Weight reduction is essential for improving health outcomes in people with obesity and type 2 diabetes. We assessed the efficacy and safety of tirzepatide, a glucose-dependent insulinotropic ...polypeptide and glucagon-like peptide-1 receptor agonist, versus placebo, for weight management in people living with obesity and type 2 diabetes.
This phase 3, double-blind, randomised, placebo-controlled trial was conducted in seven countries. Adults (aged ≥18 years) with a body-mass index (BMI) of 27 kg/m2 or higher and glycated haemoglobin (HbA1c) of 7–10% (53–86 mmol/mol) were randomly assigned (1:1:1), using a computer-generated random sequence via a validated interactive web-response system, to receive either once-weekly, subcutaneous tirzepatide (10 mg or 15 mg) or placebo for 72 weeks. All participants, investigators, and the sponsor were masked to treatment assignment. Coprimary endpoints were the percent change in bodyweight from baseline and bodyweight reduction of 5% or higher. The treatment-regimen estimand assessed effects regardless of treatment discontinuation or initiation of antihyperglycaemic rescue therapy. Efficacy and safety endpoints were analysed with data from all randomly assigned participants (intention-to-treat population). This trial is registered with ClinicalTrials.gov, NCT04657003.
Between March 29, 2021, and April 10, 2023, of 1514 adults assessed for eligibility, 938 (mean age 54·2 years SD 10·6, 476 51% were female, 710 76% were White, and 561 60% were Hispanic or Latino) were randomly assigned and received at least one dose of tirzepatide 10 mg (n=312), tirzepatide 15 mg (n=311), or placebo (n=315). Baseline mean bodyweight was 100·7 kg (SD 21·1), BMI 36·1 kg/m2 (SD 6·6), and HbA1c 8·02% (SD 0·89; 64·1 mmol/mol SD 9·7). Least-squares mean change in bodyweight at week 72 with tirzepatide 10 mg and 15 mg was –12·8% (SE 0·6) and –14·7% (0·5), respectively, and –3·2% (0·5) with placebo, resulting in estimated treatment differences versus placebo of –9·6% percentage points (95% CI –11·1 to –8·1) with tirzepatide 10 mg and –11·6% percentage points (–13·0 to –10·1) with tirzepatide 15 mg (all p<0·0001). More participants treated with tirzepatide versus placebo met bodyweight reduction thresholds of 5% or higher (79–83% vs 32%). The most frequent adverse events with tirzepatide were gastrointestinal-related, including nausea, diarrhoea, and vomiting and were mostly mild to moderate in severity, with few events leading to treatment discontinuation (<5%). Serious adverse events were reported by 68 (7%) participants overall and two deaths occurred in the tirzepatide 10 mg group, but deaths were not considered to be related to the study treatment by the investigator.
In this 72-week trial in adults living with obesity and type 2 diabetes, once-weekly tirzepatide 10 mg and 15 mg provided substantial and clinically meaningful reduction in bodyweight, with a safety profile that was similar to other incretin-based therapies for weight management.
Eli Lilly and Company.
1 Department of Medicine and
2 Department of Cell and Molecular
Pharmacology and Experimental Therapeutics, Medical University of South
Carolina and Ralph H. Johnson Department of Veterans Affairs
...Medical Center, Charleston, South Carolina 29425
Vascular smooth muscle cell (VSMC) proliferation is a prominent
feature of the atherosclerotic process occurring after endothelial injury. A vascular wall kallikrein-kinin system has been described. The
contribution of this system to vascular disease is undefined. In the
present study we characterized the signal transduction pathway leading
to mitogen-activated protein kinase (MAPK) activation in response to
bradykinin (BK) in VSMC. Addition of
10 10 -10 7
M BK to VSMC resulted in a rapid and concentration-dependent increase
in tyrosine phosphorylation of several 144- to 40-kDa proteins. This
effect of BK was abolished by the
B 2 -kinin receptor antagonist
HOE-140, but not by the B 1 -kinin
receptor antagonist des-Arg 9 -Leu 8 -BK.
Immunoprecipitation with anti-phosphotyrosine antibodies followed by
immunoblot revealed that
10 9 M BK induced tyrosine
phosphorylation of focal adhesion kinase (p125 FAK ). BK
(10 8 M) promoted the
association of p60 src with the
adapter protein growth factor receptor binding protein-2 and also
induced a significant increase in MAPK activity. Pertussis and cholera
toxins did not inhibit BK-induced MAPK tyrosine phosphorylation. Protein kinase C downregulation by phorbol 12-myristate 13-acetate and/or inhibitors to protein kinase C,
p60 src kinase, and MAPK kinase
inhibited BK-induced MAPK tyrosine phosphorylation. These findings
provide evidence that activation of the
B 2 -kinin receptor in VSMC leads to
generation of multiple second messengers that converge to activate
MAPK. The activation of this crucial kinase by BK provides a strong
rationale to investigate the mitogenic actions of BK on VSMC
proliferation in disease states of vascular injury.
