Type 2 diabetes - A 2016 update by Zeena Nackerdien

Type 2 Diabetes

Definition

Epidemiology

Etiology

Diagnosis

Treatment

Prevention

Disease Characteristics and Goals

Reduce risk of

complications

•BP, lipid, and glycemic management to reduce risk of macrovascular complications

•BP control and glycemic management to reduce risk of microvascular complications

Cardiovascular risk factor reduction a

key goal

•Treat cardiovascular risk factors to achieve individualized targets

•Smoking cessations, antihypertensive agents, and lipid medications are among the recommended agents

Individualize treatment

•Lifestyle changes + metformin as initial antihyperglycemic therapy for most patients

•Glycemic goals and treatment choices are individualized

• Insulin resistance and relative insulin insufficiency

https://online.epocrates.com/diseases/2411/Type-2-diabetes-mellitus-in-adults/Key-HighlightsBP, blood pressure

Key complications: Nerve, kidney,

eye, and cardiovascular

diseases

https://online.epocrates.com/diseases/2411/Type-2-diabetes-mellitus-in-adults/Key-Highlights

Type 2 Diabetes

Definition

Epidemiology

Etiology

Diagnosis

Treatment

Prevention

Prediabetes• Prediabetes is a metabolic condition

characterized by hyperglycemia

– Diagnostic criteria below those used to define Type 2 diabetes eg, fasting plasma glucose concentrations are 5·6 mmol/L or higher but less than 7·0 mmol/L (termed impaired fasting glucose [IFG])

Est., estimatedGarber AJ, Abrahamson MJ, Barzilay JI, Endocrine Practice. 2016;22(1):84-113.Stefan N, Fritsche A, Schick F, et al. TLancet Diabetes & Endocrinology. 2016;4(9):789-98.

USA>38% est.

to have prediabetesChina

>50% est.to have prediabetes

In terms of pathophysiology, prediabetes reflects failing pancreatic islet β-cell compensation for an underlying state of

insulin resistance, most commonly caused by excess body weight or obesity.

Type 2 Diabetes

Definition

Epidemiology

Etiology

Diagnosis

Treatment

Prevention

Phenotyping of patients with prediabetes • Stefan et al. (2016) proposed stratifying patients

into low- and high-risk groups– High-risk: low insulin secretion or low insulin

sensitivity plus non-alcoholic fatty liver disease (NAFLD)

– Low-risk: Other combinations related to insulin secretion, insulin sensitivity, and NAFLD eg, high body mass index or visceral obesity

.CVD, cardiovascular diseases; NAFLD, non-alcohol fatty liver disease; NGR, normal glucose regulationStefan N, Fritsche A, Schick F, et al. TLancet Diabetes & Endocrinology. 2016;4(9):789-98.

Prediabetes

and no stratificatio

n at baseline

Maybe intensive lifestyle interventionwill restore NGR

Prediabetes

and stratificatio

n at baseline

Better predictive poweras to the effectivenessof lifestyle intervention

in restoring NGR; Improves classification of hyperglycemia

and risk of CVD in prediabetics

Diabetes Epidemiology

Definition

Etiology

Diagnosis

Treatment

Prevention

Epidemiology

415 million people worldwide have diabetes; by 2040 this will rise to 642 million

(2015 International Diabetes Federation estimates)

The estimated annual global health expenditure attributable to diabetes ranged from USD 612 billion (to USD 1099 billion. Together, the North America and Caribbean Region and the Europe Region were responsible for over 69% of the costs, and less than 10% of the costs were from the Africa Region, South East Asia Region, and Middle East and North Africa Region combined.

MENA, Middle East and North Africada Rocha Fernandes J, Ogurtsova K, Linnenkamp U, et al. Diab. Res. Clinical Prac. 2016;117:48-54.http://www.diabetesatlas.org/

Every 6 secondssomeone diesfrom diabetes

3.2%

In Africa, more than two-thirds are undiagnosed;Prevalence in MENA: 9.1%

Regional Prevalence (%)

North America & Caribbean12.9%

South & CentralAmerica9.4%

South-EastAsia8.5%

9.1%

37% of the diabetics across the globe live in the Western Pacific (a region comprising 39 countries, including China)

http://www.diabetesatlas.org/

Type 2 Diabetes: Etiology/Pathophysiology

Definition

Epidemiology

Etiology

Diagnosis

Treatment

Prevention

• ≥40 years old• Hereditary predisposition• Pre-diabetic• Woman who had gestational diabetes• Woman who gave birth to a ≥9 lb baby• Overweight/excess abdominal weight• High BP or cholesterol issues• Psychosocial disorders/HIV infection/polycystic

ovarian syndrome/acanthosis nigricans• Specific medications eg, antipsychotics/anti-

inflammatory steroids

What are the risk factors?

