Biochem Biophys Res Commun.
2005 Mar 11;328(2):484-90.
Glimepiride enhances intrinsic peroxisome proliferator-activated
receptor-gamma activity in 3T3-L1 adipocytes.
Inukai K, Watanabe M, Nakashima Y, Takata N, Isoyama A, Sawa T,
Kurihara S, Awata T, Katayama S.
Division of Endocrinology and Diabetes, Department of Medicine,
Saitama Medical School, Morohongo 38, Moroyama, Iruma-gun, Saitama
350-0495, Japan.
Glimepiride, a third-generation sulfonylurea (SU), exerts its effects
mainly by stimulating insulin secretion but has also been shown
to have pleiotropic effects. Recent clinical studies showed glimepiride
to enhance insulin sensitivity. In the present study, to clarify
the mechanism by which insulin resistance is improved, we investigated
the effects of glimepiride on AMP-activated protein kinase (AMPK)
and peroxisome proliferator-activated receptor-gamma (PPARgamma)
activity, using cultured adipocytes and muscle cells. When we treated
fully differentiated 3T3-L1 adipocytes with 1muM glimepiride, endogenous
PPARgamma transcriptional activity was significantly elevated, while
AICAR-induced phosphorylation of AMPK was not affected in differentiated
C2C12 myoblasts. The maximum PPARgamma activity enhancing effect
of glimepiride is approximately 20% that of 1muM pioglitazone. In
contrast, this mild PPARgamma-stimulatory effect was not observed
under the same conditions with a 2nd generation SU, glibenclamide.
Furthermore, with glimepiride treatment, transcriptional levels
of aP2, the adipogenic marker gene, were increased 2.4- and 3.7-fold
in 3T3-L1 adipocytes and fibroblasts, respectively. Analysis of
triglyceride contents revealed glimepiride to promote differentiation
of 3T3-L1 adipocytes. These results indicate that glimepiride has
the potential to induce PPARgamma activity, thereby improving insulin
resistance.
J Assoc Physicians India. 2004 Jun;52:459-63.
Use of glimepiride and insulin sensitizers in the treatment of
type 2 diabetes--a study in Indians.
Ramachandran A, Snehalatha C, Salini J, Vijay V.
Diabetes Research Centre and M.V. Hospital for Diabetes WHO Collaborating
Centre for Research, Education and Training in Diabetes Royapuram,
Chennai.
AIM: Short-term efficacy of glimepiride, metformin and pioglitazone
in newly diagnosed type 2 diabetes was compared with a group treated
with diet and exercise. Effects on insulin secretion and sensitivity
were also assessed. METHODS: New type 2 diabetic subjects, aged
30-60 years with BMI < 30 kg/m2 were selected. Subjects having
glycosylated haemoglobin (HbA1c) of < 8.5% were advised diet
and exercise (control group). Others having HbA1c > or = 8.5
to 11.0% were randomized to receive glimepiride (group 2), metformin
(group 3) and pioglitazone (group 4). At the final review between
12-14 weeks, changes in plasma glucose, HbA1c, lipid profile,
HOMA insulin resistance (HOMA-IR), beta cell function (HOMA-BF)
and insulinogenic index (delta I/G) were measured. Comparisons
were made using appropriate statistical analyses. RESULTS: Seventy-seven
of the 97 subjects randomized equally into four groups, were available
for review. Glycaemic parameters improved in all groups. Mean
cholesterol decreased significantly in groups treated with metformin
and pioglitazone. HDL-cholesterol increased with pioglitazone.
Insulin resistance decreased significantly with metformin and
pioglitazone, beta cell fuhction also showed improvement CONCLUSIONS:
Glycaemic control was seen in all study groups, the improvement
was better in drug treated groups than in the control group. Glimepiride
improved insulin secretion including the early phase secretion
and reduced plasma triglycerides. Metformin and pioglitazone had
beneficial effects on lipid levels, improved insulin sensitivity
and improved insulin secretion also.
J Diabetes Complications. 2004 Nov-Dec;18(6):367-76.
