazone
treatment: C reactive protein (3.6 to 1.6 mg/L, P<0.01; 2.5 to 1.5
mg/L, P<0.02); PAI-1 (6.6 to 2.1 ng/mL, P<0.02; 5.0 to 1.8 ng/mL,
P<0.07); and E-selectin (50 to 41 ng/mL, P<0.01; 54 to 48 ng/mL,
P<0.07).
They found no clear correlation between decreases in the markers and
changes in insulin resistance or fasting plasma glucose level. "There
was no constant relationship between changes in the markers and other
metabolic or [coronary heart disease] risks." said Dr. Chu.
However, the researchers noted that their data indicated that rosiglitazone
treatment had a direct effect on metabolic measures, lowering glucose
and circulating markers, and indicating a decrease in selected protein
levels.
Dr. Chu noted that this study raises the core questions of whether
rosiglitazone therapy decreases cardiovascular risk of insulin resistant
syndrome and whether it also decreases the potential for development
of diabetes.
[Study title: Vascular and Inflammatory Markers in Rosiglitazone-Treated
Insulin-Resistant Subjects Are Independent of Changes in Insulin Sensitivity
or Glycemic Control. Abstract 325-
Ginseng Improves Glucose Control
The finding that American ginseng may help to normalize blood glucose
levels emphasizes the need to ask diabetic patients if they are taking
any complementary medicines, Canadian researchers say.
University of Toronto investigators spoke about the implications of
their trial during a poster session here on June 14th at the American
Diabetes Association's 63rd Scientific Sessions.
The researchers enrolled 30 well-controlled type 2 diabetics into a
double-blind, randomised, placebo-controlled, crossover-designed study.
The participants, who were kept on their standard anti-diabetic regimen
of oral hypoglycaemic agents or lifestyle intervention alone, were randomly
assigned to receive either 3 g of ground-up North American-grown ginseng
and 7 g of a highly viscous Konjac mannan fibre blend, or placebo, daily.
After a 40 week run-in period, the patients were given one treatment
for 12 weeks, followed by an 8 week wash-out period. Then, they were
administered the alternate treatment for another 12 weeks.
The average hemoglobin A1C level fell from 7.0% at baseline to 6.5%
when patients were taking the ginseng preparation, compared with 6.8%
when they were taking placebo (p=0.006), the study showed.
The results are comparable to those obtained with adjunct therapy with
other hypoglycaemic agents, such as the alpha-glucosidase inhibitors,
in well-controlled patients, said Alexandra Jenkins, BSc, RD, a research
associate at the University of Toronto.
The herbal preparation appeared to be safe, with liver, kidney and
haemostatic function not adversely affected, compared with placebo,
the study showed.
Dr. Jenkins stressed that such a preliminary, short-term study is not
a reason to recommend ginseng to patients.
"We tried several 5 different sources of ginseng roots, testing
them on ourselves, before finding one that seemed to have activity in
regulating blood sugar," she said.
Even if such a preparation was available at the health food store,
there would be no way to know its purity due to poor regulation and
labelling in the herbal industry, said John L. Sievenpiper, a PhD candidate
at the University of Toronto and Dr. Jenkin's co-investigator.
But, the findings are every reason to ask diabetic patients if they
are taking ginseng or other complementary therapies, as standard medication
dosing may need to be adjusted, he said.
In a recent survey, physicians estimated that about 75% take complementary
medicines, including herbs, Mr. Sievenpiper said.
[Study title: Reduction of HbA1c after Long Term Administration of American
Ginseng and Konjac Mannan Fiber in Type 2 Diabetes.]
Improvement of Glycemic Control with Orlistat
in Overweight and Obese Patients with Metabolic Syndrome and Type 2
Diabetes
Excess weight is an important risk factor for type 2 diabetes (T2D).
Overweight and obese patients, especially those with T2D, exhibit a
range of metabolic abnormalities and are at increased risk of cardiovascular
disease. This clustering of excess weight and metabolic abnormalities
is increasingly recognized as the metabolic syndrome. The response to
orlistat (ORL) treatment in overweight and obese patients with T2D and
other metabolic abnormalities was investigated.
A retrospective analysis of pooled data from 7 multicenter, double-blind
trials enrolling overweight or obese patients (BMI 28-43 kg/m²)
with T2D and treated with metformin, sulfonylurea (SU) and/or insulin
was performed. Patients were randomized to treatment with ORL 120mg
or placebo (PL) tid plus a mildly reduced-calorie diet for up to 1 year.