BP, blood pressure; HIV, human immunodeficiency virusCheng AY. and members of the Clinical Practice Guideline Committees. CJD. 2013;37 Suppl 1:227 pp.


Definition

Epidemiology

Etiology

Diagnosis

Treatment

Prevention

• Blood glucose appearance is a function of meal-derived sources and hepatic glucose production

– Regulation occurs by pancreatic and gut hormones– Liver and skeletal muscle responsiveness to insulin

decline with progressive β-cell dysfunction– Insulin is a key anabolic hormone secreted in

response to increased blood glucose and amino acids following a meal

What role does insulin play?

Brunton SA, Kruger DF, Funnell MM. Clinical Diabetes. 2016;34(1):34-43; www.slideteam.netAronoff SL, Berkowitz K, Shreiner B et al.Diabetes Spectrum. 2004;17(3):183-90..

http://www.slideteam.net/


Definition

Epidemiology

Etiology

Diagnosis

Treatment

Prevention

• Insulin resistance is aggravated by aging, physical inactivity, and overweight (BMI 25-29.9 kg/m2) or obesity (BMI >30 kg/m2)

• Complexity of intracellular derangements suggest the disease may be stratified into many subtypes

Etiology

PathophysiologyThe precise

mechanism by which the diabetic

metabolic state leads to

microvascular and

macrovascular complications is

only partly understood.

Uncontrolled BP and uncontrolled glucose, increasing the risk of microvascular complications such as retinopathy and nephropathy

With respect to macrovascular complications, high BP and glucose raise risk, but so do lipid abnormalities and tobacco use.One unifying theory postulates a

metabolic syndrome that includes diabetes mellitus, hypertension, dyslipidemias, and obesity, and predisposes to coronary heart disease, stroke, and peripheral artery disease. However, this theory is not universally accepted.

https://online.epocrates.com/diseases/2424/Type-2-diabetes-mellitus-in-adults/Etiology

https://online.epocrates.com/diseases/2424/Type-2-diabetes-mellitus-in-adults/Etiology

Type 2 Diabetes – Diagnostic Approach

Definition

Epidemiology

Etiology

Diagnosis

Treatment

Prevention

• impaired glucose tolerance, impaired fasting glucose, or metabolic syndrome are risk factors

– Any one of these factors is associated with a 5-fold increase in future T2D risk

• Three tests indicate prediabetes– Fasting plasma glucose test (blood sugar is 100-

125)– Oral glucose tolerance test (blood sugar is 140-199

after the second test)– A1C test: (blood sugar is 5.7 to 6.4%)

Prediabetes

http://www.webmd.com/diabetes/type-2-diabetes-guide/what-is-prediabetes-or-borderline-diabetesGarber AJ, Abrahamson MJ, Barzilay JI, et al,. Endocrine Practice 2016;22(1):84-113.

http://www.webmd.com/diabetes/type-2-diabetes-guide/what-is-prediabetes-or-borderline-diabetes

Type 2 Diabetes – Diagnostic Approach

Definition

Epidemiology

Etiology

Diagnosis

Treatment

Prevention

• Symptomatic patients may present with: fatigue; polyuria, polydipsia, polyphagia, or weight loss (usually when hyperglycemia is more severe, e.g., >300 mg/dL); blurred vision; paresthesias; unintentional weight loss; nocturia; skin infections (bacterial or candidal); urinary infections; or acanthosis nigricans

Diagnosis should be verified by repeat testing.