B 2 -kinin receptors; G protein
receptors; tyrosine phosphorylation; signal transduction; mitogen-ativated protein kinase
IMPORTANCE: The effect of continued treatment with tirzepatide on maintaining initial weight reduction is unknown. OBJECTIVE: To assess the effect of tirzepatide, with diet and physical activity, on ...the maintenance of weight reduction. DESIGN, SETTING, AND PARTICIPANTS: This phase 3, randomized withdrawal clinical trial conducted at 70 sites in 4 countries with a 36-week, open-label tirzepatide lead-in period followed by a 52-week, double-blind, placebo-controlled period included adults with a body mass index greater than or equal to 30 or greater than or equal to 27 and a weight-related complication, excluding diabetes. INTERVENTIONS: Participants (n = 783) enrolled in an open-label lead-in period received once-weekly subcutaneous maximum tolerated dose (10 or 15 mg) of tirzepatide for 36 weeks. At week 36, a total of 670 participants were randomized (1:1) to continue receiving tirzepatide (n = 335) or switch to placebo (n = 335) for 52 weeks. MAIN OUTCOMES AND MEASURES: The primary end point was the mean percent change in weight from week 36 (randomization) to week 88. Key secondary end points included the proportion of participants at week 88 who maintained at least 80% of the weight loss during the lead-in period. RESULTS: Participants (n = 670; mean age, 48 years; 473 71% women; mean weight, 107.3 kg) who completed the 36-week lead-in period experienced a mean weight reduction of 20.9%. The mean percent weight change from week 36 to week 88 was −5.5% with tirzepatide vs 14.0% with placebo (difference, −19.4% 95% CI, −21.2% to −17.7%; P < .001). Overall, 300 participants (89.5%) receiving tirzepatide at 88 weeks maintained at least 80% of the weight loss during the lead-in period compared with 16.6% receiving placebo (P < .001). The overall mean weight reduction from week 0 to 88 was 25.3% for tirzepatide and 9.9% for placebo. The most common adverse events were mostly mild to moderate gastrointestinal events, which occurred more commonly with tirzepatide vs placebo. CONCLUSIONS AND RELEVANCE: In participants with obesity or overweight, withdrawing tirzepatide led to substantial regain of lost weight, whereas continued treatment maintained and augmented initial weight reduction. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04660643
1 Department of Medicine and 2 Departments of Cell
and Molecular Pharmacology and Experimental Therapeutics, Medical
University of South Carolina, and 3 Ralph H. Johnson Veterans
Affairs Medical ...Center, Charleston, South Carolina 29425
The development of vascular disease is
accelerated in hyperglycemic states. Vascular injury plays a pivotal
role in the progression of atherosclerotic vascular disease in
diabetes, which is characterized by increased vascular smooth muscle
cell (VSMC) proliferation and extracellular matrix accumulation. We
previously reported that diabetes alters the activity of the
kallikrein-kinin system and results in the upregulation of kinin
receptors in the vessel wall. To determine whether glucose can directly
influence the regulation of kinin receptors, the independent effect of
high glucose (25 mM) on B 2 -kinin receptors (B2KR) in VSMC
was examined. A threefold increase in B2KR protein levels and a 40%
increase in B2KR surface receptors were observed after treatment with
high glucose after 24 h. The mRNA levels of B2KR were also
significantly increased by high glucose as early as 4 h later. To
elucidate the cellular mechanisms by which glucose regulates B2KR, we
examined the role of protein kinase C (PKC). High glucose increased
total PKC activity and resulted in the translocation of conventional PKC isoforms ( 1 and 2 ), novel ( ), and
atypical ( ) PKC isoforms into the membrane. Inhibition of
PKC activity prevented the increase in B2KR levels induced by ambient
high glucose. These findings provide the first evidence that glucose
regulates the expression of B 2 receptors in VSMC and
provide a rationale to further study the interaction between glucose
and kinins on the pathogenesis of atherosclerotic vascular disease in diabetes.
protein kinase C; bradykinin; intracellular calcium
Native and modified LDL activate extracellular signal-regulated kinases in mesangial cells.
A J Jenkins ,
V Velarde ,
R L Klein ,
K C Joyce ,
K D Phillips ,
R K Mayfield ,
T J Lyons and
A A Jaffa
...Department of Medicine, Medical University of South Carolina, Charleston 29425, USA.
