dm 1 1

DIABETES MELLITUSRabia Tahir, Pharm.D.

Department of Veterans AffairsNYHHCS

Objectives

Identify the development of signs and symptoms of diabetes mellitus.

List diagnostic criteria for diabetes mellitus. Identify complications and risks of

concurrent disease states due to diabetes mellitus.

Discuss management of diabetes mellitus and complications.

Definition

Diabetes Mellitus (DM) is a group of metabolic diseases characterized by hyperglycemia and abnormalities in carbohydrate, fat and protein metabolism.

DM is a result of defects in insulin secretion, insulin sensitivity, or both.

DM leads to microvascular, macrovascular, and neuropathic complications.

Pathogenesis

Type 1:Type 1: Due to the cellular-mediated autoimmune destruction of pancreatic ß-cells resulting in a complete absence of insulin secretion. Process is likely initiated by exposure of a genetically susceptible individual to an environmental agent. There is a long preclinical phase and a transient remission followed by established disease.

Type 2:Type 2: Due to insulin resistance and relative insulin deficiency. Usually there is an impairment in insulin secretion, resulting in the inability of ß-cells to compensate for the insulin resistance. Insulin resistance is manifested by increased lipolysis and free fatty acid production, increased hepatic glucose production, and decreased skeletal muscle uptake of glucose. ß-cell dysfunction is progressive and contributes to worsening blood glucose over time.

CharacteristicsType 1Type 1 Type 2Type 2

Percentage 10% 90%

Age at onset Usually childhood or adolescent, but can occur at any age

Usually >40years old but growing prevalence among obese children

Family history Generally not strong Strong

Obesity Uncommon Common (60-90%)

History of ketoacidosis Common Rare, unless under stress (e.g. infection)

Clinical presentation Moderate to severe symptoms, usually progressing rapidly

Mild symptoms, progressing gradually, but Pts may often be asymptomatic

Development of Signs and Symptoms

Insulin cannot be utilized → cells cannot take up glucose from the blood → hyperglycemia → the capacity for glucose reabsorption by the kidney is exceeded → glucose spills into urine → osmotic diuresis → polyuria.polyuria.

Polyuria → dehydration → polydipsia polydipsia Type 1 DM is also associated with fatigue, fatigue,

weight loss, polyphagiaweight loss, polyphagia, and diabetic diabetic ketoacidosis (DKA). ketoacidosis (DKA).

Role of Insulin

After meal is eaten → blood glucose rises, simulating beta cells to release insulin. Insulin serves three main purposes:

1. Promotes conversion of glucose to glycogen in the liver.

2. Promotes incorporation of fatty acids into TGs in adipose tissue.

3. Promotes incorporation of amino acids into protein in muscle.

Thus insulin prevents breakdown of glycogen, fat, and proteins.

Three Sources of Energy Carbohydrate (body’s main source of energy) Fat ProteinWhen insulin is deficient, the body’s cells can not

utilize glucose for energy. The body responds by breaking down:

Glycogen → glucose (worsening hyperglycemia) Lipids → glycerol and free fatty acids →

gluconeogenesis (further worsening hyperglycemia) & ketone production.

Protein → amino acids → gluconeogenesis (further worsening hyperglycemia).

Criteria For Testing: Asymptomatic, Undiagnosed

Individuals Type 1: Due to low prevalence and acuteness of

symptoms, screening is not recommended. Routine testing for immune markers is not recommended outside of a clinical trail setting due to.

1. Cut off values for immune markers assays have not been established.

2. No consensus as to what action should be taken when a positive autoab test result is obtained.

Type 2: Testing should be done for all individuals ≥ 45 years of age and if normal should be repeated every 3 years. Testing should be considered at a younger age, or carried out more frequently in individuals who at a higher risk for diabetes.

Diagnosis of Diabetes Mellitus

Results must be confirmed by any of the three criteria on a separate day.