1

324 One of 4 tests can confirm

a diagnosis of diabetes

1. Fasting plasma glucose (FPG) >125 mg/dL (most commonly used)

2. Random plasma glucose ≥200 mg/dL with diabetes symptoms such as polyuria, polydipsia, fatigue, or weight loss

3. 2-hour post-load glucose ≥200 mg/dL on a 75 g oral glucose tolerance tests

4. HbA1c ≥6.5%

https://online.epocrates.com/diseases/2431/Type-2-diabetes-mellitus-in-adults/Diagnostic-Approach

https://online.epocrates.com/diseases/2431/Type-2-diabetes-mellitus-in-adults/Diagnostic-Approach

Type 2 Diabetes – Goals for Glycemic Control

Definition

Epidemiology

Etiology

Diagnosis

Treatment

Prevention

• Strong risk factors, which also indicate the need for screening, include: older age; overweight/obesity; black, Hispanic, or Native American ancestry; family history of Type 2 Diabetes; history of gestational diabetes; presence of prediabetes; physical inactivity; polycystic ovary syndrome; hypertension; dyslipidemia; or known cardiovascular disease

For patients with concurrent serious illness and at high risk for hypoglycemia

Diagnosis should be verified by repeat testing.

A1C ≤6.5%

A1C >6.5

%

For patients without concurrent serious illness and at low hypoglycemic risk

A1C, glycated hemoglobinhttp://www.diabetes.org/living-with-diabetes/treatment-and-care/blood-glucose-control/a1chttp://answers.webmd.com/answers/1180327/what-blood-sugar-levels-are-considered-normal-and-what-levels-are-diabetichttp://www.webmd.com/diabetes/tc/criteria-for-diagnosing-diabetes-topic-overview/Garber AJ, Abrahamson MJ, Barzilay JI, et al.Endocrine Practice 2016;22(1):84-113.

2. Glucose enters red blood cells and glycates with molecules of hemoglobin (A1C).. By measuring the percentage of A1C in the blood, one gets an overview of your average blood glucose control for the past few months.

1. Hemoglobin, a protein that links up with sugars such as glucose, is found inside red blood cells. Its job is to carry oxygen from the lungs to all the cells of the body.

Addtl glucose notes

http://www.diabetes.org/living-with-diabetes/treatment-and-care/blood-glucose-control/a1c/



Type 2 Diabetes Treatment

Definition

Epidemiology

Etiology

Diagnosis

Treatment

Prevention

• Since patients are 2x likely to die from CVDs vs. the general population, a 1◦ goal is treatment of CVD risk factors to individualize targets

Approach

Corn

erst

one

trea

tmen

t fo

r al

l pat

ient

s

Init

ial g

luco

se-lo

wer

ing

phar

mac

othe

rapi

es

CVD

ris

k fa

ctor

sSmoking cessationBlood pressure controlStatin useAspirin use for patients with known coronary heart diseaseACE inhibitors for patients with chronic kidney disease/proteinuria

MetforminDual-drug combinations

Self-management programNutrition education

This is a progressive disease and prompt initiation and intensification of pharmacotherapy to achieve and maintain clinical goals is central to diabetes care.

https://online.epocrates.com/diseases/2441/Type-2-diabetes-mellitus-in-adults/Treatment-ApproachCVD, cardiovascular disease

https://online.epocrates.com/diseases/2441/Type-2-diabetes-mellitus-in-adults/Treatment-Approach


Definition

Epidemiology

Etiology

Diagnosis

Treatment

Prevention

• The priority in management is to minimize the risks of hypoglycemia and weight gain. The AACE preferentially recommends agents that do not increase these risks

Pharmacologic Agentsa

Smoking cessationBlood pressure controlStatin useAspirin use for patients with known coronary heart diseaseACE inhibitors for patients with chronic kidney disease/proteinuria



Abbreviations: AACE = American Association for Clinical Endocrinology; AGI = α-glucosidase inhibitors; BCR-QR = bromocriptine quick release; DPP4I = dipeptidyl peptidase 4inhibitors; GLP1RA = glucagon-like peptide 1 receptor agonists; SGLT2I = sodium-glucose cotransporter 2 inhibitors; SU = sulfonylureas;TZD = thiazolidinediones; a Intensify therapy whenever A1C exceeds individualized target. Boldface denotes little or no risk of hypoglycemia or weight gain, few adverse events, and/or the possibility of benefits beyond glucose

lowering. b Use with caution. Handelsman Y, Bloomgarden ZT, Grunberger G,et al. Endocrine Practice. 2015;21 Suppl 1:1-87.