The role of glimepiride in the effective management of Type 2
diabetes.
Davis SN.
Division of Diabetes Endocrinology and Metabolism, Vanderbilt
University Medical School, 715 Preston Research Building, Nashville,
TN 37232-6303, USA.
Type 2 diabetes mellitus, a disorder of impaired insulin secretion
and insulin resistance, has reached epidemic proportions. The
effective management of Type 2 diabetes is of vital concern to
clinicians. The identification of high-risk individuals and lifestyle
management can help control diabetes; however, most patients require
pharmacologic intervention. The goals of pharmacologic therapy
are to achieve adequate glycemic control while avoiding hypoglycemia
and weight gain and to minimize the risk of future micro- and
macrovascular complications. There are a number of available glucose-lowering
agents from which to choose. This review focuses on the sulfonylureas,
the first oral agents introduced for the management of Type 2
diabetes, which are effective, well-tolerated, and well-established
drugs, Second-generation sulfonylureas are now widely used in
the management of Type 2 diabetes. The most recent addition, glimepiride,
can be used in combination with metformin, the thiazolidinediones,
alpha-glucosidase inhibitors, and insulin. The unique properties
of glimepiride may provide advantages over other currently available
insulin secretagogues.
Manag Care. 2004 Jul;13(7):48-9, 53-6, 58-9.
Cost-effective management of hyperglycemia in patients with type
2 diabetes using oral agents.
Kabadi UM.
Division of Endocrinology, University of Iowa Hospitals and Clinics,
Iowa City 52246-2208, USA.
Diabetes exacts an enormous toll on health care resources, with
extremely high costs attributable to care of diabetes patients
in proportion to the afflicted population. Though individual treatment
strategies are required for each patient, newer long-acting sulfonylureas
may be the initial drugs of choice, as they may be the only oral
agents that inhibit the processes inducing hyperglycemia--hepatic
glucose production and glucose utilization by the tissues--by
improving insulin secretion and insulin resistance. Sulfonylureas
also represent the most cost-effective therapeutic option, alone
or in combination with other oral agents or insulin. The newer
long-acting agents, glimepiride and glipizide GITS, may be more
attractive among sulfonylureas, due to their greater insulin-sparing
property, fewer hypoglycemic events, weight neutrality, and once-daily
dosing. Glimepiride may be preferred due to its safety profile,
especially for the elderly and those with hepatic and/or renal
dysfunction.
Diabetes Nutr Metab. 2004 Jun;17(3):143-50.
Metabolic variations with oral antidiabetic drugs in patients
with Type 2 diabetes: comparison between glimepiride and metformin.
Derosa G, Franzetti I, Gadaleta G, Ciccarelli L, Fogari R.
Department of Internal Medicine and Therapeutics, University of
Pavia, Pavia, Italy.
Patients with Type 2 diabetes (T2DM) are at high risk of morbidity
and mortality from cardiovascular complications, and hypoglycaemia
increases this risk. Furthermore, other metabolic parameters exacerbate
cardiovascular risk in these patients. The aim of the study was
to compare the metabolic effects of glimepiride and metformin
in patients with T2DM. We evaluated 164 patients with T2DM (80
males, 84 females) in a multicentre, randomised, controlled, open,
parallel group study comparing glimepiride with metformin. Eighty-one
patients (aged 56+/-10 yr) received glimepiride (3+/-1 mg/d);
83 patients (aged 58+/-9 yr) received metformin (2500+/-500 mg/d).