Fasting plasma glucose(FPG)

Casual plasma glucose

Oral glucose tolerance test (OGTT)

Diabetes FPG ≥ 126mg/dL Glucose level ≥ 200mg/dL AND symptoms of DM

2-hr plasma glucose (2hPG) ≥ 200mg/dL

Impaired Glucose Homeostasis

Impaired fasting glucose (IFG) is when FPG is ≥ 100 and < 126mg/dL

Impaired glucose tolerance (IGT) is when 2hPG ≥ 140 and < 200mg/dL

Normal FPG < 100mg/dL 2hPG < 140mg/dL

Diagnosis of Diabetes Mellitus

Fasting is defined as no caloric intake for at least 8 hours. FPG is the preferred test because its easy, convenient, inexpensive, more reproducible, and more acceptable to the Pt.

Casual is defined as any time of the day without regard to time of last meal. Classic symptoms include polyuria, polydipsia, and unexplained weight loss.

For OGTT, Pt must fast for at least 8 hours, then receive a glucose load of 75g anhydrous glucose dissolved in water. The plasma glucose is measured every 30 min for 2 hours. OGTT is not recommended for routine clinical use.

Each test must be confirmed on a subsequent day. HbA1C is not recommended for diagnosis, but is the gold

standard for long term monitoring.

Risk Factors for Type 2 DM Family history (1st degree relative: parents or siblings). Overweight (BMI ≥ 25kg/m²) or Obesity (BMI ≥ 27kg/m²). Member of high risk ethnic group (Native Americans,

Hispanic Americans, Africans Americans, and Pacific Islanders).

Previously identified impaired glucose tolerance or impaired fasting glucose.

HTN (BP ≥ 140/90 mmHg). HDL ≤ 35 mg/dl and/or TG ≥ 250 mg/dl. History of gestational diabetes mellitus or delivery of a baby

weighing > 9 lbs.

Complications of DM HTN and dyslipidemia are commonly found in

diabetic Pts, which further contribute to complications → therefore, these comorbid conditions must also be managed to prevent the onset or progression of diabetic complications.

Complications of long term hyperglycemia Complications of long term hyperglycemia include: include:

Macrovascular effects:Macrovascular effects: Large vessels involved are coronary, cerebral, and peripheral vessels. These vessels are more likely to undergo occlusion, resulting in → CAD, CVD, and PVD.CAD, CVD, and PVD.

Complications of DM (cont.)

Microvascular effects:Microvascular effects: Structural damage occurs in the arterioles and capillaries mainly in the eyes, kidneys, and nerves. As a result the diabetic Pt are prone to: Retinopathy: if untreated → blindness Nephropathy: results in proteinuria and ↓ GFR.

If untreated → renal failure. All diabetic Pts with nephropathy should take an ACE inhibitor or angiotensin receptor blocker (ARB) to reduce glomerular capillary pressure → slowing progression of renal disease.

Complications of DM (cont.)

Microvascular effects (cont): Microvascular effects (cont): Neuropathy

1. Peripheral neuropathy: initial symptoms may be painful tingling or burning, progressing to a loss of sensation. These conditions along with impaired circulation, leads to increased risk of injury and infection, especially of the feet and lower extremities, possibly resulting in amputation.

2. Autonomic neuropathy: nerve conduction in the ANS is impaired resulting in genitourinary abnormalities (neurogenic bladder), sexual dysfunction (impotence), and GI abnormalities (gastroparesis).

Diabetic Ketoacidosis (DKA)

Pathophysiology: Initiated by insulin deficiency and an ↑ in counterregulatory hormones (glucagon, catecholamines, cortisol) stimulating the production of glucose and ketoacids. Since glucose is unavailable as a source of energy → break down of glycogen, lipids, and protein in liver → ketone production due to lipolysis → ketones build up in the blood and "spill" over into the urine → ketonemia and ketonuria → blood becomes more acidic than body tissue → acidosis.

Usually precipitated by a stressful event → trauma, infection, surgery or myocardial infarction; characteristic of an ↑ release of cortisol, glucagon, and catecholamines.

Clinical presentation: DKA affects electrolyte balance, fluid levels, renal function, and CNS. Hyperglycemia → osmotic diuresis → dehydration. DKA can cause nausea and vomitting, worsening dehydration. ↑ fluid elimination → hypovolemia → ↓ GFR → serum hyperosmolality → hyperventilation and altered mental status.

