Diabetes in clincal practice 2015

Diabetes in clinical practiceDr. Hazem Samy Matar

Assistant lecturer of internal medicine,diabetes and endocrinology

Diabetes mellitusDefinition:A clinical syndrome characterized by chronic hyperglycaemia due to absolute or relative insulin

deficiency or insulin resistance or both leading to disturbance of metabolism of carbohydrates ,protein ,fat ,water and electrolytes.

Why syndrome?

The Developmental Origin of Type 2 Diabetes Provides a Conceptual Framework to Explain the Multiple Organ Defects in Type 2 Diabetes

Vaag A.Diabetologia (2012) 55:2085–2088

2. CLASSIFICATION AND DIAGNOSIS OF DIABETES

Classification of Diabetes

• Type 1 diabetes– β-cell destruction

• Type 2 diabetes– Progressive insulin secretory defect

• Other specific types of diabetes– Genetic defects in β-cell function, insulin action– Diseases of the exocrine pancreas– Drug- or chemical-induced

• Gestational diabetes mellitus (GDM)

ADA. 2. Classification and Diagnosis. Diabetes Care 2015;38(suppl 1):S8

Criteria for the Diagnosis of Diabetes

A1C ≥6.5%OR

Fasting plasma glucose (FPG)≥126 mg/dL (7.0 mmol/L)

OR

2-h plasma glucose ≥200 mg/dL(11.1 mmol/L) during an OGTT

OR

A random plasma glucose ≥200 mg/dL (11.1 mmol/L)

ADA. 2. Classification and Diagnosis. Diabetes Care 2015;38(suppl 1):S9; Table 2.1


A1C ≥6.5%

The test should be performed in a laboratory using a method that is

NGSP certified and standardizedto the DCCT assay*

*In the absence of unequivocal hyperglycemia, result should be confirmed by repeat testing.

ADA. 2. Classification and Diagnosis. Diabetes Care 2015;38(suppl 1):S9; Table 2


Fasting plasma glucose (FPG)≥126 mg/dL (7.0 mmol/L)

Fasting is defined as no caloric intakefor at least 8 h*




2-h plasma glucose ≥200 mg/dL(11.1 mmol/L) during an OGTT

The test should be performed as described by the WHO, using a

glucose load containing the equivalentof 75 g anhydrous glucose

dissolved in water*




In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis,

a random plasma glucose ≥200 mg/dL (11.1 mmol/L)


FPG 100–125 mg/dL (5.6–6.9 mmol/L): IFGOR

2-h plasma glucose in the 75-g OGTT140–199 mg/dL (7.8–11.0 mmol/L): IGT

OR

A1C 5.7–6.4%

*For all three tests, risk is continuous, extending below the lower limit of a range and becoming disproportionately greater at higher ends of the range.


Categories of Increased Risk for Diabetes (Prediabetes)*

Recommendations: Testing for Diabetes in Asymptomatic Patients• Consider testing overweight/obese adults (BMI ≥25

kg/m2 or ≥ 23 kg/m2 in Asian Americans) with one or more additional risk factors for type 2 diabetes; for all patients, particularly those who are overweight, testing should begin at age 45 years B

• If tests are normal, repeat testing at least at 3-year intervals is reasonable C

• To test for diabetes/prediabetes, the A1C, FPG, or 2-h 75-g OGTT are appropriate B

• In those with prediabetes, identify and, if appropriate, treat other CVD risk factors B


Criteria for Testing for Diabetes in Asymptomatic Adult Individuals (1)

•Physical inactivity•First-degree relative with

diabetes•High-risk race/ethnicity (e.g.,

African American, Latino, Native American, Asian American, Pacific Islander)

•Women who delivered a baby weighing >9 lb or were diagnosed with GDM

•Hypertension (≥140/90 mmHg or on therapy for hypertension)

• HDL cholesterol level<35 mg/dL (0.90 mmol/L) and/or a triglyceride level >250 mg/dL (2.82 mmol/L)

• Women with polycystic ovarian syndrome (PCOS)

• A1C ≥5.7%, IGT, or IFG on previous testing

• Other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis nigricans)

• History of CVD

1. Testing should be considered in all adults who are overweight(BMI ≥25 kg/m2* or ≥23 kg/m2 in Asian Americans) and have additional risk factors:


2. In the absence of criteria (risk factors on previous slide), and particularly in those who are overweight or obese, testing for diabetes should begin at age 45 years

3. If results are normal, testing should be repeated at least at 3-year intervals, with consideration of more frequent testing depending on initial results (e.g., those with prediabetes should be tested yearly), and risk status

ADA. 2.Classification and Diagnosis. Diabetes Care 2015;38(suppl 1):S10; Table 2.2

Criteria for Testing for Diabetes in Asymptomatic Adult Individuals (2)

• Testing to detect type 2 diabetes and prediabetes should be considered in children and adolescents who are overweight and who have two or more additional risk factors for diabetes E

Recommendation: Screening forType 2 Diabetes in Children


3. INITIAL EVALUATION AND DIABETES MANAGEMENT PLANNING

• A complete medical evaluation should be performed to– Classify the diabetes

• Detect presence of diabetes complications• Review previous treatment, risk factor control in patients with established

diabetes• Assist in formulating a management plan• Provide a basis for continuing care

