This document presents arguments for changing the current treatment paradigm for type 2 diabetes that recommends metformin as first-line therapy. It argues that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) should instead be the first-line treatment, as they directly address the underlying pathophysiological defects that drive hyperglycemia and disease progression. GLP-1 RAs improve beta-cell function, suppress glucagon secretion, promote weight loss and reduce cardiovascular risk factors. In contrast, metformin addresses only hepatic glucose production and does not correct other defects. The document outlines the complex pathophysiology of type 2 diabetes and presents evidence that GLP-1 RAs normalize multiple metabolic disturbances, thereby providing more effective gly
International Journal of Pharmaceutical Science Invention (IJPSI)inventionjournals
International Journal of Pharmaceutical Science Invention (IJPSI) is an international journal intended for professionals and researchers in all fields of Pahrmaceutical Science. IJPSI publishes research articles and reviews within the whole field Pharmacy and Pharmaceutical Science, new teaching methods, assessment, validation and the impact of new technologies and it will continue to provide information on the latest trends and developments in this ever-expanding subject. The publications of papers are selected through double peer reviewed to ensure originality, relevance, and readability. The articles published in our journal can be accessed online.
Presentation on co drug strategy for treating hypertension in type iiLatika Budhalakoti
This presentation is on co-drug design, two drugs are chemically linked together for their improved delivery properties so as to reach a site simultaneously achieving better absorption as compared to when co-administered in separate dosage forms.
International Journal of Pharmaceutical Science Invention (IJPSI)inventionjournals
International Journal of Pharmaceutical Science Invention (IJPSI) is an international journal intended for professionals and researchers in all fields of Pahrmaceutical Science. IJPSI publishes research articles and reviews within the whole field Pharmacy and Pharmaceutical Science, new teaching methods, assessment, validation and the impact of new technologies and it will continue to provide information on the latest trends and developments in this ever-expanding subject. The publications of papers are selected through double peer reviewed to ensure originality, relevance, and readability. The articles published in our journal can be accessed online.
Presentation on co drug strategy for treating hypertension in type iiLatika Budhalakoti
This presentation is on co-drug design, two drugs are chemically linked together for their improved delivery properties so as to reach a site simultaneously achieving better absorption as compared to when co-administered in separate dosage forms.
Dipeptidyl peptidase inhibitors(DPP-IV): A deep insightRxVichuZ
This presentation deals with DPP-IV inhibitors, that are implicated for use in diabetes mellitus. Generalized pharmacology, including a precise insight into individual drugs have been elucidated.
Newer Anti-Hyperglycemic agents in type 2 Diabetes Mellitus e Expanding the h...Apollo Hospitals
Diabetes mellitus is a common, chronic and progressive disease resulting in micro and macrovascular complications. Many classes of drugs are available for treatment but still the search for newer anti-hyperglycemic agents continues to combat significant adverse effect profile, loss of efficacy, progressive nature of disease and improve patient compliance. New emerging therapies in pipeline include drugs targeting various pathophysiologic mechanisms like incretin based therapies, sodium glucose co-transporter inhibitors, glucokinase inhibitors, 11b hydroxy steroid dehydrogenase inhibitors, drugs modulating fatty acid metabolism, selective PPARg receptor modulators and anti inflammatory agents.
ABSTRACT
Over the last decade, diabetes mellitus has emerged as an important clinical and public health
problem throughout the world. The aim of the study is perceive the Potentiality of a newer oral
Antihyperglycemic combination therapy over conventional therapy in type 2 diabetes. The
prospective study was conducted over a period of six months in the department of Medicine,
Guntur City Hospital. The prevalence of type2 diabetes was high in male 65.79 % than female
34.21%. Majority of the patients (23.68 %) belonged to age group of 51–55 years. Majority of
patients (55.26%) having a family history of Diabetes. Majority of patients receiving Combination
of Glibenclamide + Metformin (60.53%), evaluated for effect on FPG for both combinations. The
mean changes in FPG were noted. In the same way effect on HbA1c also noted. Mean changes in
for every month HbA1c will be noted. Our study reveals that Combination therapy with Metformin
plus Glimepiride is more effective than Glibenclamide plus Metformin; in improving glycemic
control in type 2 diabetes, while also allowing a reduction of the dosage of each drug.
Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient- Centered App...Mgfamiliar Net
Update to a Position Statement of the American Diabetes Association and the European Association for the Study of Diabetes
Diabetes Care 2015;38:140–149 | DOI: 10.2337/dc14-2441
Dipeptidyl peptidase inhibitors(DPP-IV): A deep insightRxVichuZ
This presentation deals with DPP-IV inhibitors, that are implicated for use in diabetes mellitus. Generalized pharmacology, including a precise insight into individual drugs have been elucidated.
Newer Anti-Hyperglycemic agents in type 2 Diabetes Mellitus e Expanding the h...Apollo Hospitals
Diabetes mellitus is a common, chronic and progressive disease resulting in micro and macrovascular complications. Many classes of drugs are available for treatment but still the search for newer anti-hyperglycemic agents continues to combat significant adverse effect profile, loss of efficacy, progressive nature of disease and improve patient compliance. New emerging therapies in pipeline include drugs targeting various pathophysiologic mechanisms like incretin based therapies, sodium glucose co-transporter inhibitors, glucokinase inhibitors, 11b hydroxy steroid dehydrogenase inhibitors, drugs modulating fatty acid metabolism, selective PPARg receptor modulators and anti inflammatory agents.