Abstract
Glycation and/or oxidation of LDL may promote diabetic nephropathy. The mitogen-activated protein kinase (MAPK) cascade, which
includes extracellular signal-regulated protein kinases (ERKs), modulates cell function. Therefore, we examined the effects
of LDL on ERK phosphorylation in cultured rat mesangial cells. In cells exposed to 100 microg/ml native LDL or LDL modified
by glycation, and/or mild or marked (copper-mediated) oxidation, ERK activation peaked at 5 min. Five minutes of exposure
to 10-100 microg/ml native or modified LDL produced a concentration-dependent (up to sevenfold) increase in ERK activity.
Also, 10 microg/ml native LDL and mildly modified LDL (glycated and/or mildly oxidized) produced significantly greater ERK
activation than that induced by copper-oxidized LDL +/- glycation (P < 0.05). Pretreatment of cells with Src kinase and MAPK
kinase inhibitors blocked ERK activation by 50-80% (P < 0.05). Native and mildly modified LDL, which are recognized by the
native LDL receptor, induced a transient spike of intracellular calcium. Copper-oxidized (+/- glycation) LDL, recognized by
the scavenger receptor, induced a sustained rise in intracellular calcium. The intracellular calcium chelator (EGTA/AM) further
increased ERK activation by native and mildly modified LDL (P < 0.05). These findings demonstrate that native and modified
LDL activate ERKs 1 and 2, an early mitogenic signal, in mesangial cells and provide evidence for a potential link between
modified LDL and the development of glomerular injury in diabetes.
Departments of 1 Medicine and 2 Cell and Molecular
Pharmacology and Experimental Therapeutics, Medical University of South
Carolina, and 3 Ralph H. Johnson Veteran Affairs Medical Center,
...Charleston, South Carolina 29425
Accumulation of
extracellular matrix (ECM) is a hallmark feature of vascular disease.
We have previously shown that hyperglycemia induces the expression of
B 2 -kinin receptors in vascular smooth muscle cells (VSMC)
and that bradykinin (BK) and hyperglycemia synergize to stimulate ECM
production. The present study examined the cellular mechanisms through
which BK contributes to VSMC fibrosis. VSMC treated with BK
(10 8 M) for 24 h significantly increased
2 (I) collagen mRNA levels. In addition, BK produced a
two- to threefold increase in 2 (I) collagen promoter
activity in VSMC transfected with a plasmid containing the
2 (I) collagen promoter. Furthermore, treatment of VSMC
with BK for 24 h produced a two- to threefold increase in the
secretion rate of tissue inhibitor of metalloproteinase 1 (TIMP-1). The
increase in 2 (I) collagen mRNA levels and
2 (I) collagen promoter activity, as well as TIMP-1
secretion, in response to BK were blocked by anti-transforming growth
factor- (anti-TGF- ) neutralizing antibodies. BK
(10 8 M) increased the endogenous production of TGF- 1
mRNA and protein levels. Inhibition of the mitogen-activated protein
kinase (MAPK) pathway by PD-98059 inhibited the increase of
2 (I) collagen promoter activity, TIMP-1 production, and
TGF- 1 protein levels observed in response to BK. These findings
provide the first evidence that BK induces collagen type I and TIMP-1
production via autocrine activation of TGF- 1 and implicate MAPK
pathway as a key player in VSMC fibrosis in response of BK.
collagen; tissue inhibitor of metalloproteinase 1; transforming
growth factor- ; mitogen-activated protein kinase
Renal kallikrein is increased in diabetic patients and streptozotocin (STZ)-induced diabetic rats with hyperfiltration. Chronic inhibition of renal kallikrein reduces glomerular filtration rate (GFR) ...and renal plasma flow (RPF) in hyperfiltering STZ-induced diabetic rats. To investigate whether these actions of kallikrein and its inhibition are kinin-mediated, we used a B2-kinin receptor antagonist (BKA). In STZ-induced diabetic rats with hyperfiltration, renal kallikrein excretion rate was significantly increased (P < or = 0.01), and kinin excretion rate was increased 57%, as compared with control rats. Left kidney GFR and RPF were measured before and during a 40-min infusion of BKA (0.5 micrograms.kg-1.min-1) or vehicle. Infusion of the kinin receptor antagonist reduced the GFR and RPF significantly. GFR was reduced by 18%, from an average baseline value of 2.07 +/- 0.11 to 1.70 +/- 0.06 ml/min, P < or = 0.001 (means +/- SE). RPF was reduced by 25%, from 6.74 +/- 0.38 to 5.06 +/- 0.17 ml/min, P < or = 0.001. Total renal vascular resistance was significantly increased during BKA infusion, P < or = 0.001. Vehicle infusion for the same period had no significant effect on GFR, RPF, or renal vascular resistance. These findings further support the hypothesis that increased renal production of kinins contributes to the renal vasodilation of diabetes.