• Perform laboratory tests necessary to evaluate each patient’s medical condition

Screening Recommendation• Consider screening those with type 1 diabetes for other

autoimmune diseases (thyroid, vitamin B12 deficiency, celiac) as appropriate B

Diabetes Care: Initial Evaluation

ADA. 3. Initial Evaluation and Diabetes Management Planning. Diabetes Care 2015;38(suppl 1):S17

Medical history (1)• Age and characteristics of onset of diabetes (e.g., DKA,

asymptomatic laboratory finding• Eating patterns, physical activity habits, nutritional status, and

weight history; growth and development in children and adolescents

• Diabetes education history• Review of previous treatment regimens and response to

therapy (A1C records)

Components of the Comprehensive Diabetes

Evaluation (1)


Medical history (2)• Current treatment of diabetes, including medications,

adherence and barriers thereto, meal plan, physical activity patterns, readiness for behavior change

• Results of glucose monitoring, patient’s use of data• DKA frequency, severity, cause• Hypoglycemic episodes

– Hypoglycemic awareness– Any severe hypoglycemia: frequency, cause


Evaluation (2)



Evaluation (3)

*See appropriate referrals for these categories.

Medical history (3)• History of diabetes-related complications

– Microvascular: retinopathy, nephropathy, neuropathy• Sensory neuropathy, including history of foot lesions• Autonomic neuropathy, including sexual dysfunction and gastroparesis

– Macrovascular: CHD, cerebrovascular disease, PAD– Other: psychosocial problems,* dental disease*



Evaluation (4)Physical examination (1)• Height, weight, BMI• Blood pressure determination, including orthostatic

measurements when indicated• Fundoscopic examination• Thyroid palpation• Skin examination (for acanthosis nigricans and insulin

injection sites)



Evaluation (5)Physical examination (2)• Comprehensive foot examination

– Inspection– Palpation of dorsalis pedis and posterior tibial pulses– Presence/absence of patellar and Achilles reflexes– Determination of proprioception, vibration, and

monofilament sensation



Evaluation (6)Laboratory evaluation• A1C, if results not available within past

3 months• If not performed/available within past year

– Fasting lipid profile, including total, LDL, and HDL cholesterol and triglycerides

– Liver function tests– Test for urine albumin excretion with spot urine albumin-to-creatinine ratio– Serum creatinine and calculated GFR– TSH in type 1 diabetes, dyslipidemia, or women over age 50 years



Evaluation (7)Referrals• Eye care professional for annual dilated eye exam• Family planning for women of reproductive age• Registered dietitian for MNT• Diabetes self-management education/support• Dentist for comprehensive periodontal examination• Mental health professional, if needed


5. PREVENTION/DELAY OF TYPE 2 DIABETES

Recommendations:Prevention/Delay of Type 2 Diabetes• Refer patients with IGT A, IFG E, or A1C 5.7–6.4%

E to ongoing support program– Targeting weight loss of 7% of body weight– Increasing physical activity to at least 150 min/week of

moderate activity (eg, walking)• Follow-up counseling appears to be important for

success B• Based on cost-effectiveness of diabetes prevention,

such programs should be covered by third-party payers B

ADA. 5. Prevention/Delay of Type 2 Diabetes. Diabetes Care 2015;38(suppl 1):S31

Recommendations:Prevention/Delay of Type 2 Diabetes• Consider metformin for prevention of type 2 diabetes

if IGT A, IFG E, or A1C 5.7–6.4% E– Especially for those with BMI >35 kg/m2,

age <60 years, and women with prior GDM A• In those with prediabetes, monitor for development

of diabetes annually E• Screen for and treat modifiable risk factors for CVD

B• DSME/DSMS programs are approparite venues for

people with prediabetes to develop and maintain behaviors that can prevent or delay the onset of diabetes C

ADA. 5. Prevention/Delay of Type 2 Diabetes. Diabetes Care 2015;38(suppl 1):S31

Glycemic Recommendations forNonpregnant Adults with Diabetes (1)

A1C <7.0%*

Preprandial capillary plasma glucose

80–130 mg/dL* (4.4–7.2 mmol/L)

Peak postprandial capillary plasma glucose†

<180 mg/dL* (<10.0 mmol/L)

*Goals should be individualized.†Postprandial glucose measurements should be made 1–2 h after the beginning of the meal, generally peak levels in patients with diabetes.

ADA. 6. Glycemic Targets. Diabetes Care 2015;38(suppl 1):S37; Table 6.2

• Goals should be individualized based on– Duration of diabetes– Age/life expectancy– Comorbid conditions– Known CVD or advanced microvascular complications– Hypoglycemia unawareness– Individual patient considerations

Glycemic Recommendations forNonpregnant Adults with Diabetes (2)

ADA. 6. Glycemic Targets. Diabetes Care 2015;38(suppl 1):S37; Table 6.2

Approach to the Management of Hyperglycemia

ADA. 6. Glycemic Targets. Diabetes Care 2015;38(suppl 1):S37. Figure 6.1; adapted with permission from Inzucchi SE, et al. Diabetes Care, 2015;38:140-149

• Individuals at risk for hypoglycemia should be asked about symptomatic and asymptomatic hypoglycemia at each encounter C

• Glucose (15–20 g) preferred treatment for conscious individual with hypoglycemia E