ABSTRACT
Over the last decade, diabetes mellitus has emerged as an important clinical and public health
problem throughout the world. The aim of the study is perceive the Potentiality of a newer oral
Antihyperglycemic combination therapy over conventional therapy in type 2 diabetes. The
prospective study was conducted over a period of six months in the department of Medicine,
Guntur City Hospital. The prevalence of type2 diabetes was high in male 65.79 % than female
34.21%. Majority of the patients (23.68 %) belonged to age group of 51–55 years. Majority of
patients (55.26%) having a family history of Diabetes. Majority of patients receiving Combination
of Glibenclamide + Metformin (60.53%), evaluated for effect on FPG for both combinations. The
mean changes in FPG were noted. In the same way effect on HbA1c also noted. Mean changes in
for every month HbA1c will be noted. Our study reveals that Combination therapy with Metformin
plus Glimepiride is more effective than Glibenclamide plus Metformin; in improving glycemic
control in type 2 diabetes, while also allowing a reduction of the dosage of each drug.
Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient- Centered App...Mgfamiliar Net
Update to a Position Statement of the American Diabetes Association and the European Association for the Study of Diabetes
Diabetes Care 2015;38:140–149 | DOI: 10.2337/dc14-2441
O futuro na terapia baseada em incretins.Ruy Pantoja
Neste belo artigo realcei em amarelo as partes que mais me instigaram. Depois traço um paralelismo com a bela conferência do Prof. Buse, realizada em San Diego há um mês.
Obesity context of type 2 diabetes and medication perspectivesApollo Hospitals
Drug therapy of obesity has harsh antecedent that many earlier introduced drugs are withdrawn from market. The drugs in present use lack sufficient long-term efficacy and safety data. The difficulty of reversing changing dietary habits and decline in physical activity, however, offers major scope for anti-obesity therapeutics, implied in managing the epidemic chronic inflammatory maladies and cardiovascular sequel. Metabolic syndrome, pre-diabetes and type 2 diabetes mellitus, commonly associate with obesity. Weight reduction is crucial to prevent and control type 2 diabetes. This emphasizes rational choice of therapeutic regimens that do not themselves cause weight gain, and better promote weight loss. Such an aspect is addressed briefly focusing upon the available newer anti-obesity drug options, in particular.
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
HOT NEW PRODUCT! BIG SALES FAST SHIPPING NOW FROM CHINA!! EU KU DB BK substit...GL Anaacs
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Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
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These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
2. to result in a sustained reduction in
HbA1c. It is well established that type 2
diabetes (T2D) is a complex metabolic/
cardiovascular disorder with at least eight
distinct pathophysiological disturbances,
referred to as the Ominous Octet (1). Hy-
perglycemia is a manifestation of these
eight pathophysiological abnormalities.
Nonetheless, the current recommended
approach in T2D management still fo-
cuses on lowering the plasma glucose
concentration rather than correcting the
underlying metabolic abnormalities that
cause the hyperglycemia (2–4). There-
fore, it is not surprising that current ther-
apeutic guidelines (2–4) do not result in a
sustained HbA1c reduction (5–8). In this
Point-Counterpoint, we argue that it is
time to apply the modern concepts of
clinical practice to diabetes management
and base therapy on pathophysiology.
Thereby, GLP-1 receptor agonists (GLP-1
RAs), which 1) correct six of the eight
components of the Ominous Octet, 2)
prevent/reverse the progressive b-cell
failure and rise in HbA1c, and 3) lower
cardiovascular risk in T2D independent
of their glucose-lowering ability (9,10),
should replace metformin as the recom-
mended first-line therapy in newly diag-
nosed T2D patients.
PATHOPHYSIOLOGY OF T2D
TheetiologyofT2Discomplexandinvolves
multiple pathophysiological disturbances
involving multiple organs (1) (Fig. 1).
Insulin resistance in skeletal muscle, liver,
and adipocytes (11–15) and b-cell dys-
function (16–22) remain the major core
defects responsible for the development
and progression of hyperglycemia. Insulin
resistance is also associated with multiple
metabolic abnormalities, e.g., hyperten-
sion, dyslipidemia, endothelial dysfunc-
tion, procoagulant state, inflammation,
and visceral obesity, which collectively
are known as the insulin resistance (met-
abolic) syndrome (23–25). Each individual
component of the insulin resistance syn-
drome, as well as the basic molecular
etiology of the insulin resistance (25), is
causally related to the development of
atherosclerotic cardiovascular disease
(CVD) and contributes to the increased
risk for CVD in T2D patients.
Because progressive b-cell failure is
the principal factor responsible for the
development and progression of hyper-
glycemia in T2D patients (1,16–19), only
therapies that halt/reverse the progres-
sive b-cell failure will be effective in low-
ering and maintaining HbA1c at the target
level, and ideally this should be ac-
complished without increasing the risk
of hypoglycemia.
In addition to insulin resistance and
b-cell dysfunction, impaired incretin
effect in T2D plays a major role in the
progression of b-cell failure and hyper-
glycemia (26,27). Further, T2D patients
have elevated fasting plasma glucagon
levels that fail to suppress normally after
a meal and enhanced hepatic sensitivity
to glucagon (28,29), in part due to resis-
tance to GLP-1 (26,30); these pathophys-
iological abnormalities can be reversed
with GLP-1 RA therapy (26,31).