Patients had been diagnosed for < or = 6 months; they were
non-smokers; had no hypertension or coronary heart disease; were
not taking hypolipidaemic drugs, diuretics, beta-blockers or thyroxin;
and had normal renal function. Metabolic parameters were measured
after 6 and 12 months of treatment. Glimepiride significantly
lowered lipoprotein(a) [Lp(a)] and homocysteine levels (HCT) at
6 and 12 months. Both glimepiride and metformin lowered plasminogen
activator inhibitor Type 1 (PAI-1) at 12 months and significantly
improved levels of glycosylated haemoglobin, fasting plasma glucose
and post-prandial plasma glucose after 6 and 12 months. Metformin
significantly lowered fasting plasma insulin and postprandial
plasma insulin. Glimepiride and metformin also reduced levels
of other metabolic parameters in patients with T2DM. In particular,
glimepiride significantly reduced HCT, Lp(a), and PAI-1 levels,
important metabolic risk factors for atherosclerotic vascular
disease. These reductions may be owing to improved glucose metabolism,
but it cannot be excluded that these drugs have a direct effect
on additional metabolic parameters.
Clin Ther. 2004 May;26(5):744-54.
Metabolic effects of pioglitazone and rosiglitazone in patients
with diabetes and metabolic syndrome treated with glimepiride:
a twelve-month, multicenter, double-blind, randomized, controlled,
parallel-group trial.
Derosa G, Cicero AF, Gaddi A, Ragonesi PD, Fogari E, Bertone G,
Ciccarelli L, Piccinni MN.
Department of Internal Medicine and Therapeutics, University of
Pavia, Piazzale C. Golgi 2, 27100 Pavia, Italy.
BACKGROUND: Glimepiride is approved as monotherapy and in combination
with metformin or with insulin, whereas the combination of glimepiride
with other antihyperglycemic drugs is under investigation. OBJECTIVE:
The aim of this study was to assess the differential effect on
glucose and lipid variables and tolerability of the combination
of glimepiride plus pioglitazone or rosiglitazone in patients
with type 2 diabetes mellitus (DM) and metabolic syndrome. METHODS:
This 12-month, multicenter, double-blind, randomized, controlled,
parallel-group trial was conducted at 3 study sites in Italy.
We assessed patients with type 2 DM (duration, > or =6 months)
and with metabolic syndrome. All patients were required to have
poor glycemic control with, or to have experienced > or =1
adverse effect (AE) with, diet and oral hypoglycemic agents such
as sulfonylureas or metformin, both given up to the maximum tolerated
dose. All patients received a fixed oral dose of glimepiride,
4 mg/d divided into 2 doses, self-administered for 12 months.
Patients also were randomized to receive oral pioglitazone (15
mg once daily) (G + P group) or oral rosiglitazone (4 mg once
daily) (G + R group), self-administered for 12 months. We assessed
body mass index (BMI), glycemic control (glycosylated hemoglobin
[HbA(1c)], fasting and postprandial plasma glucose and insulin
levels [FPG, PPG, FPI, and PPI, respectively], and homeostasis
model assessment index), lipid profile (total cholesterol [TC],
low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein
cholesterol [HDL-C], and triglycerides [TG]), and lipoprotein
variables (apolipoprotein [apo] A-I and apo B) at baseline and
at 3, 6, 9, and 12 months of treatment. Treatment tolerability
was assessed at each study visit using a thorough interview of
patients, and comparisons of clinical and laboratory values to
baseline levels. RESULTS: A total of 91 patients were enrolled
in the study; 87 patients completed it (G + P group: 24 women,
21 men; mean [SD] age, 53 [6] years; G + R group: 20 women, 22
men; mean [SD] age, 54 [5] years). Patients in the G + P and G
+ R groups experienced significant increases in mean BMI at 12
months compared with baseline (4.92% and 6.17%, respectively;
both, P < 0.05). The combination of glimepiride with pioglitazone
or rosiglitazone significantly improved glycemic control in the
study patients. At 12 months, we observed a 1.3% improvement in
mean values for plasma HbA(1c) concentration (P < 0.01) 19.3%
in FPG (P < 0.01), 16.3% in PPG (P < 0.01), 42.4% in FPI
), and 23.3% in PPI (P <0.05); no significant differences were
found between treatment groups. Although the G + P group experienced
a significant improvement at 12 months in almost all variables
of lipid metabolism from baseline (TC, - 11%; LDL-C, -12%; HDL-C,
15%; and apo B, - 10.6% [all, P , 0.05]), the G + R group experienced
a significant increase in mostly the lipid risk factors for cardiovascular
disease (TC, 14.9%; LDL-C, 16.5%; TG, 17.9%; and apo B, 10.3%
[all, P , 0.05]). Overall, no statistically significant changes
in plasma aminotransferase activities were observed. Of the 87
patients who completed the study, 6.7% (3/45) of patients in the
G + P group and 11.9% (5/42) of patients in the G + R group had
transient, mild to moderate AEs that did not cause withdrawal
from the trial. CONCLUSION: In this study of patients with type
2 DM and metabolic syndrome who did not respond adequately to,
or experienced AEs with, diet and either a sulfonylurea or metformin
previously, the combination of glimepiride plus pioglitazone was
associated with a significant improvement in lipid and lipoprotein
variables, whereas the combination of glimepiride plus rosiglitazone
appears to not have had any clinically significant effect on lipid
metabolism.