Diabetic Ketoacidosis (DKA)

Clinical presentation (cont.): ↑ ketones → lethargy, fruity odor in breath, abdominal pain, polydipsia, polyuria, dry skin, and tachycardia.

Diagnosis: Testing ketones in urine, serum bicarbonate levels, and ph of blood.

Treatment: IV fluid replacement (to correct dehydration and hyperglycemia) with

normal saline (2-3L over first 3 hours). Insulin (↓ plasma glucose and ketone level) continuous infusion (0.1

units/kg). Electrolyte replacement, especially Na & K (to prevent development

of CV problems). Routine use of bicarbonate is not recommended, but can be used in

critical patients if their acidosis was not corrected with hydration and insulin.

Asses the cause of DKA (trauma, infection, non-compliance with meds).

Patients should be monitored closely.

Risk of CHD

According to the National Cholesterol Education Program (NCEP) guidelines (ATP III):

DM is considered to be a CHD risk equivalent, placing Pts in the highest risk category for the development of CHD.

CHD risk equivalent signifies that the risk of a major coronary event is equal to that of established CHD.

Therefore it is important to aggressively treat DM, as well as any other risk factors diabetic Pts may have, to reduce the risk of coronary event.

Aspirin (ASA) has been proven to reduce the risk of MI and strokes. Therefore all diabetic Pts should receive ASA 81 - 325 mg daily, unless contraindicated.

Metabolic Syndrome The most widely used criteria to define this syndrome was

published as part of the National Cholesterol Education Program Adult Treatment Panel III for the treatment of hypercholesterolemia.

ATP III diagnosis of metabolic syndrome → three out of five criteria present.

Commonly seen in diabetic Pts and consists of a combination of features including: Central obesity HTN Dyslipidemia (↑ TGs, ↑ small dense LDL, ↓ HDL) Insulin resistance, hyperinsulinemia, hyperglycemia Polycystic ovary syndrome (PCOS) ↑ plasminogen activator inhibitor type 1 (PAI-1) → clotting

abnormalities by inhibiting fibrinolysis.

Diagnosis of Metabolic Syndrome

Three or more parameters must be present for diagnosis

ParameterParameter CriteriaCriteria

Waist circumference Male > 40 inches

Female > 35 inches

Triglycerides level ≥ 150 mg/dl

HDL level Male < 40 mg/dl

Female < 50 mg/dl

Blood pressure ≥ 135/85 mmHg

FPG ≥ 110 mg/dl

Management of Dyslipidemia

In Type 2 DM Pts → insulin resistance, relative insulin deficiency, and obesity is associated with ↑ TGs and ↓ HDL.

Secondary Prevention of CHDSecondary Prevention of CHD The Scandinavian Simvistatin Survival Study (4S trial)The Scandinavian Simvistatin Survival Study (4S trial) → Pts

with diabetes or IFG treated with simvistatin, resulted in significant reduction (42%) in major coronary events, revascularizations, and total and coronary mortality when compared to placebo.

CARECARE → Pts with diabetes or IGT treated with pravastatin, showed a decreased rate of cardiac events when compared to placebo.

CARE and LIPIDLIPID → Diabetic Pts with low LDL concentrations taking pravastatin, showed a significant reduction of coronary events as compared to nondiabetic Pts with low LDL concentrations taking placebo.

Neither the 4S trial or CARE trial evaluate the efficacy of treating hypertriglyceridemia (the most common abnormality in diabetic Pts) → whether correction of ↑ TGs is beneficial remains unproven.


Primary Prevention of CHDPrimary Prevention of CHD Heart Protection StudyHeart Protection Study → Diabetic Pts (including those

with no know history of CV disease and normal LDL levels) on simvastatin therapy showed reduced risk of major vascular surgery events.

CARDS → Diabetic Pts with normal LDL levels → rate of CV events ↓ by 37%, rate of CHD ↓ by 36%, rate of coronary revascularization ↓ by 31%, rate of stroke ↓ by 48%, and rate of death ↓ by 27% in diabetic Pts taking atorvastatin. Atorvastatin therapy appears to be effective for the primary

prevention of CV events in Pts with Type 2 DM with normal LDL but at least one risk factor for CV disease.