BIOLOGICAL ACTIONS
OF GLP-1 RAs
Activation of GLP-1 receptors in the b-cell
amplifies glucose-stimulated insulin se-
cretion but only under conditions of hy-
perglycemia (26,32), whereas in the
a-cell, GLP-1 suppresses glucagon secre-
tion, leading to correction of postmeal
hyperglycemia in T2D (26,27,30). GLP-1
RAs improve b-cell function by enhancing
b-cell responsiveness to glucose, i.e., im-
proving b-cell glucose sensitivity; this
beneficial effect on the b-cell can be ob-
served within 8 h after a single injection
of the GLP-1 RA (liraglutide) (33), is main-
tained at 3 months (semaglutide) (34),
and persists for at least 3 years (exenatide)
(35). Thus, GLP-1 RAs produce a rapid and
durable reduction in HbA1c with low risk
of hypoglycemia (36,37).
GLP-1 also exerts multiple nonglyce-
mic actions, all of which improve meta-
bolic control in T2D patients (Table 1),
including 1) delayed gastric emptying,
which slows the absorption of ingested
glucose (32), 2) appetite suppression,
which promotes weight loss (26,38,39),
3) reduction of hepatic and visceral fat
content (40), making them an attractive
intervention to prevent/reverse non-
alcoholic fatty liver disease/nonalcoholic
steatohepatitis (41), and 4) prevention
of diabetic nephropathy in Liraglutide Ef-
fect and Action in Diabetes: Evaluation of
Cardiovascular Outcome ResultsdA Long
Term Evaluation (LEADER) (42). Recent ev-
idence suggests that gut stimulation
of GLP-1 secretion by the L cells is an im-
portant mechanism via which metformin
suppresses hepatic glucose production
(43,44).
GLP-1 RAs AND CVD
CVD is the leading cause of death in T2D
patients (45), accounting for ;80% of
mortality, and T2D is best viewed as a
cardiometabolic disorder (25,46). Thus,
reducing CVD risk is a high priority in
T2D management, and reduction in blood
pressure and correction of diabetic dysli-
pidemia are essential components of
diabetes management. Considerable evi-
dence documents that hyperglycemia
is a weak risk factor for cardiovascular
Figure 1—GLP-1 RAs correct six components of the Ominous Octet, whereas metformin corrects
only one component.
1122 Point Diabetes Care Volume 40, August 2017
3. complications and improving glucose
control has little benefit on macrovascu-
lar disease risk (UK Prospective Diabetes
Study [UKPDS], Action to Control Cardio-
vascular Risk in Diabetes [ACCORD], Ac-
tion in Diabetes and Vascular Disease:
Preterax and Diamicron MR Controlled
Evaluation [ADVANCE], Veterans Affairs
Diabetes Trial [VADT]), especially when
it is well established. Numerous clinical tri-
als have demonstrated that antidiabetes
agentsthatreduceplasmaglucosewithout
altering other cardiovascular risk factors
fail to reduce CVD risk in T2D patients.
Conversely, antidiabetes medications that
in addition to lowering the plasma glu-
cose concentration also improve car-
diovascular risk factors, e.g., GLP-1 RAs
(9,10), pioglitazone (47,48), and SGLT2
inhibitors (49,50), significantly reduce
cardiovascular events in T2D with estab-
lished CVD. Thus, these agents should be
favored over agents that lower plasma glu-
cose but have no effect on cardiovascular
risk factors or CVD, e.g., sulfonylureas
(51,52), DPP-4 inhibitors (53–55), and in-
sulin (56) (Fig. 2). GLP-1 RAs consistently
have been shown to reduce many CVD
risk factors (Table 2) (25,34,57–60).
Thus, it is not surprising that two large,
prospective, randomized, double-blind,
placebo-controlledtrials (9,10)havedem-
onstrated that liraglutide and semaglu-
tide significantly lower the incidence of
3-pointMACE(majoradversecardiovascu-
lar events), which includes nonfatal myo-
cardial infarction, nonfatal stroke, and
cardiovascular death, by 13% and 24%, re-
spectively, in T2D patients with existing
CVD. Of note, despite the high CVD risk
in the patient populations in both LEADER
and Trial to Evaluate Cardiovascular and
Other Long-term Outcomes With Sema-
glutide in Subjects With Type 2 Diabetes
(SUSTAIN-6), all cardiovascular risk factors,
including blood pressure and LDL choles-
terol, were well controlled at baseline,
consistent with the high number of pa-
tients receiving statins, ACE inhibitors, an-
giotensin receptor blockers, and aspirin
therapy. Addition of the GLP-1 RA to the
patients’ antidiabetes treatment resulted
in only modest reductions in HbA1c (0.4%)
andsystolic blood pressure (;2–3mmHg)
in LEADER and SUSTAIN-6; these glucose-
and blood pressure–lowering effects are
quite modest and unlikely to explain the
CVD benefit of liraglutide and semaglu-
tide. This suggests the GLP-1 RAs may
have a direct beneficial action to slow the
atherosclerotic process, independent of
theireffecttoreduceglycemiaandimprove
traditional cardiovascular risk factors (59).
The above review demonstrates that
GLP-1RAsdirectlyand/orindirectlycorrect/
improve six of the eight pathophysiological
defects responsible for hyperglycemia
in T2D, improve cardiovascular risk factors,
and reduce MACE in two large, well-
designed, prospective cardiovascular inter-
vention trials.