Metabolic syndrome was diagnosed by the ATP III criteria in 2086/2550
(82%) patients.
Overall, ORL-treated patients had significantly greater improvements
in weight loss, glycemic control, blood pressure and lipid profile than
PL-treated patients after 52 weeks.
Change at endpoint vs baseline (mean) in
T2D patients with metabolic syndrome
PL ORL P value
Weight (kg) -1.41 -3.92 <0.0001
HbA1c (%) -0.28 -0.71 <0.0001
FPG (mmol/L) -0.41 -1.41 <0.0001
PPG (mmol/L) -0.12 -1.66 <0.0001
LDL-cholesterol (%) 7.03 -1.86 <0.0001
Systolic BP (mmHg) -0.27 -1.99 <0.05
Diastolic BP (mmHg) -1.27 -2.32 <0.05
In conclusion, ORL treatment is associated with clinically beneficial
improvements in glycemic control and other metabolic parameters in overweight
and obese patients with T2D and metabolic syndrome. Given the impact
of ORL treatment in this group of patients, ORL represents a clinically
beneficial adjunct to anti-diabetic therapy.
[2413-PO] Improvement of Glycemic Control with Orlistat in Overweight
and Obese Patients with Metabolic Syndrome and Type 2 Diabetes PRISCILLA
HOLLANDER, AILA RISSANEN, MIKE RABBIA, JONATHAN HAUPTMAN, MARK BOLDRIN.
Dallas, TX; Helsinki, Finland; Nutley, NJ.
ACE ACE ACE: Begin Patients On An Ace Inhibitor
at Diagnosis of Type 2
The angiotensin-converting (ACE) enzyme inhibitor enalapril decreases
albuminuria in normotensive type 2 diabetics
The findings suggest that all type 2 diabetics should be started on
an ACE inhibitor upon diagnosis, said Jamal Ahmad, MD, PhD, from Aligarh
Muslim University, in Aligarh, India, who presented the results.
Dr. Ahmad and colleagues enrolled 103 type 2 diabetics who had normal
blood pressure levels and a persistent albumin excretion rate (AER)
of 20 to 200 mcg/min with normal renal function. Subjects were randomised
to 5 years of treatment with enalapril or placebo, after which placebo-treated
patients were switched to enalapril for another 5 years.
In enalapril-treated patients, AER decreased from 55 to 20 mcg/min
after 5 years; in the placebo group, AER increased from 53 to 85 mcg/min.
Overall, 7.7% of enalapril-treated patients and 23.5% of placebo-treated
patients progressed to clinical albuminuria, which translated into a
66.7% risk reduction (P<0.001).
The results also show that AER increased at an annual rate of 12.3%
in the placebo group, and declined by 16.7% in the enalapril group (P<0.001).
Results in patients who were initially assigned to placebo and then
switched to enalapril confirmed the ACE-inhibitor's renoprotective effect.
"Based on the results, we recommend all type 2 diabetics should
be started on an ACE-inhibitor immediately upon diagnosis," Dr.
Ahmad said.
[Study title: Long-Term Renoprotective Effects of Enalapril in Normotensive
Type 2 Diabetic Patients with Microalbuminuria. Abstract 209]
Exenatide, Shows Promise for Diabetes
Venom from the Gila Monster Improves Diabetes Control to Normal
Exenatide, an experimental agent derived from the venom of the gila
monster, can help to improve glycaemic control to near-normal levels
in patients who have type 2 diabetes that does not respond to oral therapy,
suggests a Phase III open-label study.
Alain Baron, MD, Senior Vice President of Clinical Research at San
Diego-based Amylin Pharmaceuticals Inc., which is co-developing exenatide
with Eli Lilly and Co., presented the findings here on June 16th at
the American Diabetes Association (ADA) 63rd Scientific Sessions.
Exenatide is the first of a new class of anti-diabetic agents -- known
as glycogen-like peptide-1 based drugs -- that work by a totally different
mechanism than medications now in use, Dr. Baron said.
The study, designed to show safety and efficacy, enrolled 155 patients
whose haemoglobin A1c (HbA1c) levels had not reached the ADA's target
goal of 7.0% after at least 3 months of treatment with at least 1,500
mg/day of metformin, the maximally effective dose of a sulfonylurea,
or both.