• Glucagon should be prescribed for all individuals at significant risk of severe hypoglycemia and caregivers/family members instructed in administration E

Recommendations: Hypoglycemia (1)

ADA. 6. Glycemic Targets. Diabetes Care 2015;38(suppl 1):S38

• Hypoglycemia unawareness or one or more episodes of severe hypoglycemia should trigger re-evaluation of the treatment regimen E

• Insulin-treated patients with hypoglycemia unawareness or an episode of severe hypoglycemia should be advised to raise glycemic targets to strictly avoid further hypoglycemia for at least several weeks, to partially reverse hypoglycemia unawareness, and to reduce risk of future episodes A




• Ongoing assessment of cognitive function is suggested with increased vigilance for hypoglycemia by the clinician, patient, and caregivers if low cognition and/or declining cognition is found B


7. APPROACHES TO GLYCEMIC TREATMENT

Non-insulin anti-diabetic drugs

Non-insulin anti-diabetic drugs The drugs for treating type 2 diabetes, other than insulin, fall into five

categories:

(1) Drugs that act on the sulfonylurea receptor complex of the beta

(2) Drugs that principally lower glucose levels by their actions on liver, skeletal muscle or adipose tissue. Metformin, The peroxisome proliferator-activated receptor agonists (PPARs) rosiglitazone and pioglitazone appear to have their main effects on skeletal muscle and adipose tissue.

(3) Drugs that principally affect absorption of glucose

(4) Drugs that mimic incretin effects or prolong incretin action. Exenatide and the DPP-IV inhibitors fall into this category.

(5) Other drugs include pramlintide, which lowers glucose by suppressing glucagon and slowing gastric emptying.

(1)Drugs that Stimulate Insulin Secretion

These drugs bind to the sulfonylurea receptor complex of the beta cell.

(a)Sulfonylureas

Mechanism of Action:

Indications:

used in patients with type 2 diabetes used either alone or in combination with other oral agents or insulin. preparations:

a-First-Generation Sulfonylureas (Tolbutamide, Tolazamide, Acetohexamide, and Chlorpropamide)

b-Second-Generation Sulfonylureas: Glyburide, Glipizide, Gliclazide, and Glimepiride

Glyburide (Glibenclamide) DIABIN,GLUCOVANCE

supplied in tablets containing 1.25, 2.5, and 5 mg. The usual starting dose is 2.5 mg/d, and the average maintenance dose is

5–10 mg/d given as a single morning dose. metabolized in the liver into products with such low hypoglycemic activity

that they are considered clinically unimportant unless renal excretion is compromised.

biologic effects of glyburide clearly persist for 24 hours after a single morning dose in diabetic patients.

few adverse effects other than its potential for causing hypoglycemia. It is particularly hazardous in patients over 65 years of age, in whom serious, protracted, and even fatal hypoglycemia can occur even with relatively small daily doses.

Glipizide (Glydiazinamide) Minidiab supplied in tablets containing 5 and 10 mg. should be ingested 30 minutes before breakfast recommended starting dose is 5 mg/d, with up to 15 mg/d given as a

single daily dose. When higher daily doses are required, they should be divided and

given before meals. The maximum recommended dose is 40 mg/d, At least 90% of glipizide is metabolized in the liver to inactive

products, and only a small fraction is excreted unchanged in the urine. Because of its lower potency and shorter half-life, glyburide therapy is

preferable in elderly patients. contraindicated in patients who have hepatic impairment who would

therefore be at high risk for hypoglycemia.

Gliclazide (Not Available in USA) Diamicron available as 80-mg,30MR,60MR tablets(ONCEDAILY,MAX

120mgld). intermediate duration sulfonylurea with a duration of action

of about 12 hours recommended starting dose is 40–80 mg/d with a maximum

dose of 320 mg. Doses of 160 mg and above are given as divided doses

before breakfast and dinner. metabolized by the liver, and the metabolites and

conjugates have no hypoglycemic effect. An extended release preparation is also available.

Glimepiride :Amaryl,Dolcyl in tablets containing 1, 2, and 4 mg. long duration of effect with a half-life of 5 hours,

allowing once-daily administration. A single daily dose of 1 mg/d has been shown to be

effective, and the maximal recommended dose is 8 mg.

completely metabolized by the liver to relatively inactive metabolic products.

(b)Meglitinide Analogs

Repaglinide Novonorm

structure is similar to that of glyburide but lacks the sulfonic acid-urea moiety. acts by binding to the sulfonylurea receptor . rapidly absorbed from the intestine and then undergoes complete metabolism in the

liver to inactive biliary products, giving it a plasma half-life of less than 1 hour. causes a brief but rapid pulse of insulin. supplied as 0.5, 1, and 2 mg tablets. starting dose is 0.5 mg three times a day 15 minutes before each meal. dose can be titrated to a maximum daily dose of 16 mg. Like the sulfonylureas, repaglinide can be used in combination with metformin. Hypoglycemia is the main side effect.Like the sulfonylureas, it causes weight gain. Metabolism is by cytochrome P4503A4 isoenzyme may be useful in patients with renal impairment or in the elderly.

-Phenylalanine Derivative Nateglinide supplied in tablets of 60 and 120 mg binds the sulfonylurea receptor causes a brief rapid pulse of insulin recommended starting and maintenance dosage is 120

mg three times a day before meals. main side effects are hypoglycemia and weight gain.