GLP-1 RAs, NOT METFORMIN,
SHOULD BE THE FIRST-LINE
THERAPY IN T2D
GLP-1 RAs correct six members of the
Ominous Octet, whereas the only known
action of metformin is to inhibit hepatic
glucose production (61) (Fig. 1 and Table
2). Contrary to common belief, metfor-
min is not an insulin sensitizer in muscle
or adipocytes (61–63) in the absence of
weight loss, which is a frequent occur-
rence in patients treated with the bigua-
nide (Fig. 3A). Consistent with this,
following intravenous administration of
11
C-metformin, none of the biguanide
can be detected in muscle (64). Most im-
portantly, and in direct contrast to the
GLP-1 RAs, metformin lacks any effect
on b-cell function (61,62) (Fig. 3B), which
is the primary pathophysiological distur-
bance responsible for progressive hyper-
glycemia in T2D patients (1). This is most
graphically demonstrated in the UKPDS
(65) and A Diabetes Outcome Progression
Trial (ADOPT) (5) (Fig. 3D) in which, after
an initial decline during the first year,
HbA1c rose progressively because of pro-
gressive b-cell failure. This stands in
marked contrast to the GLP-1 RAs, which
exert a potent protective effect on the
b-cell that persists for at least 3 years
(34). Because the GLP-1 RAs cause signif-
icant weight loss, they also improve insu-
lin sensitivity in muscle. Thus, GLP-1 RAs,
but not metformin, correct the two
Table 1—Metabolic actions of
GLP-1 RAs
c Pancreas
Potentiate glucose-mediated insulin
secretion
Preserve b-cell function/reverse b-cell
failure
Inhibit glucagon secretion in
a glucose-dependent fashion
c Cardiovascular system
Reduce MACE
Reduce systolic blood pressure
Reduce pulmonary capillary wedge
pressure
Increase myocardial salvage following
myocardial infarction
Improve endothelial dysfunction
c GI
Slow gastric emptying
Inhibit hepatic glucose production
Decrease liver fat content
Decrease visceral fat
c Central nervous system
Suppress appetite
c Kidney
Preserve renal function
Increase sodium excretion
c General
Promote weight loss
Figure 2—Not all antidiabetes agents are equal in their ability to reduce cardiovascular risk.
care.diabetesjournals.org Abdul-Ghani and DeFronzo 1123
4. major core defects in T2D patients, i.e.,
b-cell dysfunction and muscle insulin re-
sistance. The major mechanism of action
of metformin to reduce glycemia is in-
hibition of hepatic gluconeogenesis
(61,62) (Fig. 3C), whereas the GLP-1 RAs
also effectively reduce hepatic glucose
production but by multiple other mecha-
nisms, i.e., inhibition of glucagon secre-
tion, stimulation of insulin secretion,
direct effect on the liver, and depletion
of liver fat (26,27,30,59,66–68).
Although the UKPDS demonstrated
that metformin caused a reduction in
cardiovascular events in T2D patients
(65), the patient population consisted
of a small number of obese T2D subjects
(n 5 342); these results, by today’s stan-
dards, would never be accepted as evi-
dence for a cardiovascular benefit of
the biguanide. Moreover, a beneficial
Table 2—Benefits of GLP-1 RAs far outweigh those of metformin
GLP-1 RAs Metformin
Pathophysiological defects in T2D (see Fig. 1) Corrects six of the defects Corrects only one of the defects
Glucose-lowering efficacy Strong Strong
Durability of HbA1c reduction Strong None
Weight loss 3–4 kg 1–2 kg
Blood pressure ;2–3 mmHg reduction Neutral
Lipid profile Lowers triglycerides, increases HDL cholesterol Neutral
Cardiovascular protection (MACE) Reduction by 13–26% Neutral
Renal protection Reduction by 22% Neutral
Tolerability ;10–15% GI side effects ;10–15% GI side effects
Dosing Weekly subcutaneous injection Once to twice daily oral administration
Cost High Low
Figure 3—Effect of metformin on glycemic control, insulin secretion, and insulin sensitivity in T2D. A: Metformin does not improve muscle insulin
sensitivity (measured with euglycemic insulin clamp) in T2D individuals (n 5 20) inthe absence of weight loss (72).B: Metformin hasno effect on
b-cell function in T2D individuals (n 5 14) (measured with an oral glucose tolerance test [OGTT] and hyperglycemic clamp) (73). C: The primary effect
via which metformin reduces the HbA1c in T2D is related to the suppression of hepatic glucose production (HGP) via inhibition of
gluconeogenesis (72). FPG, fasting plasma glucose. D: Effect of metformin on HbA1c. Because metformin does not affect muscle insulin sensitivity or
b-cell function, following an initial decline after metformin administration, the HbA1c rises progressively in T2D patients (5,6,74). KPNW, Kaiser Perma-
nente Northwest.
1124 Point Diabetes Care Volume 40, August 2017
5. effect on cardiovascular events was not
observed in other clinical studies with met-
formin, i.e., the ADOPT study (5), which
included twice the number of patients
as the UKPDS (n 5 818). To the contrary,
subjects receiving metformin in ADOPT
experienced more cardiovascular events
than subjects receiving glyburide, al-
though this difference was not statisti-
cally significant. This emphasizes the
problemofinterpreting resultsfromstud-
ies that are markedly underpowered to
detect clinically significant differences in
cardiac event rates. Conversely, the CVD
benefit of GLP-1 RAs has conclusively
been demonstrated in two very large,
prospective cardiovascular intervention
trials, LEADER and SUSTAIN-6 (9,10).