Pharmacotherapy. 2004 May;24(5):606-20.
Sulfonylurea treatment of type 2 diabetes mellitus: focus on glimepiride.
Korytkowski MT.
Center for Diabetes and Endocrinology, Division of Endocrinology,
Department of Medicine, University of Pittsburgh, Pittsburgh,
Pennsylvania 15213, USA.
Sulfonylureas, which have evolved through two generations since
their introduction nearly 50 years ago, remain the most frequently
prescribed oral agents for treatment of patients with type 2 diabetes
mellitus. Glyburide, glipizide, and glimepiride, the newest sulfonylureas,
are as effective at lowering plasma glucose concentrations as
first-generation agents but are more potent, better tolerated,
and associated with a lower risk of adverse effects. Differences
in their binding affinity to the beta-cell sulfonylurea receptor
have been described, with preservation of cardioprotective responses
to ischemia with glimepiride. Clinical studies have shown glimepiride
to be safe and effective in reducing fasting and postprandial
glucose levels, as well as glycosylated hemoglobin concentrations,
with dosages of 1-8 mg/day. In comparative trials, glimepiride
was as effective in lowering glucose levels as glyburide and glipizide,
but glimepiride was associated with a reduced likelihood of hypoglycemia
and a smaller increase in fasting insulin and C-peptide levels
than glyburide, and a more rapid lowering of fasting plasma glucose
levels than glipizide. Glimepiride also improves first-phase insulin
secretion, which plays an important role in reducing postprandial
hyperglycemia. Insulin secretagogues, specifically glimepiride,
merit consideration as first-line therapy for patients with type
2 diabetes.
Drugs Today (Barc). 1998 May;34(5):401-8.
Clinical trials with glimepiride.
Clark CM Jr, Helmy AW.
Regenstrief Institute for Health Care, Richard L. Roudebush Veterans
Affairs Medical Center and the Indiana University School of Medicine,
Indianapolis, Indiana 46202, USA.
Data from 21 placebo-controlled, active-controlled or noncomparative
studies involving more than 6500 patients, more than 4220 of whom
were treated with glimepiride, are reviewed. Glimepiride has a
rapid onset of action and is effective at a single daily dose.
It is equally effective as the other second-generation sulfonylureas
at doses of 1-8 mg/day, with doses above 4 mg/day reserved for
patients with initial HbA(1c) above 8%. Glimepiride (at doses
yielding the same blood-lowering effect as glyburide and glipizide),
has a safety profile somewhat superior to that of glyburide, glipizide
and gliclazide at a lower mg/day dose. Glimepiride also has been
shown to be safe and effective in combination with insulin. Finally,
glimepiride has two pharmacologic properties which have theoretical
advantages over the other currently available sulfonylureas, but
which have not as yet been shown to be clinically significant:
it does not activate the cardiovascular K(ATP) channel and it
achieves equivalent metabolic control at lower insulin secretion
levels than the other sulfonylureas.
Drugs Today (Barc). 1998 May;34(5):391-400.
Preclinical studies of glimepiride.
Nguyen C, Pan J, Charles MA.
Diabetes Research Program, University of California, Irvine, California
92697, USA.