(2)Drugs that Principally Lower insulin resistance

(a)Biguanides phenformin was discontinued in the USA because of its association with the

development of lactic acidosis in patients with coexisting liver or kidney disease. Metformin:,Glucophage,Cidophage a biguanide that is much less likely to produce lactic acidosis, has replaced

phenformin in the treatment of diabetic patients. primary action is on the liver, reducing hepatic gluconeogenesis half-life of 1.5–3 hours, is not bound to plasma proteins, and is not metabolized in

humans, being excreted unchanged by the kidneys.

Mechanism of Action: The molecular mechanisms of metformin action are not fully known.

1) primary action is on the liver, reducing hepatic gluconeogenesis 2) increases insulin-mediated glucose utilization in peripheral tissues (such

as muscle and liver), particularly after meals.3) antilipolytic effect that lowers serum free fatty acid concentrations,

thereby reducing substrate availability for gluconeogenesis

4) increases intestinal glucose utilization via nonoxidative metabolism, at least in experimental animals . The lactate produced by this process is largely metabolized in the liver as a substrate for gluconeogenesis . The latter effect could protect against hypoglycemia.

5) In case-control and cohort studies in patients with type 2 diabetes, metformin use has been associated with a reduced risk of cancer and lower cancer mortality

Indications type 2 diabetes, particularly those who are obese or

are not responding optimally to maximal doses of sulfonylureas.

improve both fasting and postprandial hyperglycemia and hypertriglyceridemia in obese patients with diabetes without the weight gain .

not indicated for patients with type 1 diabetes

Adverse Reactions The most frequent are gastrointestinal symptoms (anorexia,

nausea, vomiting, abdominal discomfort, diarrhea),dose-related, tend to occur at onset of therapy, and often are transient.

Absorption of vitamin B12 appears to be reduced during chronic metformin therapy, and annual screening of serum vitamin B12 levels and red blood cell parameters has been encouraged by the manufacturer.

Lactic acidosis has been reported as a side effect but is uncommon with metformin in contrast to phenformin.

Hypoglycemia does not occur with therapeutic doses.

ContraIndications diabetic patients with renal insufficiency. patients with hepatic insufficiency or abusers of

ethanol . relatively contraindicated in patients with

cardiorespiratory insufficiency. relatively after the age of 65–70 years.

Dosage dispensed as 500 mg, 850 mg, and 1000 mg,1000XR

tablets. The dosage range is from 500 mg to a maximum of 2550 mg

daily(i.e.850 mg three times a day) little benefit from giving more than 2000 mg daily. important to begin with a low dose and increase the dosage

very gradually in divided doses—taken with meals—to reduce minor gastrointestinal upsets

common schedule would be one 500 mg tablet three times a day with meals or one 850 mg or 1000 mg tablet twice daily at breakfast and dinner.

(b)Peroxisome Proliferator-Activated Receptor Agonists (PPARs)

Thiazolidinediones exert their antidiabetic effects through the activation of PPAR,

which is found predominantly in adipocytes and macrophages. PPAR- activation by polyunsaturated fatty acids and fibrates

increases HDL cholesterol synthesis and reduces triglycerides. Drugs of this class sensitize peripheral tissues to insulin. They regulate the release of the adipokines—resistin and

adiponectin—from adipocytes. Like the biguanides, this class of drugs does not cause

hypoglycemia.

Troglitazone, the first drug in this class to go into widespread clinical use, has been withdrawn from clinical use because of drug-associated fatal liver failure.

rosiglitazone and pioglitazone: Avandia,Diabetinorm Both are effective as monotherapy and in combination with

sulfonylureas, metformin, or insulin.

When used as monotherapy, these drugs lower HbA1c by about 1 or 2 percentage points. When used in combination with insulin, they can result in a 30–50% reduction in insulin dosage, and some patients can come off insulin completely.(About 25% of patients in clinical trials fail to respond to these drugs)

Pioglitazone in clinical trials lowered triglycerides (9%) and increased HDL cholesterol (15%) but did not cause a consistent change in total cholesterol and LDL cholesterol levels.

Adverse Reactions Anemia occurs in 4% of patients( may be due to a

dilutional effect of increased plasma volume ) Weight gain occurs especially when the drug is combined

with a sulfonylurea or insulin. Edema occurs in about 3–4% of patients (more frequently

(10–15%) in patients receiving concomitant insulin therapy and may result in congestive heart failure.

Rosiglitazone has recently been reported as being associated with new onset or worsening macular edema.

ContraIndications NYHA class III and IV cardiac status. FDA has recommended that patients should not initiate

drug therapy if there is clinical evidence of active liver disease or their (ALT) is 2.5 times greater than the upper limit of normal.

Dosage rosiglitazone is 4–8 mg daily and of pioglitazone 15–45 mg

daily do not have to be taken with food.

(3)Drugs that Affect Glucose Absorption

Drugs of this family are competitive inhibitors of intestinal brush border -glucosidases.

Acarbose binds 1000 times more avidly to the intestinal disaccharidases than do products of carbohydrate digestion or sucrose.