With regard to safety, both metformin
and GLP-1 RAs are associated with gastro-
intestinal (GI) adverse events. Approxi-
mately 15–20% of T2D patients do not
tolerate metformin because of GI side
effects (66). The incidence of GI side ef-
fects with the long-acting GLP-1 RAs is
similar to that of metformin. Further,
and unlike those with metformin, the GI
side effects usually are mild to moderate,
waning over the first 4–6 weeks of initi-
ating therapy. The percentage of patients
who discontinue long-acting GLP-1 RAs
because of GI side effects is signifi-
cantly lower than that of metformin
(67). Some postmarketing reports have
suggested an increased risk of acute pan-
creatitis with GLP-1 RA use. However,
three large, prospective, double-blind,
placebo-controlled clinical trials including
;20,000 patients followed for 2–4 years
have demonstrated no increased risk of
acute pancreatitis with GLP-1 RA use
(9,10,68).
Metformin is administered orally ver-
sus via injection for GLP-1 RAs. However,
intermediate-acting metformin requires
multiple daily dosing, whereas two long-
acting GLP-1 RAs (exenatide and dulaglu-
tide) are available as weekly injections
and a third (semaglutide) is under review
by the U.S. Food and Drug Administra-
tion. A subcutaneously implanted os-
motic mini pump that continuously
delivers exenatide for 6 months is ex-
pected to be approved within the next
year (69), and an oral formulation of the
GLP-1 RA semaglutide is in phase 3 trials
(70) and is anticipated to be available
within 3–4 years. These modern delivery
methods will improve patient compliance
for GLP-1 RAs versus metformin.
Lastly, metformin is generic and inex-
pensive, whereas GLP-1 RAs are still un-
der patent and, therefore, expensive.
However, most large health care plans
have at least one GLP-1 RA on formulary
with a modest copay. Moreover, lira-
glutide (Victoza) is expected to become
generic by the end of 2017, and this
should significantly reduce its cost. A
cost-effective analysis is beyond the
scope of this discussion, and the appro-
priate long-term, clinical, real-world stud-
ies to perform such an analysis are not
available. However, a recent cost analysis
for the treatment of T2D patients in the
U.S. by the American Diabetes Associa-
tion (71) demonstrated that only a small
portion (12%) of the cost of T2D is due to
the direct cost of antihyperglycemic med-
ications. The vast majority of the cost of
diabetes care is related to the develop-
ment of diabetic vascular complica-
tions, with CVD disease contributing
50% of that cost, and two recent stud-
ies, LEADER and SUSTAIN-6, have de-
monstrated that GLP-1 RAs decrease
cardiovascular events. Further, the cost
of medications to treat the complica-
tions of diabetes is 50% greater than
the cost of antihyperglycemic medi-
cations. It remains to be determined
whether, on a long-term basis, the use
of GLP-1 RAs, which in addition to causing
a durable reduction in the plasma glu-
cose concentration (thereby decreas-
ing microvascular complications) also
reduce cardiovascular events, will be
cost-effective.
In summary, the currently available
clinical and scientific evidence (Table 2)
is overwhelmingly in favor of the use
of GLP-1 RAs over metformin as first-
line therapy in newly diagnosed T2D pa-
tients.
Funding. M.A.-G. receives funding from the
National Institutes of Health (DK 097554-01)
and the Qatar Foundation (National Priorities
Research Program 4-248-3-076), and R.A.D. re-
ceives funding from the National Institutes of
Health (DK 024092-42). R.A.D.’s salary is, in part,
supported by the South Texas Veterans Health
Care System, Audie L. Murphy Division.
Duality of Interest. R.A.D. is on the advisory
board of AstraZeneca, Janssen, Novo Nordisk,
Boehringer Ingelheim, and Intarcia. R.A.D. has re-
ceived grants from AstraZeneca, Janssen, and
Boehringer Ingelheim. R.A.D. is a member of
the speakers’ bureau for AstraZeneca and Novo
Nordisk. No other potential conflicts of interest
relevant to this article were reported.
References
1. DeFronzoRA. Banting Lecture. Fromthe trium-
virate to the ominous octet: a new paradigm for
the treatment of type 2 diabetes mellitus. Diabe-
tes 2009;58:773–795
2. InzucchiSE,BergenstalRM,BuseJB,etal.Man-
agement of hyperglycemia in type 2 diabetes,
2015: a patient-centered approach: update to a
position statement of the American Diabetes As-
sociation and the European Association for the
Study of Diabetes. Diabetes Care 2015;38:140–
149
3. Garber AJ, Abrahamson MJ, Barzilay JI, et al.;
American Association of Clinical Endocrinologists
(AACE); American College of Endocrinology (ACE).
Consensusstatement of the AmericanAssociation
of Clinical Endocrinology and American College of
Endocrinology on the comprehensive type 2
diabetes algorithm–2015 executive summary.
Endocr Pract 2015;21:1403–1414
4. International Diabetes Federation Clinical
Guidelines Task Force. Global Guideline for
Type 2 Diabetes. Brussels, Belgium, International
Diabetes Federation, 2012, p. 44–46
5. Kahn SE, Haffner SM, Heise MA, et al.; ADOPT
Study Group. Glycemic durability of rosiglitazone,
metformin, or glyburide monotherapy. N Engl J
Med 2006;355:2427–2443
6. United Kingdom Prospective Diabetes Study
(UKPDS). 13: relative efficacy of randomly allo-
cated diet, sulphonylurea, insulin, or metformin
in patients with newly diagnosed non-insulin de-
pendent diabetes followed for three years. BMJ
1995;310:83–88
7. Abdul-Ghani MA, Puckett C, Triplitt C, et al.
Initial combination therapy with metformin,
pioglitazone and exenatide is more effective
than sequential add-on therapy in subjects with
new-onset diabetes. Results from the Efficacy and
Durability of Initial Combination Therapy for
Type 2 Diabetes (EDICT): a randomized trial.