The renal kallikrein-kinin system and the renin-angiotensin system are implicated in the pathogenesis of diabetic nephropathy. We have shown that renal kallikrein and renin gene expression are ...altered by diabetes. To investigate the cellular mechanisms responsible for these changes, we examined the effects of acute insulin and insulin-like growth factor I (IGF-I) treatment on renal kallikrein-kinin and renin-angiotensin system components. Three weeks after induction of diabetes, we measured renal kallikrein and renin mRNA levels, renal kallikrein and renal renin activity, and plasma renin activity in control and diabetic rats and diabetic rats treated with insulin or IGF-I for 2 or 5 h. In diabetic rats, kallikrein and renin mRNA levels were reduced >50% compared with control rats. Renal tissue kallikrein levels and plasma renin activity were decreased, whereas renal renin content was unchanged. Insulin increased kallikrein and renin mRNA levels after 2 h. IGF-I, at a dosage that stimulated kallikrein mRNA levels in control rats, had no effect on renal kallikrein and renin content or mRNA levels in diabetic rats. However, infusion of a fivefold higher IGF-I dosage resulted in a two- to threefold increase in kallikrein and renin mRNA levels in 2 h. These data suggest that 1) diabetes suppresses kallikrein and renin gene expression, and these abnormalities are reversed by insulin or IGF-I; and 2) the diabetic state produces resistance to IGF-I induction of kallikrein and renin gene expression. These changes in regulated synthesis of kallikrein and renin in the kidney may underlie renal vascular changes that develop in diabetes.
1 Departments of Medicine,
2 Obstetrics, and Gynecology, and
3 Cell and Molecular
Pharmacology and Experimental Therapeutics, Medical University of
South Carolina and Ralph H. Johnson Department ...of Veterans Affairs
Medical Center, Charleston, South Carolina 29425
The vasoactive peptide bradykinin (BK) has
been implicated in the pathophysiology of a number of vascular wall
abnormalities, but the cellular mechanisms by which BK generates second
messengers that alter vascular function are as yet undefined. Exposure
of vascular smooth muscle cells (VSMC) to BK
(10 7 M) produced a rapid
and transient rise in intracellular calcium, which preceded an increase
in tyrosine phosphorylation of mitogen-activated protein kinase (MAPK).
MAPK activation by BK was observed as early as 1 min, peaked at 5 min,
and returned to baseline by 20 min. Treatment of cells with the
intracellular calcium chelator EGTA-acetoxymethyl ester inhibited
BK-stimulated MAPK activation, suggesting that intracellular calcium
mobilization contributes to the activation of MAPK. The calmodulin
inhibitor W-7 also markedly inhibited BK-induced MAPK phosphorylation
in the cytoplasm as well as in the nucleus. Moreover, the BK-induced
increase in c- fos mRNA levels was
significantly inhibited by the calmodulin inhibitor, indicating that
calmodulin is required for BK signaling leading to
c- fos induction. These results
implicate the calcium-calmodulin pathway in the mechanisms for
regulating MAPK activity and the resultant c- fos expression induced by BK in VSMC.
B 2 -kinin receptor; signal
transduction; extracellular regulated kinases
Glomerular hypertension and glomerular hypertrophy act early and synergistically to promote glomerular injury in diabetes. We have previously shown that increased renal kinin production contributes ...to the glomerular hemodynamic abnormalities associated with diabetes. Glomerulosclerosis, characterized by mesangial cell proliferation and matrix expansion, is the final pathway leading to renal failure. The signal(s) initiating mesangial cell proliferation is ill defined. In the present study, we utilized immunofluorescence, immunoprecipitation, and immunoblotting techniques to identify substrates that are tyrosine phosphorylated in response to bradykinin action in mesangial cells. Immunofluorescence microscopy of mesangial cells stained with anti-phosphotyrosine (anti-PY) antibodies following bradykinin treatment (10(-9)-10(-6) M) revealed a dose-dependent increase in the labeling of cytoplasmic and nuclear proteins. Immunoprecipitation with anti-PY, followed by immunoblot revealed bradykinin-induced tyrosyl phosphorylation of tubulin and mitogen-activated protein kinase (MAPK). Confocal microscopy of mesangial cells stained for MAPK indicated that bradykinin stimulation resulted in translocation of MAPK from the cytoplasm to the nucleus by 2 h. These data demonstrate that bradykinin action results in the tyrosine phosphorylation of cellular proteins in mesangial cells and suggest a role for tubulin and MAPK in the signaling cascade of bradykinin leading to altered mesangial function.
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