Acarbose(Gluobay) available as 50 and 100 mg tablets. recommended starting dose is 50 mg twice daily, gradually

increasing to 100 mg three times daily. For maximal benefit on postprandial hyperglycemia, acarbose

should be given with the first mouthful of food ingested. Adverse Reactions in 20–30% of patients flatulence. In 3% of cases, troublesome diarrhea occurs. When acarbose is given alone, there is no risk of hypoglycemia.

However, if combined with insulin or sulfonylureas, it may increase risk of hypoglycemia from these agents.

Miglitol similar to acarbose in terms of its clinical effects. used in diet- or sulfonylurea-treated patients with type

2 diabetes. initiated at the lowest effective dosage of 25 mg three

times a day. The usual maintenance dose is 50 mg three times a day

should not be used in renal failure because its clearance is impaired in this setting.

(4)Incretins

Oral glucose provokes a 3- to 4-fold higher insulin response than an equivalent dose of glucose given intravenously. This is because the oral glucose causes a release of gut hormones, principally GLP-1 and glucose-dependent insulinotropic polypeptide (GIP1), that amplify the glucose-induced insulin release.

This "incretin effect" is reduced in patients with type 2 diabetes. GLP-1 secretion (but not GIP1) is impaired in patients with type 2 diabetes,

and when GLP1 is infused in patients with type 2 diabetes, it stimulates insulin secretion and lowers glucose levels.

L L L

GLP-1

GLP-1 GLP-

1

InsulinGlucagon

Slowed gastric emptying Early SatietyGLP-1

Incretin Effect: Role of Glucagon-like Peptide -1 (GLP-1)

Mechanism of action in addition to its insulin stimulatory effect It suppresses glucagon secretion and so may ameliorate the

hyperglucagonemia that is present in people with diabetes. GLP-1 preserves islet integrity and reduces apoptotic cell death of human

islets in culture. GLP-1 acts on the stomach delaying gastric emptying—the importance of

this effect on glucose-lowering is illustrated by the observation that antagonizing the deceleration of gastric emptying markedly reduces the glucose lowering effect of GLP-1.

Advantage GLP-1, unlike the sulfonylureas, has only a modest insulin stimulatory effect

at normoglycemic concentrations. This means that GLP-1 administration has a lower risk of causing hypoglycemia than the sulfonylureas.

Exenatide

GLP-1 is rapidly proteolyzed by DPP-IV and therefore would need to be administered as a continuous infusion for clinical effect.

a GLP-1 receptor agonist that is more resistant to DPP-IV action. given to patients with type 2 diabetes by subcutaneous injection twice a

day dispensed as two fixed-dose pens (5 mcg and 10 mcg). It is injected 60

minutes before breakfast and before dinner. The drug is less stable than insulin and needs to be refrigerated between

injections. Adverse Reactions

The main side effect was nausea, affecting over 40% of the patients. The nausea was dose-dependent and declined with time.

The risk of hypoglycemia was higher in subjects on sulfonylureas.

Sitagliptin(Januvia) Oral DPP-IV inhibitors, which work by prolonging the action of

endogenously released GLP-1. A 100 mg dose is given once a day either alone or in

combination with metformin or a thiazolidindione. The drug is removed by the kidney and so the dose is

reduced in renal failure. Adverse Reactions the main adverse reactions reported are ~1.5- to 2- fold

increases in respiratory tract infections, nasopharyngitis, and headaches.

A small increase in neutrophil count has also been noted.

(5)Others

Pramlintide a synthetic analog of islet amyloid polypeptide (IAPP or amylin) when given subcutaneously

1) delays gastric emptying,

2) suppresses glucagon secretion, and

3) decreases appetite. It is approved for use both in type 1 and insulin-treated type 2 patients. The drug is given immediately before the meal by injection.

Adverse Reactions Hypoglycemia can occur, and it is recommended that the short-

acting or premixed insulin doses be reduced by 50% when the drug is started.

Nausea was the other main side effect affecting 30–50% of subjects. It tended to improve with time.

Dosage In patients with type 1 diabetes, pramlintide is initiated at the dose

of 15 mcg before each meal and titrated by 15 mcg increments to a maintenance dose of 30 or 60 mcg before each meal.

In patients with type 2 diabetes, the initiation dose is 60 mcg premeals increased to 120 mcg in 3–7 days if no significant nausea occurs.

Recommendations: Pharmacological Therapy For Type 1 Diabetes

Most people with type 1 diabetes should:• Be treated with MDI injections (3–4 injections per day of

basal and prandial insulin) or continuous subcutaneous insulin infusion (CSII) A

• Be educated in how to match prandial insulin dose to carbohydrate intake, premeal blood glucose, and anticipated activity E

• Use insulin analogs to reduce hypoglycemia risk A

ADA. 7. Approaches to Glycemic Treatment. Diabetes Care 2015;38(suppl 1):S41

• Metformin, if not contraindicated andif tolerated, is the preferred initial pharmacological agent for type 2diabetes A

• In patients with newly diagnosed type 2 diabetes and markedly symptomatic and/or elevated blood glucose levels or A1C, consider insulin therapy (with or without additional agents) E

Recommendations: Pharmacological Therapy For Type 2 Diabetes (1)


Recommendations:Therapy for Type 2 Diabetes (2)

• If noninsulin monotherapy at maximal tolerated dose does not achieve or maintain the A1C target over 3 months, add a second oral agent, a GLP-1 receptor agonist, or insulin A