Diabetes Obes Metab 2015;17:268–275
8. Abdul-Ghani M, Mujahid O, Mujahid A,
et al. Combination therapy with exenatide plus
pioglitazone versus basal/bolus insulin in patients
with poorly controlled type 2 diabetes on sulfo-
nylurea plus metformin: the QATAR Study. Diabe-
tes Care 2017;40:325–331
9. Marso SP, Daniels GH, Brown-Frandsen K,
et al.; LEADER Steering Committee; LEADER Trial
Investigators. Liraglutide and cardiovascular out-
comes in type 2 diabetes. N Engl J Med 2016;375:
311–322
10. MarsoSP,BainSC,ConsoliA, etal.;SUSTAIN-6
Investigators. Semaglutide and cardiovascu-
lar outcomes in patients with type 2 diabetes.
N Engl J Med 2016;375:1834–1844
11. Abdul-Ghani MA, DeFronzo RA. Pathogenesis
of insulin resistance in skeletal muscle. J Biomed
Biotechnol 2010;2010:476279
12. Groop LC, Wid´en E, Ferrannini E. Insulin re-
sistance andinsulindeficiencyinthe pathogenesis
of type 2 (non-insulin-dependent) diabetes melli-
tus: errors of metabolism or of methods? Diabe-
tologia 1993;36:1326–1331
13. Shalata A, Jazmawi W, Aslan O, et al. Early
metabolic defects in Arab subjects with strong
family history of type 2 diabetes. J Endocrinol In-
vest 2013;36:417–421
14. Reaven GM. Relationships among insulin re-
sistance, type 2 diabetes, essential hypertension,
and cardiovascular disease: similarities and
care.diabetesjournals.org Abdul-Ghani and DeFronzo 1125
6. differences. J Clin Hypertens (Greenwich) 2011;
13:238–243
15. Kashyap S, Belfort R, Gastaldelli A, et al. A
sustained increase in plasma free fatty acids im-
pairs insulin secretion in nondiabetic subjects ge-
netically predisposed to develop type 2 diabetes.
Diabetes 2003;52:2461–2474
16. Kahn SE, Cooper ME, Del Prato S. Pathophys-
iology and treatment of type 2 diabetes: perspec-
tives on the past, present, and future. Lancet
2014;383:1068–1083
17. Alejandro EU, Gregg B, Blandino-Rosano M,
Cras-M´eneur C, Bernal-Mizrachi E. Natural history
of b-cell adaptation and failure in type 2 diabetes.
Mol Aspects Med 2015;42:19–41
18. Halban PA, Polonsky KS, Bowden DW, et al.
b-Cell failure in type 2 diabetes: postulated mech-
anisms and prospects for prevention and treat-
ment. Diabetes Care 2014;37:1751–1758
19. Saad MF, Knowler WC, Pettitt DJ, Nelson RG,
Mott DM, Bennett PH. The natural history of im-
paired glucose tolerance in the Pima Indians.
N Engl J Med 1988;319:1500–1506
20. Ferrannini E, Gastaldelli A, Miyazaki Y,
Matsuda M, Mari A, DeFronzo RA. b-Cell function
in subjects spanning the range from normal glu-
cose tolerance to overt diabetes: a new analysis.
J Clin Endocrinol Metab 2005;90:493–500
21. Ferrannini E, Mari A. b-Cell function in type 2
diabetes. Metabolism 2014;63:1217–1227
22. Polonsky KS. Lilly Lecture 1994. The b-cell in
diabetes: from molecular genetics to clinical re-
search. Diabetes 1995;44:705–717
23. Jornayvaz FR, Samuel VT, Shulman GI. The
role of muscle insulin resistance in the pathogen-
esis of atherogenic dyslipidemia and nonalcoholic
fatty liver disease associated with the metabolic
syndrome. Annu Rev Nutr 2010;30:273–290
24. Reaven GM. Insulin resistance: the link be-
tween obesity and cardiovascular disease. Med
Clin North Am 2011;95:875–892
25. DeFronzo RA. Insulin resistance, lipotoxicity,
type 2 diabetes and atherosclerosis: the missing
links. The Claude Bernard Lecture 2009. Diabeto-
logia 2010;53:1270–1287
26. Nauck MA, Meier JJ. The incretin effect in
healthy individuals and those with type 2 diabe-
tes: physiology, pathophysiology, and response to
therapeutic interventions. Lancet Diabetes Endo-
crinol 2016;4:525–536
27. Holst JJ, Gribble F, Horowitz M, Rayner CK.
Roles of the gut in glucose homeostasis. Diabetes
Care 2016;39:884–892
28. Matsuda M, DeFronzo RA, Glass L, et al. Glu-
cagon dose-response curve for hepatic glucose
production and glucose disposal in type 2 diabetic
patients and normal individuals. Metabolism
2002;51:1111–1119
29. Knop FK, Vilsbøll T, Madsbad S, Holst JJ,
Krarup T. Inappropriate suppression of glucagon
during OGTT but not during isoglycaemic i.v. glu-
cose infusion contributes to the reduced incretin
effect in type 2 diabetes mellitus. Diabetologia
2007;50:797–805
30. Sandoval DA, D’Alessio DA. Physiology of
proglucagon peptides: role of glucagon and
GLP-1 in health and disease. Physiol Rev 2015;
95:513–548
31. Gamble JM, Clarke A, Myers KJ, et al. Incretin-
based medications for type 2 diabetes: an over-
view of reviews. Diabetes Obes Metab 2015;17:
649–658
32. Umapathysivam MM, Lee MY, Jones KL, et al.
Comparative effects of prolonged and intermittent
stimulation of the glucagon-like peptide 1 receptor
on gastric emptying and glycemia. Diabetes 2014;
63:785–790
33. Chang AM, Jakobsen G, Sturis J, et al. The
GLP-1 derivative NN2211 restores b-cell sensitiv-
ity to glucose in type 2 diabetic patients after a
single dose. Diabetes 2003;52:1786–1791
34. Kapitza C, Dahl K, Jacobsen JB, Axelsen MB,
Flint A. The effects of semaglutide on b-cell func-
tion in subjects with type 2 diabetes (Abstract).
Diabetes 2016;65(Suppl. 1):A262
35. Bunck MC, Corn´er A, Eliasson B, et al. Effects
of exenatide on measures of b-cell function after
3 years in metformin-treated patients with type
2 diabetes. Diabetes Care 2011;34:2041–2047
36. Klonoff DC, Buse JB, Nielsen LL, et al. Exena-
tide effects on diabetes, obesity, cardiovascular
risk factors and hepatic biomarkers in patients
with type 2 diabetes treated for at least 3 years.
Curr Med Res Opin 2008;24:275–286
37. Diamant M, Van Gaal L, Guerci B, et al. Exena-
tide once weekly versus insulin glargine for type 2
diabetes (DURATION-3): 3-year results of an
open-label randomised trial. Lancet Diabetes
Endocrinol 2014;2:464–473
38. Eldor R, Daniele G, Huerta C, et al. Discor-
dance between central (brain) and pancreatic ac-
tion of exenatide in lean and obese subjects.
Diabetes Care 2016;39:1804–1810
39. van Bloemendaal L, Ten Kulve JS, la Fleur SE,
Ijzerman RG, Diamant M. Effects of glucagon-like
peptide 1 on appetite and body weight: focus on
the CNS. J Endocrinol 2014;221:T1–T16
40. Armstrong MJ, Hull D, Guo K, et al. Glucagon-
like peptide 1 decreases lipotoxicity in non-alcoholic
steatohepatitis. J Hepatol 2016;64:399–408
41. Cusi K. Treatment of patients with type 2 di-
abetes and non-alcoholic fatty liver disease: current
approaches and future directions. Diabetologia
2016;59:1112–1120
42. Mann JF, Brown Frandsen K, Daniels G, et al.
Liraglutide and renal outcomes in type 2 diabetes:
results of the LEADER trial (Abstract). J Am Soc
Nephrol 2016;27(Abstract Edition):1B
43. Buse JB, DeFronzo RA, Rosenstock J, et al. The
primary glucose-lowering effect of metformin re-
sides in the gut, not the circulation: results from
short-term pharmacokinetic and 12-week dose-
ranging studies. Diabetes Care 2016;39:198–205
44. DeFronzo RA, Buse JB, Kim T, et al. Once-daily
delayed-release metformin lowers plasma glu-
cose and enhances fasting and postprandial
GLP-1 and PYY: results from two randomised tri-
als. Diabetologia 2016;59:1645–1654
45. Sarwar N, Gao P, Seshasai SR, et al.; Emerging
Risk Factors Collaboration. Diabetes mellitus, fast-
ing blood glucose concentration, and risk of vas-
cular disease: a collaborative meta-analysis of
102 prospective studies. Lancet 2010;375:2215–
2222
46. Di Angelantonio E, Kaptoge S, Wormser D,
et al.; Emerging Risk Factors Collaboration. Asso-
ciation of cardiometabolic multimorbidity with
mortality [published correction appears in JAMA
205;314:1179]. JAMA 2015;314:52–60
47. Dormandy JA, Charbonnel B, Eckland DJ,
et al.; PROactive Investigators. Secondary preven-
tion of macrovascular events in patients with type
2 diabetes in the PROactive Study (PROspective
pioglitAzone Clinical Trial In macroVascular Events):
a randomised controlled trial. Lancet 2005;366:
1279–1289
48. Kernan WN, Viscoli CM, Furie KL, et al.; IRIS
Trial Investigators. Pioglitazone after ischemic
stroke or transient ischemic attack. N Engl J Med
2016;374:1321–1331
49. Zinman B, Wanner C, Lachin JM, et al.; EMPA-
REG OUTCOME Investigators. Empagliflozin, car-
diovascular outcomes, and mortality in type 2
diabetes. N Engl J Med 2015;373:2117–2128
50. Wu JH, Foote C, Blomster J, et al. Effects of
sodium-glucose cotransporter-2 inhibitors on car-
diovascular events, death, and major safety out-
comes in adults with type 2 diabetes: a systematic
review and meta-analysis. Lancet Diabetes Endo-
crinol 2016;4:411–419
51. Simpson SH, Majumdar SR, Tsuyuki RT, Eurich
DT, Johnson JA. Dose-response relation between
sulfonylurea drugs and mortality in type 2 diabe-
tes mellitus: a population-based cohort study.