Metformin; GLP1RA; SGLT2I; DPP4I; AGI; TZDb; SU/glinideb

GLP1RA; SGLT2I; TZDb; Basal insulinb; DPP4I; Colesevelam; BCR-QR; AGI; SU/glinideb

GLP1RA; SGLT2I; DPP4I; TZDb; Basal insulinb; Colesevelam; BCR-QR; AGI; SU/glinideb

1First-line treatment

2Metformin (or other

first-line agent) plus

3First- and

second-lineagent plus


Definition

Epidemiology

Etiology

Diagnosis

Treatment

Prevention

• Research on two incretins ie, glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), led to the development of GLP-1 receptor (GLP-1R) agonists and DPP-IV inhibitors

Incretins: Key non-insulin therapies




DPP IV, Dipeptidyl Peptidase IV; GLP-1,R Glucagon-like peptide- receptors; MOA, mechanism of action; Chatterjee S, Davies MJ. Postgrad Med J. 2015;91(1081):612-21.

Can be used in conjunction with insulin tooptimize control, reduce its weight gain effects and lower daily insulin dose requirements

GLP-1R agonist use

Improved HbA1c (up to 1.6%); minimal risk of hypoglycemia and oftensignificant weight loss/neutrality dependingon the incretin and patient factors

Result

Can be used safely in worsening renal impairment, with some agents such as linagliptin,which is mainly excreted enterohepatically requiring no dose adjustment even in end-stage renal failure

DPP IV inhibitor use

MOA Increase insulin secretion (via β cells) and reduce glucagon secretion, hepatic glucose production and glucose uptake from the stomach and promote satiety


Definition

Epidemiology

Etiology

Diagnosis

Treatment

Prevention

• Synthetic insulin (6,000 Da) consists of an A chain of 21 amino acids and a B chain of 30 amino acids

• In the body, insulin is generated by cleavage of the C-peptide from proinsulin

Insulin Synthesis




Brunton SA, Kruger DF, Funnell MM. Role of Emerging Insulin Clinical Diabetes. 2016;34(1):34-43Fu Z, Gilbert ER, Liu D. Current Diabetes Reviews. 2013;9(1):25-53; http://www.slideteam.net/..

http://www.slideteam.net/


Definition

Epidemiology

Etiology

Diagnosis

Treatment

Prevention

• Typically-used insulin classes are shown here– Administration modes are via

pen/pump/syringe/subcutaneous infusion

– Many novel insulin products and delivery systems may provide T2D patients to initiate insulin more comfortably and earlier in the disease process

Types of Insulin




http://guidelines.diabetes.ca/cdacpg_resources/Ch12_Table1_Types_of_Insulin_updated_Aug_5.pdf

Bolus (prandial) insulins

Basalinsulins

Premixedinsulins

http://guidelines.diabetes.ca/cdacpg_resources/Ch12_Table1_Types_of_Insulin_updated_Aug_5.pdf


Definition

Epidemiology

Etiology

Diagnosis

Treatment

Prevention

• Insulin should be intensified within 3-6 months of failure to meet glycemic targets (Brunton et al, 2016)

– Benefits of early use/intensification eg, improvements in glycemic control/QoL/treatment satisfaction

– Insulin is often initiated late in the natural history of the disease

The Insulin Conundrum




QoL, quality of lifeBrunton SA, Kruger DF, Funnell MM. Clinical Diabetes. 2016;34(1):34-43.

Patient BarriersConcerns over safety and efficacy of

insulin

Hypoglycemia or weight gain concerns

Psychological eg, a perceived failure to take the hormone

Concern that insulin is associated with complications or even death

Fear of a loss of independence

Clinician Barriers

Need for education about the benefits of appropriately-initiated insulin therapy

Patients reluctance to use injected insulin may preclude initiation of a chat about the hormoneTime-consuming for staff to provide patient training regarding insulin use/Remote practices may not have access to needed training materials

Overall goal of insulin and non-insulin therapies is to lower basal hepatic glucose production and increase muscle glucose

uptake


Definition

Epidemiology

Etiology

Diagnosis

Treatment

Prevention

• Guidelines promote personalized management with a special focus on safety beyond efficacy based on prespecified approaches

AACE/ACE Management Algorithm (Part 1)


education

Garber AJ, Abrahamson MJ, Barzilay JI, et al. Endocrine Practice 2016;22(1):84-113.

Lifestyle therapy, including medically Supervised weight loss.

The A1C targetmust be individualized.; Glycemic control Targets include fasting & postprandial glucoses

Patient characteristics, net costs to patients, formulary restrictions, & personal preferences are among the factors to be taken into account in the choice of therapies.

Minimizing risk of hypoglycemia is a priority.

Minimizing risk of weight gain is a priority.

Total cost of care adds up eg, monitoring requirements, initial acquisition cost of medications, weight gain, safety etc..