Preliminary clinical evidence that lipid lowering may slow the rate of progression of diabetic nephropathy.


Goal values Primary goal is reduction of serum LDL

concentrations. ADA recommends a target goal for LDL of < 100 mg/dl.

Behavioral intervention should be initiated when LDL is ≥ 100 mg/dl. Drug therapy should be started in Pts who do not achieve goal with lifestyle modifications.

2004 ADA guidelines recommend in adults with diabetes over age 40 and with total cholesterol ≥ 135mg/dl, statin therapy to achieve LDL reduction of approx. 30% regardless of baseline LDL, is appropriate.

ATP III states diabetes is a risk equivalent and serum LDL goal is < 100 mg/dl. Drug therapy in combination with lifestyle changes is recommended if serum LDL ≥ 130 mg/dl and is optional at values between 100 and 129 mg/dl if goal is not achieved by nonpharmacologic means.


Goal values Conflicting recommendations concerning

drug therapy for hypertriglyceridemia. ATP III guidelines emphasize the treatment of serum

non HDL cholesterol (non HDL goal < 130mg/dl) in diabetic Pts with serum TG above 200 mg/dl.

ADA recommends treatment of serum TG concentrations between 200 and 400 mg/dl, be left to the discretion of the physician but puts second priority on raising HDL levels.


In diabetic Pts lifestyle modifications is an important part of therapy due to obesity, physical inactivity, and high fat diet contributing to TG elevation and HDL reductions.

Choice of lipid lowering agent should depend on how much each lipoprotein (LDL, TGs and HDL) needs to be altered to achieve target levels.

Use of Lipid Lowering Agents in Diabetic Dyslipidemia

HMG-CoA reductase inhibitors (aka statins): first choice for LDL lowering. Statins ↓ LDL by 18-55%, ↑ HDL by 5-15%, and ↓ TGs by 7-30%. Caution due to myopathy and hepatotoxicity, especially if combined with interacting drugs (e.g. CYP450 3A4 inhibitors)

Fibric acid derivatives: ↓ LDL by 5-20%, ↑ HDL by 10-20%, and ↓ TGs by 20-50%. Use commonly when TGs need to be significantly lowered and/or HDL needs to elevated. If combined with a statin → increased risk of myopathy.

Use of Lipid Lowering Agents in Diabetic Dyslipidemia

Bile acid binding resins: ↓ LDL by 15-30%, ↑ HDL by 3-5%, and ↑ TGs. Usually avoided because of intolerability (bloating, constipation, flatulence) and many drug interactions (digoxin, warfarin, levothyroxine, etc.)

Nicotinic acid: ↓ LDL by 5-25%, ↑ HDL by 15-35%, and ↓ TGs by 20-50%. Effective in elevating HDL and reducing TGs. Not a favorable agent in diabetes because it can cause insulin resistance and may elevate blood glucose. Many other side effects as well (flushing, HA, hyperuricemia, peptic ulcers, urticaria, etc.). If combined with statin → increased risk for hepatotoxicity.

Management of HTN in Diabetics

UKPDS and HTN Optimization Treatment: HTN ↑ micro. and macrovascular risks in diabetic Pts.

Pathogenesis: diabetic nephropathy, hyperinsulinemia, volume expansion and increased arterial stiffness.

Treatment: Early treatment is important to prevent CV disease and to minimize progression of renal disease and diabetic retinopathy. Initial therapy → nonpharmacologic methods → weight reduction,

exercise, sodium restriction, smoking cessation and strict alcohol consumption.

Diabetic Pts with BP > 130/80 mmHg are at ↑ of CV complications → should begin antihypertensive drug therapy also.

Normal < 140/90 mmHg Systolic BP Diastolic BP

Goal for diabetic HTN (ADA)

< 130 mmHg < 80 mmHg

Choice of Antihypertensive Agents

ALLHATALLHAT → high risk Pts, including diabetics, have a better CV outcome with a thiazide than an ACE.

SHEPSHEP → low dose thiazide is beneficial in older diabetic Pts wIth isolated systolic HTN.