Recommendations:Therapy for Type 2 Diabetes (3)

• A patient-centered approach should be used to guide choice of pharmacological agents– Considerations include efficacy, cost, potential side effects,

effects on weight, comorbidities, hypoglycemia risk, and patient preferences E

• Due to the progressive nature of type 2 diabetes, insulin therapy is eventually indicated for many patients with type 2 diabetes B


Class Mechanism Advantages Disadvantages CostBiguanides • Activates AMP-kinase

• Hepatic glucose production

• Extensive experience• No hypoglycemia• Weight neutral• ? CVD

• Gastrointestinal• Lactic acidosis• B-12 deficiency• Contraindications

Low

SUs / Meglitinides

• Closes KATP channels• Insulin secretion

• Extensive experience• Microvasc. risk

• Hypoglycemia• Weight gain• Low durability• ? Ischemic preconditioning

Low

TZDs • PPAR-g activator• insulin sensitivity

• No hypoglycemia• Durability• TGs, HDL-C • ? CVD (pio)

• Weight gain• Edema / heart failure• Bone fractures• ? MI (rosi)• ? Bladder ca (pio)

High

a-GIs • Inhibits a-glucosidase• Slows carbohydrate absorption

• No hypoglycemia• Nonsystemic• Post-prandial glucose• ? CVD events

• Gastrointestinal• Dosing frequency• Modest A1c

Mod.

Class Mechanism Advantages Disadvantages CostDPP-4inhibitors

• Inhibits DPP-4• Increases GLP-1, GIP

• No hypoglycemia• Well tolerated

• Modest A1c • ? Pancreatitis• Urticaria

High

GLP-1 receptor agonists

• Activates GLP-1 R• Insulin, glucagon• gastric emptying• satiety

• Weight loss• No hypoglycemia• ? Beta cell mass• ? CV protection

• GI• ? Pancreatitis• Medullary ca• Injectable

High

Amylin mimetics

• Activates amylin receptor• glucagon• gastric emptying• satiety

• Weight loss• PPG

• GI• Modest A1c • Injectable• Hypo w/ insulin• Dosing frequency

High

Bile acid sequestrants

• Bind bile acids• Hepatic glucose production

• No hypoglycemia• Nonsystemic• Post-prandial glucose• CVD events

• GI• Modest A1c• Dosing frequency

High

Dopamine-2agonists

• Activates DA receptor• Modulates hypothalamic control of metabolism• insulin sensitivity

• No hypoglyemia• ? CVD events

• Modest A1c• Dizziness/syncope• Nausea• Fatigue

High

Class Mechanism Advantages Disadvantages CostInsulin • Activates insulin

receptor• peripheral glucose uptake

• Universally effective• Unlimited efficacy• Microvascular risk

• Hypoglycemia• Weight gain• ? Mitogenicity• Injectable• Training requirements• “Stigma”

Variable

Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Antihyperglycemic Therapy inType 2 Diabetes

ADA. 7. Approaches to Glycemic Treatment. Diabetes Care 2015;38(suppl 1):S43. Figure 7.1; adapted with permission from Inzucchi SE, et al. Diabetes Care, 2015;38:140-149

Approach To Starting and Adjusting Insulin in Type 2 Diabetes

ADA. 7. Approaches to Glycemic Treatment. Diabetes Care 2015;38(suppl 1):S46. Figure 7.2; adapted with permission from Inzucchi SE, et al. Diabetes Care, 2015;38:140-149

Insulin Therapy Indications

(1) When significant hyperglycemia (metabolic derangement) is present at diagnosis (e.g., HbA1c

≥10%); or fasting plasma glucose (FPG) is >13.9 mmol/L (>250 mg/dl) or random glucose is >16.7 mmol/L (>300 mg/dl)

(2) When symptomatic (e.g., sudden persistent weight loss, ketosis)

(3) When multiple non-insulin therapies fail to achieve individualized glycemic targets

(4) When rapid achievement of glucose control is desired (e.g., to induce “clinical remission,” see Module 2)

HbA1c ≥ 9%

Insulin as initial drug

therapy

Insulin is strongly

considered Insulin is

mandatory

Significantly hyperglycemic symptoms

PG > (300-350 mg/dl)

HbA1c ≥ (10-12%)

When it is the time for insulin!!

Catabolic features are exhibited

Ketonurea is demonstrated

American Diabetes Association. Diabetes Care. 2012;35:1364-1379

Insulin as 3rd drug agent to

two drug combination

HbA1c ≥ 8.5%

Preparation for Insulin Initiation

Clinicians are required to:

1. Identify the glycemic defect (i.e., periods of hyperglycemia—fasting hyperglycemia, postprandial hyperglycemia, and overall glycemic derangement)

2. Address the concerns of the person with diabetes (see Module 6)

3. Select the appropriate insulin regimen and insulin-delivery device

4. Review/adjust non-insulin therapies

5. Assess the risk of hypoglycemia

6. Review diet and activities of daily living

Clinical Effectiveness-Glycemic Response and Attainment of A1C Goals Following Newly

Initiated Insulin Therapy for Type 2 Diabetes

Nicholls et al. Diabetes Care 35:495–497, 2012

Basal Insulin

Basal insulin in type 2 diabetes(e.g. LA 0.1-0.2 U/kg or 10U)