The participants, whose HbA1c levels ranged from 7.5% to 12.0%, received
5 mcg of exenatide twice a day for 4 weeks, followed by 10 mcg twice
a day for 20 more weeks. Throughout the trial, participants continued
to take their standard therapy.
In the 63 patients who completed 24 weeks of treatment, HbA1c levels
decreased from an average of 8.6% to 7.2%, Dr. Baron said. Forty-five
percent of patients achieved the glycaemic target of 7.0% or less, while
HbA1c levels decreased to 6.5% or less in 16% of patients, he said.
The patients lost an average of 5 pounds in the 24-week trial.
The most frequent side was mild to moderate nausea, which affected
about 27% of participants.
The development of antibodies, a major concern, did not appear to be
a problem, he said. Low anti-exenatide antibody titers were observed
in a number of participants, but were not associated with any adverse
effects, he said.
Unlike insulin, exenatide offers fixed dosing, with one injection
effective for 6 hours.
"We've never seen this kind of benefit except with insulin, and
that is usually accompanied by weight gain," Dr. Baron said. "And
unlike insulin, that has to be adjusted according to blood glucose levels,
exenatide is a fixed compound."
The bottom line, he said, is the "exenatide can achieve near-normal
glycaemic control on patients taking other oral agents is the context
of weight loss."
The first of the pivotal randomised double-blind, placebo controlled
pivotal Phase III trial using the same dosing will be presented at the
International Diabetes Federation Congress in Paris in late August,
Dr. Baron said.
[Study title: Exenatide (synthetic exendin-4) Showed Marked High HbA1c
Decline Over 5 Months in Patients with Type 2 Diabetes Failing Oral
Agents in an Open-Label Study. Abstract LB-3]
Novel Drugs Target Gut Hormones to Prevent
Diabetes
At a time when government researchers are predicting that one in three
American children will develop diabetes in his or her lifetime, pharmaceutical
companies are racing to develop therapies to stop the epidemic. Some
are working on agents that attack the disease in new ways, while others
are searching for new uses for drugs already on the market.
"It's probably fair to say that every major drug company is working
on an agent for diabetes," said Daniel J. Drucker, MD, director
of the Banting and Best Diabetes Centre at Toronto General Hospital
in Ontario.
Some of the hottest research focuses on a new class of agents dubbed
the gut peptides. Unlike many of the drugs in development, these drugs
work by a different mechanism than those now in use, he said at the
American Diabetes Association 63rd Scientific Sessions, where a number
of advances were discussed this week.
Development of the gut peptide drugs was a decades-long process that
grew out of a better understanding of the body's gut hormones, which
control everything from when we get hungry to when we push back from
the table. By stimulating those gut hormones that suppress appetite
and speed up metabolism and by blocking those hormones that stimulate
hunger and slow energy expenditure, researchers reasoned, novel drugs
could help obese people to lose weight, control blood glucose, and even
improve insulin secretion and sensitivity. And early trials are proving
them right.
The furthest along in development are the glucagon-like peptide-1 (GLP-1)
drugs, which pack a triple whammy against the disease, stimulating insulin
secretion, suppressing glucagon secretion, and inhibiting gastric emptying.
The furthest along in its class is exenatide, a synthetic version of
a GLP-1-like substance found in the saliva of the Gila monster. An open-label
study reported at the meeting showed that about half of patients failing
oral therapy achieved near-normal glycemic control when exenatide was
added to their regimen.
There may be a fourth mechanism of action as well. Researchers at Novo
Nordisk Pharmaceuticals, Inc., in Princeton, New Jersey, reported that
their long-acting GLP-1 derivative liraglutide appeared to restore pancreatic
beta cell sensitivity to glucose in patients with type 2 diabetes. In
the study, insulin secretion after a single subcutaneous injection of
the drug was similar in 10 patients with type 2 diabetes compared with
that in 10 healthy controls.
Other researchers are targeting other gut hormones. Researchers at
Stanford University reported that levels of ghrelin, a hormone thought
to play an important role in both appetite and satiety, are significantly
lower in obese insulin-resistant individuals than in equally obese insulin-sensitive
persons. The results suggest that insulin may have a role in regulating
body weight, via modulation of ghrelin, the researchers said.