ACE inhibitors offer a number of advantages → lowers BP, no specific toxicity, no adverse effects seen on lipid metabolism, and may lower plasma glucose concentrations by increasing responsiveness to insulin. HOPEHOPE → ramipril in diabetic Pts, lowered the incidence of MI,

stroke, and total mortality. Number of trails of Pts with HTN or CV disease has shown that ACE

inhibitors and ARBs significantly reduce the incidence of new onset Type 2 DM, protect against the development of progressive neuropathy, due to Type 1 and 2 DM, and may slow the progression of retinopathy.


IDNTIDNT and RENAALRENAAL → clear benefit, in terms of renoprotection with ARBs in Pts with nephropathy due to Type 2 DM, but neither study showed significant CV reduction.

LIFE LIFE → efficacy of ARB was compared with a beta blocker, reported significant reduction in CV M&M with losartan compared to atenolol, in a subset of high-risk Pts with moderate HTN and LVH.

LIFELIFE → ARBs significantly reduced the incidence of new onset Type 2 DM.

LIFE LIFE → losartan provided significantly more protection from adverse CV outcomes than atenolol.

ABCDABCD and FACETFACET → increased CV complications with dihydropyridine Calcium channel blockers compared to ACE inhibitors.

UKPDSUKPDS → atenolol was as effective as captopril in Type 2 DM Pts in terms of both BP lowering and protection against microvascular disease.


Goal BP reduction HOT → Lower target diastolic pressure has a

cardioprotective effect in diabetics and a diastolic pressure of 80 rather than 85 mmHg should be the preferred goal.

ABCD and UKPDS → showed similar observations in terms of a lower target BP (lowest risk occurs with a SP < 120 mmHg- UKPDS).

Recommendations ADA: Initial drug therapy may be with ACE inhibitor,

ARBs, Beta blockers, or diuretics. However because ACE inhibitors and ARBs have shown to benefit both macrovascuar and microvascular complications in Pts with HTN → routinely choosing an ACE inhibitor or ARB as first line agent in diabetic Pts is reasonable.


Recommendations ACE inhibitor should be strongly considered in

HTN Pts with microalbuminuria or clinical albuminuria.

Choice of initial therapy may not have great clinical relevance since combination therapy will be likely required to achieve goal BP.

BP goals are generally more difficult to achieve than glycemic goals or lipid goals in most diabetic Pts.

Summary of Recommendations for Adults with DM

Endpoint Target

HbA1C < 7%

Preprandial glucose

< 120 mg/dl

2hrPG < 140 mg/dl

Bedtime glucose 100- 120 mg/dl

BP < 130/80 mmHg

Weight BMI ≤ 25 kg/m²

Tot. Chol. < 200 mg/dl

Endpoint Target

LDL < 100 mg/dl

HDL Male > 45 mg/dl

Female > 55 mg/dl

TGs < 150 mg/dl

Salt intake ≤ 6g NaCl/d or ≤ 2g Na/d

Smoking Cessation

Alcohol intake ≤ 1 oz ethanol/day

Glycosylated Hemoglobin (Hemoglobin A1C)

On the hemoglobin chain, glucose binds irreversibly to A1C fragment. Therefore, HbA1C test represents the % of HbA1C that is glycosylated.

Average RBC lifespan is 120 days, HbA1C value reflects the average blood glucose over the past 3-4 months. Normal HbA1C value is < 6%.

Each % represents 30-35 mg/dl increment in mean blood glucose.

ADA guidelines: HbA1C test should be performed every 3 months. Should be performed at least 2x a year in Pts meeting treatment goals and quarterly in Pts whose therapy has changed or are not meeting glycemic control.

Overview of DM Management

Treatment regimens should be individualized Type 1 DM

Lifetime insulin therapy is necessary for survival. Lifestyle modification (diet and exercise).

Type 2 DM Diet and exercise are the mainstay of therapy. Oral medications (SU, biguanides, TZD, meglitinides,

alpha glucosidase inhibitors). Insulin

Comorbid conditions especially HTN and dyslipidemia must also be treated.