Non-insulin therapies

LA = Long-Acting insulin: Glargine, Detemir

Basal Insulin in Type 2 Diabetes

Basal Insulin Options

Glargine and Detemir:• Lasts up to 24 hours; BID dosing may be required (less

common in T2DM vs. T1DM) • Decreases risk of hypoglycemia (especially nocturnal)• Less weight gain• Less variability in effect

Neutral Protamine Hagedorn (NPH):• Lasts 10–16 hours• Peaks 8–10 hours• Less expensive• May partly cover meal (e.g., breakfast if taken in morning)

but can result in later hypoglycemia (e.g., early afternoon)

Riddle et al. Diabetes Care. 26:3080-3086; 2003Raskin et al Diabetes Care. 28:260-265; 2005

8.5

9.0

8.0

7.5

7.0

6.5

0 4 8 12 16 20 24

HbA

1c (%

)

NPH + OADInsulin glargine + OAD

Weeks

0

2

4

6

8

10

12

14

16 21% risk reduction p <0.02

42% risk reduction p

<0.01

Overall Nocturnal Hypoglycemia

Eve

nts

per

patie

nt p

er y

ear

Insulin Glargine vs. NPH in Treat-to-Target Trial: HbA1c and Hypoglycemia

Riddle et al. Diabetes Care 2003;26:3080-6.

Insulin Detemir vs. NPH in Treat-to-Target Trial: HbA1c and Hypoglycemia

Hermansen et al. Diabetes Care 29:1269, 2006

-2 0 12 24

8.5

9.0

8.0

7.5

7.0

6.5

HbA

1c (%

)

Weeks

NPH + OADInsulin detemir + OAD 47% risk reduction

p < 0.001

Even

ts p

er p

atie

nt p

er y

ear

55% risk reduction p < 0.001

0

2

4

6

8

10

12

14

16

18

Overall Nocturnal Hypoglycemia

• Most insulin regimens take into account the individual’s weight at initiation because doing so will help prevent adverse reactions caused by over-insulinization (most notably hypoglycemia and weight gain).

• Basal insulin is typically begun at a low dose (e.g., 0.1–0.2 units/kg per day).

• The most convenient strategy is with a single injection of basal insulin administered before the evening meal or at bedtime, at an initial dose of 0.1units/kg. This will ensure that changes in blood glucose levels will be gradual.

• Under special conditions, such as significant hyperglycemia (HbA1c ≥9%) and/or obesity, a starting dose of 0.2 units/kg may be used.

• An alternative, non-weight-based option is to start most individuals empirically with 10 units, or in obesity up to 20 units, of basal insulin (i.e., long-acting or intermediate-acting).

Initiating Basal Insulin

Advancing Basal InsulinIf most AM fasting BG >120 mg/dL (>6.7 mmol/L)

Titrate until fasting glucose at target BG • Increase 2 units [or 4 units if FBG >180 mg/dl or 10 mmol/L] every 3 days• If dose reaches ~0.5 units/kg body weight, consider adding mealtime insulin

If most AM fasting BG <120 mg/dL (<6.7 mmol/L) and A1C remains above target

Test pre–evening meal and bedtime (or 2-hour post–evening meal) and consider need for mealtime insulin

If hypoglycemia or FPG < 70 mg/dL

Reduce insulin dose by 3 units or 10%, whichever is greater

Premixed Insulin

Insulin Analog Mix 75/25 or 70/30

Starting Premixed Insulin Analogue Regimen

Relatively easy to use Covers insulin

requirements through most of day

Not very physiological Less flexibility than

basal(±bolus) Greater likelihood of

hypoglycemia More weight gain than

basal Emerging evidence

supports better A1C reduction with basal/bolus

Premixed Insulin Therapy

Supporting Evidence Non-supporting Evidence

• Most insulin regimens take into account the individual’s weight at initiation because doing so will help prevent adverse reactions caused by over-insulinization (most notably hypoglycemia and weight gain).

• When using premixed insulin, insulin secretagogues are often discontinued and other non-insulin therapies should be reconsidered.

• The effectiveness of these medications should be reconsidered in light of the action of the premixed insulin.

• If the HbA1c is ≥9%, the starting dose of premixed insulin is 0.2 units/kg before the morning and evening meals (total daily dose 0.4 units/kg).

• If the HbA1c is <9%, the starting dose is 0.1 units/kg before the morning and evening meals (total daily dose 0.2 units/kg).

• Based on glucose monitoring, premixed insulin adjustments of 2 units is typically recommended.

Initiating Premixed Insulin

Part 4: Advancing Insulin Therapy

Rapid-acting insulin at meals Long-acting insulin at bed

Starting a Basal and Mealtime (e.g., Basal-bolus) Insulin

Regimen

Advancing Insulin Therapy from Basal Insulin

Halt or decrease all insulin secretagogues

TZDs are often reduced or stopped due to risk of hypoglycemia, excessive weight gain, edema, and/or heart failure

Initiate SMBG before each meal (injection)

Consider reducing total basal dose by 0.1 units/kg

Identify highest consistent post meal glucose or biggest meal

Start with 0.1 units/kg or 4 units short- or rapid-acting insulin

The dose can be further modified by adding 2 units of short- or rapid-acting insulin every 3 days until postprandial glucose is ≤180 mg/dl (10 mmol/l) as per local titration guidelines.