Peter J. Havel, DVM, PhD, associate professor of nutrition at the University
of California at Davis and moderator of a symposium on GI signals and
energy balance, thinks they're right on target. "Ghrelin was originally
investigated for its activity in stimulating growth hormone," he
said. "But a number of investigators have shown that it also stimulates
food intake. Therefore, blocking its action would decrease appetite
and reduce weight."
Researchers from the Imperial College London in the U.K. reported on
another gut hormone, oxyntomodulin, that is released into the circulation
postprandially, in proportion to caloric intake. Carrying its message
that food has been ingested, oxyntomodulin appears to send signals to
the brain circuits that regulate appetite.
In a study of 13 healthy persons, oxyntomodulin, given by infusion,
significantly reduced appetite at the next meal and lowered caloric
intake over the next 12 hours.
Not all the news centered on gut hormones. Researchers from the University
of Texas Health Science Center in San Antonio reported that adding orlistat
to a healthy diet and exercise program may help to reduce the risk of
type 2 diabetes in an at-risk population. The four-year study showed
that patients with metabolic syndrome who were treated with orlistat
and healthy diet were 36% less likely to develop type 2 diabetes compared
with those on placebo and diet.
The patients in the orlistat arm also experienced other improvements,
including a significantly greater reduction in waist circumference,
a bigger drop in blood pressure levels, and a greater improvement in
glycemic control compared with those in the placebo group.The study,
which was funded by Hoffman LaRoche, which manufactures orlistat under
the brand name Xenical, randomized 3,277 obese Swedes to one of the
two regimens; 40%, or 1,320 had metabolic syndrome as defined by the
National Cholesterol Education Program.
ADA 63rd Scientific Sessions: Abstracts 486-P, 967-P, presented June
14, 2003; abstracts 1703-P, 3-LB, 5-LB, 6-LB, presented June 16, 2003.
Pramlintide, as an Adjunct to Insulin Therapy,
Led to Improved Control of Both Glycemia and Weight
in African American and Hispanic Patients with Type 2 Diabetes
An unresolved problem in the management of type 2 diabetes is that improvement
of glycemic control with insulin, insulin secretagogues, and insulin
sensitizers is often accompanied by undesired weight gain. This is of
particular concern in ethnic groups with a high propensity for diabetes
and obesity, such as African Americans (AA) and Hispanics (H). Two 1-year,
randomized, double-blind, placebo-controlled clinical trials in insulin-treated
patients with type 2 diabetes have shown that adjunctive therapy with
pramlintide (PRAM), an analog of the human b-cell hormone amylin, reduces
A1c and leads to weight loss, rather than weight gain.
To assess the effect of PRAM in various ethnic groups with type 2 diabetes,
we conducted a pooled analysis of the 2 trials which included all Caucasian
(C, n=315), AA (n=47), and H (n=48) subjects (age 56-57y, A1c 9.1-9.2%,
BMI 32-33kg/m², mean ranges) who completed 52 weeks of treatment
with either PRAM (120µg BID or 150µg TID) or placebo. Main
endpoints included changes from baseline to week 52 in A1c and body
weight.
Collectively, PRAM-treated patients achieved significant reductions
in both A1c and body weight (placebo-corrected treatment effects at
week 52: -0.5% and -2.6kg, respectively, both p<0.0001). The simultaneous
reduction in A1c and body weight at week 52 was evident across all three
ethnic groups, and appeared to be most pronounced in AA (-0.7%, -4.1kg),
followed by C (-0.5%, -2.4kg) and H (-0.3%, -2.3kg). The glycemic improvement
with PRAM was not associated with an increased incidence of hypoglycaemia
over the entire study period (43% PRAM vs. 40% placebo); the most common
adverse event associated with PRAM was mild nausea (25% PRAM vs. 16%
placebo), which was confined to the first 4 weeks of therapy.
The simultaneous improvement of glycemic and weight control makes PRAM
an attractive potential adjunctive treatment for insulin-treated African-Americans
and Hispanics with type 2 diabetes
533-P] Pramlintide, as an Adjunct to Insulin Therapy, Led to Improved
Control of Both Glycemia and Weight in African American and Hispanic
Patients with Type 2 Diabetes
ORVILLE KOLTERMAN, DAVID MAGGS, TERRIE BURRELL, SUSAN STROBEL, DAVID
BROWN, CHRISTIAN WEYER. San Diego, CA.