The treatment of NIDDM is advancing on a number of fronts, ranging
from the understanding of the mechanisms of action of existing
agents to the development of new drugs. Glimepiride, the most
recently U.S. approved sulfonylurea, is evaluated for its pancreatic
and extrapancreatic activities in addition to safety, when compared
with glibenclamide in preclinical studies. Glimepiride uniquely
binds to the 65 kDa protein K(ATP) channel in pancreatic islet
beta-cell membranes and directly stimulates insulin secretion.
Glimepiride has a lower binding affinity and causes less insulin
release than glibenclamide in normal dogs and humans. However,
in various animal models, glimepiride produces a more rapid and
pronounced blood glucose-decreasing activity than glibenclamide.
In vivo studies indicate that glimepiride also significantly reduces
HbA1c, blood glucose and fasting insulin levels via extrapancreatic
activities. These insulin mimetic effects are supported by demonstration
of stimulated lipogenesis in 3T3 adipocytes and glycogenesis in
rat diaphragm, by more efficient translocation of GLTU4 in fat
and skeletal muscle tissues, and by activation of key metabolic
enzymes. The insulin sensitivity effects of glimepiride have been
demonstrated in vivo by increased glucose disposal rates in euglycemic
clamp studies and in vitro by increased sensitivity and responsiveness
of insulin-induced glucose uptake. Moreover, glimepiride might
stimulate insulin-mediated glucose utilization in hepatocytes.
With exercise-induced hypoglycemia, a suppression of endogenous
insulin secretion was observed for glimepiride only. Data accumulated
from in vitro and animal studies suggest that glimepiride has
the least cardiotoxic potential. Its relative activities in multiple
cardiovascular studies do not correlate with its potency to lower
blood glucose levels. Similar cardiovascular effects have been
seen in human studies. In contrast to the lack of an acute action,
chronic application of glimepiride to cultured cardiomyocytes
was found to produce an approximate doubling of the basal glucose
uptake rates by an insulin-independent pathway most probably involving
increased protein expression of both GLUT1 and GLUT4. Like glibenclamide,
glimepiride possibly has antiatherogenic activity by inhibiting
platelet aggregation via suppression of arachidonic acid metabolism.
Our recent studies on rats and humans indicated that glimepiride
has immunomodulatory activity and this action appears to be related
to lowering autoimmune responses rather than metabolic action.
These studies have been extended to include glimepiride involvement
with prevention of diabetes in BB rats using an islet transplantation
model. Finally, sulfonylureas, including glimepiride, may be useful
for treating and preventing NIDDM.
Clin Ther. 2004 Jan;26(1):63-9.
Effects of glimepiride on insulin secretion and sensitivity in
patients with recently diagnosed type 2 diabetes mellitus.
Kabadi MU, Kabadi UM.
Medical Service, Veterans Affairs Medical Center, Phoenix, USA.
BACKGROUND: The exact mechanism of the efficacy of glimepiride
in the achievement of glycemic control has not yet been clearly
defined. OBJECTIVE: This study was conducted to examine the influence
of glimepiride on insulin secretion and sensitivity in patients
with type 2 diabetes mellitus (DM) of recent onset. METHODS: This
24-week, open-label, controlled trial was conducted at the Division
of Endocrinology and Metabolism, Veterans Affairs Medical Center
(Phoenix, Arizona). Study participants were aged 32 to 75 years
and had recent-onset (established by a short duration of symptoms
6 weeks to 6 months prior to the study) type 2 DM, or were age-matched
healthy volunteers (control group). In the diabetic patients,
glimepiride tablets were administered orally, initially at 2 mg
once daily in the morning, with the dosage increased by 1 mg every
2 weeks until fasting plasma glucose (FPG) decreased to 6.7 mmol/L;
the dosage was then maintained for the remainder of the 24-week
study period. Oral glucose tolerance tests (OGTTs) were conducted
in the control group and before treatment and at 24 weeks after
the achievement and maintenance of glycemic control (glycosylated
hemoglobin <7.0%) in the diabetic group. For OGTT, plasma insulin
and glucose levels were determined after the subjects fasted overnight
and then at every 15 minutes for 2 hours after glucose challenge.