Titrate to 0.2 units/kg, and if the target has not been reached consider dietary modifications and/or the addition of a second bolus injection and subsequent injection to full basal-bolus insulin regimen if needed

Adapted from Howey DC, et al. Diabetes. 1994;43(3):396-402

Hours

10

8

6

4

2

0

0 1 2 3 4 5 6 7 8 9 10 11 12

Insu

lin A

ctiv

ity RHI

Timing offood

absorbed

Analog Insulin

Rapid-acting Insulin Analogues VersusShort-acting Insulin

RHI = regular human insulin.

• A basal/bolus insulin regimen can be considered at diagnosis when rapid achievement of glucose control is desired (e.g., symptomatic, or to induce “clinical remission,” see Module 2).

• Basal/bolus regimens can also be considered when the combination of basal or premixed insulin and non-insulin therapies are no longer effective.

• The minimal starting total daily dose is 0.2 units/kg divided as 50% long- or intermediate-acting and 50% short- or rapid-acting insulin.

• The basal and bolus doses can be titrated separately. Adequate glucose monitoring should be consistent with clinical needs and safety.

• It is recommended that this intensive insulin regimen should be initiated and supervised by a specialist with expertise in diabetes.

• An additional option for intensive insulin therapy is premixed insulin 2–3 times daily (see previous section on starting and adjusting premixed insulin).

Initiating Basal-Bolus Insulin Regimen

Starting Basal + Bolus (mealtime) Insulin:

A1C <9% A1C ≥9%Basal-Bolus

insulin0.2 units/kg/ day

Basal 0.1 units/kg +

Mealtime 0.1 units/kg

0.4 units/kg/dayBasal 0.2 units/kg

+Mealtime 0.2

units/kg

• Stop or reduce insulin secretagogue• TZDs are often reduced or stopped due to risk of hypoglycemia,

excessive weight gain, edema, and/or heart failure• Select and calculate starting dose• Divide 50% background, 50% mealtime

Mazze R, et al. Staged Diabetes Management Adult Quick Guide, 5th Edition Revised, 2010International Diabetes Center

Calculating Basal + Mealtime Insulin Dose:

Calculate insulin doseWeight in kg ______ x units/kg _____ = _____units long-acting (LA)

x units/kg _____ = _____units rapid-acting (RA)

Example: T2DM Patient (80 kg) with A1C of 9.6% on metformin and insulin secretagogue

80 0.2 16

Plan Insulin AM Noon PM BedLA 16RA 5 5 6

0.2 16

Total starting dose = 0.2 units/kg

Improvement in HbA1c with Basal-Bolus Insulin Regimen (Glargine/Glulisine)

The majority of patients achieved HbA1c <7.0% Simple algorithm: 73.0% CHO counting: 69.2%

p = NS

Simple algorithm

CHO counting

Bergenstal RM, Johnson M, Powers M et al. Diabetes Care 2008;31:1305–10.

8.167.86

7.3

6.796.64 6.54

8.167.94

7.40

6.88 6.76 6.70

6.0

6.5

7.0

7.5

8.0

8.5

Baseline 2 6 12 18 24

HbA

1c (%

)

Week

The Role of Insulin Therapy

Relative InsulinDeficiency

Pre-diabetes and Type 2 Diabetes

InsulinResistance

Incretin DysfunctionInsulinDeficiency

Type 1 Diabetes

Critical role in both Type 1 and Type 2 diabetes• Greatest potency of available therapies• Demonstrated benefit – multiple clinical trials

Normal Insulin Secretion

Mealtime (bolus) insulin needs ~ 50%

Background (Basal) Insulin Needs ~ 50%

Kruszynska et al. Diabetologia 30: 16-21, 1987Polonsky et a. J. Clin. Invest. 81: 442-48, 1988

Time

Insulin Therapy Nomenclature• Basal insulin – long-acting insulin that is used to provide a background level

of insulin throughout the day and night.

• Bolus insulin – short- or rapid-acting insulin that is used to provide an increased level of insulin for a short period.

• Prandial insulin – bolus insulin administered prior to a meal.

• Correction insulin - bolus insulin administered to lower a high blood glucose level.

• Pre-mixed (or Biphasic) insulin- combination of short- or rapid-acting and intermediate or long-acting insulin used to try to cover both fasting and prandial insulin needs

Insulin Therapy Options

• Basal insulin only

• Bolus (Prandial) only

• Premixed

• Basal plus limited-meal bolus (‘Basal plus’)

• Basal-Bolus (i.e. multiple daily injections - MDI)

• Basal-Bolus (i.e. continuous subcutaneous insulin infusion [CSII], “Insulin Pump”)

Action Profiles of Injectable Insulins in T2DM Patients

• Bariatric surgery may be considered for adults with BMI > 35 kg/m2 and type 2 diabetes, especially if diabetes or associated comorbidities are difficult to control with lifestyle and pharmacological therapy B

• After surgery, life-long lifestyle support and medical monitoring is necessary B

• Insufficient evidence to recommend surgery in patients with BMI <35 kg/m2 outside of a research protocol E

Recommendations: Bariatric Surgery


Health & Medicine

Diabetes in clincal practice 2015