Definition

Epidemiology

Etiology

Diagnosis

Treatment

Prevention

• Guidelines promote personalized management with a special focus on safety beyond efficacy based on prespecified approaches

AACE/ACE Management Algorithm (Part 2)


education

Garber AJ, Abrahamson MJ, Barzilay JI, et al. Endocrine Practice 2016;22(1):84-113.

Algorithm stratifies choice of therapies based on initial A1C.

Combination therapyIs usually required &should involve agents with complementary actions.

Lipid/blood pressureprofiles and related comorbidity assessmentsshould form part of comprehensive management.

Initially therapy should be evaluatedfrequently until stable & then lessoften..

Keep therapyas simple as possible to optimize adherence

The algorithm includes every FDA-approved class of diabetes medications


Definition

Epidemiology

Etiology

Diagnosis

Treatment

Prevention

• 180 medicines are currently being developed to treat

diabetes. Other therapies are listed here.

Emerging therapies




http://www.phrma.org/sites/default/files/pdf/diabetes2014.pdfhttps://online.epocrates.com/diseases/2443/Type-2-diabetes-mellitus-in-adults/Emerging-Therapies

Bariatric surgery CinnamonOther agents eg, salsalate, human insulin

inhalation powder

Therapeutic benefits vary; younger patients (40-50)with more recent-onset disease had higher benefits than older patients with longer-duration illness.

More study is needed to confirm findings that cinnamon reduces blood sugars with minimal effect on HbA1c..

Further study is needed to confirm HbA1c-lowering capacity of salsalate; Althoughrapid-acting inhaled insulinIs FDA-approved, this drug is not preferred over injectableInsulins. The latter drugs havea longer safety track record.

https://online.epocrates.com/diseases/2443/Type-2-diabetes-mellitus-in-adults/Emerging-Therapies

https://online.epocrates.com/diseases/2443/Type-2-diabetes-mellitus-in-adults/Emerging-Therapies

Diabetes Treatment

Definition

Epidemiology

Etiology

Diagnosis

Treatment

Prevention

• Novel therapies, including immunomodulation, are being investigated to treat/prevent all forms of diabetes

Future Directions




Chatterjee S, Davies MJ.. Postgrad Med J. 2015;91(1081):612-21.

Preserving/increasing β-cell function • ‘Bionic’

pancreas• Islet

transplantsImmunomodulation • Antigen-

specific and non-antigen-specific agents

• Stem cell transplantation

Intensify prevention strategies

• Optimizing lifestyle changes/ using metformin in prediabetes may prevent T2DM, but difficult to translate clinical data into real-world practice

Pharmacological therapies

• Oral insulin• Fecal

transplants

Type 2 Diabetes

Definition

Epidemiology

Etiology

Diagnosis

Treatment

Prevention

• Goals

Patient Education

Cheng AY. and members of the Clinical Practice Guideline Committees. Canadian Diabetes Association 2013 clinical practice guidelines for the prevention and management of diabetes in Canada. CJD. 2013;37 Suppl 1:227 pp.

Smoking cessation

S

M

A

R

T

Specific, Measurable, Attainable, Relevant,Time-bound

Diabetes Education and NutritionEnable timely, culturally and literacy appropriate diabetes education and resources

Physical activity/weight loss/medication

Hypoglycemia/Self-monitoring of blood glucose (SMBG)

Foot care/Mental Health and Mood Disorders

Type 2 Diabetes: Prevention

Definition

Epidemiology

Etiology

Diagnosis

Treatment

Prevention

• 86 million are living with prediabetes, a serious health condition that increases a person’s risk of type 2 diabetes and other chronic diseases.

Control of the main disease drivers

http://www.cdc.gov/chronicdisease/resources/publications/aag/diabetes.htmhttps://online.epocrates.com/diseases/2444/Type-2-diabetes-mellitus-in-adults/Prevention

Modest weight loss; diet;

exercise; certain phamracotherapi

es subject to consideration of

side effects

Annual influenza and pneumococcal polysaccharide

vaccines as appropriate;

Regular dental care; Diabetes education as

needed

Prediabetes Type 2 diabetes

http://www.cdc.gov/chronicdisease/resources/publications/aag/diabetes.htm

https://online.epocrates.com/diseases/2444/Type-2-diabetes-mellitus-in-adults/Prevention

Health & Medicine

Type 2 diabetes - A 2016 update by Zeena Nackerdien