RESULTS: Fourteen diabetic men (mean [SEM] age, 50 [6] years;
range, 32-75 years) and 10 male healthy controls (mean [SD] age,
48 [5] years; range, 30-68 years) were enrolled. In the DM group,
FPG decreased significantly after treatment ( P<0.001); fasting
plasma insulin was markedly elevated before treatment (P<0.001
vs controls) and decreased after treatment ( P<0.01) but did
not normalize; first-phase insulin secretion was markedly inhibited
before treatment ( P<0.001 vs controls) and normalized after
treatment ( P<0.001) total insulin secretion significantly
improved after treatment ( P<0.01) but did not normalize. Finally,
the pretreatment insulin sensitivity index decreased significantly
(P<0.01) after treatment and normalized in 6 of 14 patients
(42.9%) with type 2 DM. CONCLUSIONS: In this study, glimepiride
achieved desirable glycemic control in patients with recent-onset
type 2 DM through improvement in insulin secretion and sensitivity.
Przegl Lek. 2003;60(6):409-12.
[Glimepiride in daily practice] [Article in Polish]
Jasik M.
Katedra i Klinika Gastroenterologii i Chorob, Przemiany Materii
Akademii Medycznej, w Warszawie.
Application of the strategies and principles of oral diabetic
therapy in type 2 diabetes should be individualized based on the
degree of hyperglycemia, insulin deficiency and insulin resistance.
This paper presents the evaluation of the new third-generation
sulfonylurea compound, glimepiride in daily practice. Glimepiride
appears to have several clinical advantages over conventional
sulfonylureas: different binding kinetics, advisable cardiovascular
effects and beneficial extrapancreatic activity. This may explain
the observation that glimepiride provides more stable blood glucose
control and lower risk of hypoglycemia over some second-generation
sulfonylureas. Glimepiride is safe and well tolerated in patients
with type 2 diabetes. Finally, glimepiride also has been shown
to be safe and effective in combination with other oral agents
or with insulin treatment.
Diabetes Res Clin Pract. 2003 Jul;61(1):13-9.
Effects of glimepiride on HbA(1c) and body weight in Type 2 diabetes:
results of a 1.5-year follow-up study.
Weitgasser R, Lechleitner M, Luger A, Klingler A.
1st Department of Medicine, St. Johanns Spital - Salzburg General
Hospital, Salzburg, Austria.
Sulphonylureas are effective and well tolerated in patients with
Type 2 diabetes, but may be associated with weight gain, and lack
of compliance due to multiple daily dosing. This open, uncontrolled
surveillance study examined the efficacy and safety of glimepiride,
a new sulphonylurea, administered once daily in patients with
Type 2 diabetes. A total of 1,770 patients were enrolled in the
study, and 284 patients were selected for follow-up. Patients
received 0.5 to >4 mg glimepiride once daily for 1.5 years.
HbA(1c) was reduced from 8.4% at baseline to 7.1% after 4 months
and 6.9% after 1 and 1.5 years (median intra-individual change
from baseline: -1.4, -1.5, and -1.7%, respectively; P<0.0001).
Treatment with glimepiride also resulted in significant and stable
weight loss relative to baseline, with the exception of patients
with a body mass index of <25 kg/m(2). Mean body weight was
reduced from 79.8 kg at baseline to 77.9 kg after 4 months, 77.2
kg after 1 year, and 76.9 kg after 1.5 years (mean intra-individual
change from baseline: -1.9 kg, P<0.0001; -2.9 kg, P<0.05;
-3.0 kg, P<0.005, respectively). Therefore, once daily glimepiride
provides effective glycaemic control, and may have advantages
over other sulphonylureas, because it exhibits weight neutralizing/reducing
effects in patients with Type 2 diabetes.
Med Arh. 2003;57(2):125-7.
[Glimepiride--an oral antidiabetic agent] [Article in Croatian]
Becic F, Kapic E, Becic E.