CMAJ 2006;174:169–174
52. Evans JM, Ogston SA, Emslie-Smith A, Morris
AD. Risk of mortality and adverse cardiovascular
outcomes in type 2 diabetes: a comparison of
patients treated with sulfonylureas and metfor-
min. Diabetologia 2006;49:930–936
53. Scirica BM, Bhatt DL, Braunwald E, et al.;
SAVOR-TIMI 53 Steering Committee and Investi-
gators. Saxagliptin and cardiovascular outcomes
in patients with type 2 diabetes mellitus. N Engl J
Med 2013;369:1317–1326
54. White WB, Cannon CP, Heller SR, et al.;
EXAMINE Investigators. Alogliptin after acute cor-
onary syndrome in patients with type 2 diabetes.
N Engl J Med 2013;369:1327–1335
55. Green JB, Bethel MA, Armstrong PW, et al.;
TECOS Study Group. Effect of sitagliptin on cardio-
vascular outcomes in type 2 Diabetes. N Engl J
Med 2015;373:232–242
56. Gerstein HC, Bosch J, Dagenais GR, et al.;
ORIGIN Trial Investigators. Basal insulin and car-
diovascular and other outcomes in dysglycemia.
N Engl J Med 2012;367:319–328
57. Verge D, L´opez X. Impact of GLP-1 and GLP-1
receptor agonists on cardiovascular risk factors in
type2diabetes.CurrDiabetesRev2010;6:191–200
58. Koska J, Sands M, Burciu C, et al. Exenatide
protects against glucose- and lipid-induced endo-
thelial dysfunction: evidence for direct vasodila-
tion effect of GLP-1 receptor agonists in humans.
Diabetes 2015;64:2624–2635
59. Campbell JE, Drucker DJ. Pharmacology,
physiology, and mechanisms of incretin hormone
action. Cell Metab 2013;17:819–837
60. Drucker DJ. The cardiovascular biology of
glucagon-like peptide-1. Cell Metab 2016;24:15–30
61. DeFronzo RA, Goodman AM; The Multicenter
Metformin Study Group. Efficacy of metformin in
patients with non-insulin-dependent diabetes
mellitus. N Engl J Med 1995;333:541–549
62. CusiK,DeFronzoRA.Metformin: areviewofits
metaboliceffects. Diabetes Reviews 1998;6:89–131
63. Natali A, Ferrannini E. Effects of metformin
and thiazolidinediones on suppression of hepatic
glucose production and stimulation of glucose up-
take in type 2 diabetes: a systematic review. Dia-
betologia 2006;49:434–441
64. Jensen JB, Gormsen LC, Sundelin E, et al.
Organ-specific uptake and elimination of metfor-
min can be determined in vivo in mice and humans
by PET-imaging using a novel 11
C-metformin tracer
(Abstract). Diabetes 2015;64(Suppl. 1):LB33
1126 Point Diabetes Care Volume 40, August 2017
7. 65. UK Prospective Diabetes Study (UKPDS)
Group. Effect of intensive blood-glucose control
with metformin on complications in overweight
patients with type 2 diabetes (UKPDS 34). Lancet
1998;352:854–865
66. Hare KJ, Knop FK, Asmar M, et al. Preserved
inhibitory potency of GLP-1 on glucagon secretion
in type 2 diabetes mellitus. J Clin Endocrinol
Metab 2009;94:4679–4687
67. Jendle J, Grunberger G, Blevins T, Giorgino F,
Hietpas RT, Botros FT. Efficacy and safety of dula-
glutide in the treatment of type 2 diabetes: a
comprehensive review of the dulaglutide clinical
data focusing on the AWARD phase 3 clinical trial
program. Diabetes Metab Res Rev 2016;32:776–
790
68. Pfeffer MA, Claggett B, Diaz R, et al.; ELIXA
Investigators. Lixisenatide in patients with type 2
diabetes and acute coronary syndrome. N Engl J
Med 2015;373:2247–2257
69. Henry RR, Rosenstock J, Logan D, Alessi T,
Luskey K,Baron MA.Continuoussubcutaneousde-
livery of exenatide via ITCA 650 leads to sustained
glycemic control and weight loss for 48 weeks in
metformin-treated subjects with type 2 diabetes.
J Diabetes Complications 2014;28:393–398
70. Novo Nordisk A/S. Efficacy and long-term
safety oforalsemaglutideversussitagliptininsub-
jects with type 2 diabetes (PIONEER 3). In:
ClinicalTrials.gov [Internet]. Bethesda, MD, Na-
tional Library of Medicine, 2017. Available from
https://clinicaltrials.gov/ct2/show/NCT2607865.
NLM Identifier: NCT02607865. Accessed 18 May
2017
71. American Diabetes Association. Economic
costs of diabetes in the U.S. in 2012. Diabetes
Care 2013;36:1033–1046
72. Cusi K, Consoli A, DeFronzo A. Metabolic
effects of metformin on glucose andlactate metab-
olism in noninsulin-dependent diabetes mellitus.
J Clin Endocrinol Metab 1996;81:4059–4067
73. DeFronzo RA, Barzilai N, Simonson DC. Mech-
anism of metformin action in obese and lean non-
insulin-dependent diabetic subjects. J Clin
Endocrinol Metab 1991;73:1294–1301
74. Brown JB, Conner C, Nichols GA. Secondary
failure of metformin monotherapy in clinical
practice. Diabetes Care 2010;33:501–506
care.diabetesjournals.org Abdul-Ghani and DeFronzo 1127