Institut za farmakologiju, Klinicku Farmakologiju i toksikologiju,
Medicinski fakultet Univerziteta u Sarajevu.
Glimepiride is the oral antidiabetic, second-generation sulfonylurea.
It is structurally similar to glyburide. Glimepiride exhibited
more potent glucose-lowering effects than glyburide and longer
duration of hypoglycemic effect. Glimepiride is useful in the
treatment of non-insulin-dependent (type II) diabetes mellitus.
Glimepiride is indicated as an adjunct to diet and exercise for
non-insulin dependent diabetes mellitus. Glimepiride reduces glucose
levels blood by stimulating insulin release from functional pancreatic
beta cells in response to glucose. Glimepiride in daily dose 1
to 8 mg is causing a dose-related decrease blood glucose levels
and glycosylated hemoglobin fasting state and postprandially.
If the maximum dose of glimepiride fails to lower blood glucose
sufficiently, metformine or insuline may be added to glimepiride
monotherapy. Glimepiride is very safe drug and adverse effects
causing by glimepiride are very rare. The risk of hypoglycemia
after use of glimepiride is very small, therefore is the therapy
with glimepiride is more preferable than the therapy with glibenclamide.
Ann Intern Med. 2003 Jun 17;138(12):952-9.
Glimepiride combined with morning insulin glargine, bedtime neutral
protamine hagedorn insulin, or bedtime insulin glargine in patients
with type 2 diabetes. A randomized, controlled trial.
Fritsche A, Schweitzer MA, Haring HU; 4001 Study Group.
Medizinische Klinik, Abteilung fur Endokrinologie, Stoffwechsel
und Pathobiochemie, Eberhard-Karls-Universitat, Tubingen, Germany.
BACKGROUND: Patients with type 2 diabetes are often treated with
oral antidiabetic agents plus a basal insulin. OBJECTIVE: To investigate
the efficacy and safety of glimepiride combined with either morning
or bedtime insulin glargine or bedtime neutral protamine Hagedorn
(NPH) insulin in patients with type 2 diabetes. DESIGN: Open-label,
randomized, controlled trial. SETTING: 111 centers in 13 European
countries. PATIENTS: 695 patients with type 2 diabetes who were
previously treated with oral antidiabetic agents. INTERVENTION:
Randomization to treatment with morning insulin glargine, bedtime
NPH insulin, or bedtime insulin glargine for 24 weeks in addition
to 3 mg of glimepiride. The insulin dose was titrated by using
a predefined regimen to achieve fasting blood glucose levels of
5.56 mmol/L or lower (< or =100 mg/dL). MEASUREMENTS: Hemoglobin
A(1c) values, blood glucose levels, insulin dose, and body weight.
RESULTS: Hemoglobin A(1c) levels improved by -1.24% (two-sided
90% CI, -1.10% to -1.38%) with morning insulin glargine, by -0.96%
(CI, -0.81% to -1.10%) with bedtime insulin glargine, and by -0.84%
(CI, -0.69% to -0.98%) with bedtime NPH insulin. Hemoglobin A(1c)
improvement was more pronounced with morning insulin glargine
than with NPH insulin (0.40% [CI, 0.23% to 0.58%]; P = 0.001)
or bedtime insulin glargine (0.28% [CI, 0.11% to 0.46%]; P = 0.008).
Baseline to end-point fasting blood glucose levels improved similarly
in all three groups. Nocturnal hypoglycemia was less frequent
with morning (39 of 236 patients [17%]) and bedtime insulin glargine
(52 of 227 patients [23%]) than with bedtime NPH insulin (89 of
232 patients [38%]) (P < 0.001). CONCLUSION: The risk for nocturnal
hypoglycemia was lower with glimepiride in combination with morning
and bedtime insulin glargine than with glimepiride in combination
with bedtime NPH insulin in patients with type 2 diabetes. Morning
insulin glargine provided better glycemic control than did bedtime
insulin glargine or bedtime NPH insulin.