Lifestyle Modifications

Medical Nutrition Therapy (MNT)Nutrient Recommended IntakeCarbohydrate ~50-60% of total calories

(percentage varies with tx goal)Protein 15-20% of total cal.Total fat 25-35% of total cal.Saturated fat < 10% of total cal (< 7% in

dyslipidemia)Polyunsaturated fat ~10% of total cal.Monounsaturated fat Upto 20% of total cal.Cholesterol < 300 mg/d (< 200 mg/d in

dyslipidemia)Total calories Adjust based on age, weight and

height.

Lifestyle Modifications

Decreasing caloric intake → weight loss Exercise recommendation:

ADA: 30-60 min. of aerobic activity 3-4 times a week Surgeon General Report: Accumulate 30 min. of

moderate physical activity on most days of the week. Exercise → improves glycemic control, BP, lipid

profile and weight loss. Weight loss → ↑ sensitivity of peripheral insulin

receptors to endogenous and exogenous insulin. Exercise regimens should be individualized.

Oral Drug Therapy for Diabetes

Sulfonylureas: 1st and 2nd generations. Meglitinides Biguanides

Thiazolidinediones α-Glucosidase Inhibitors

Insulins (refer to handout)

Sulfonylureas MOA: ↑ insulin release from pancreatic β-cells. Minor effects include ↓ hepatic

glucose output and ↑ peripheral glucose utilization. AE’s:

Hypoglycemia – with especially long acting agents (highest with glyburide, and lowest with tolbutamide) and with individuals that are at high risk.

Elderly, skipping meals, exercising vigorously, loss of weight Weight gain GI disturbances (nausea, heartburn) Rash Disulfiram reaction and SIADH are mostly associated with chlopropamide

Role in therapy: Commonly prescribed as initial drug therapy. Useful only in patients with some ß-cell function. Most likely to be effective in patients whose weight is normal or slightly

increased. All SU are equally effective in lowering blood glucose when administered in

equipotent doses. HgA1C has been showned to decrease by 1.5-2% and FPG by 60 to 70mg/dL. UKPDS → SU showed reduction of microvascular complications.

Sulfonylureas Advantages: Very effective, many can be dosed once daily, rapid onset

of effect (1 week), inexpensive. Disadvantages:

Risk of hypoglycemia (especially in elderly). Weight gain Effectiveness may ↓ after five years of treatment; addition of a second

agent or insulin therapy is often necessary. SU may be associated with poorer outcomes after a myocardial

infarction due to worse left ventricular function (SU at the time of a MI, prevents adequate coronary vasodilation and thus may result in a larger area of myocardial damage)

Preparations: Different SU’s are equally effective in lowering blood glucose

concentrations, however there are differences in absorption and metabolism, as well as in effective dosage.

2nd gen. agents are more potent, longer-acting, equal in efficacy, and cause fewer adverse effects (except for hypoglycemia) compared to 1st gen. agents.

Sulfonylureas Pharmacokinetics:

SU’s undergo liver metabolism. Therefore, be cautious in hepatic impairment.

Most 1st gen. metabolites are metabolized to active and inactive metabolites, whereas 2nd gen. agents are metabolized to only inactive compounds. Metabolites are renally eliminated.

Half life of drug relates directly to risk of hypoglycemia. Dosing: Dose may be increased every 1-2 weeks. SU’s are best given

30 min. before a meal. Drugs with longer half-lives (particularly chlorpropamide, glyburide,

and glimepiride) can be given once daily. They also cause greater suppression of overnight hepatic glucose output, thereby lowering fasting blood glucose concentrations more.

Shorter acting drugs should probably be used in elderly patients, Pts with renal insufficiency and liver disease.

Hypoglycemia in low dose short acting SUs may dictate a short acting insulin secretagogue.

SulfonylureasInitial doseInitial dose Usual total daily doseUsual total daily dose

Acetohexamide(Dymelor®)

250-500mg QD 0.25-1.5g (QD-BID)

Tolazamide(Orinase®)

100-250mg QD 0.2-1g (QD or BID)

Tolbutamide(Orinase®)

1.0-2.0g QD or BID 0.25-3g (BID or TID)

Chlorpropramide(Diabinese®)

100-250mg QD 0.1-0.5g (QD)

Glipizide(Glucotrol®)

5mg QD (2.5mg QD for elderly)

2.5-40mg (QD or BID)

Glipizide XL(Glucotrol XL®)

5mg QD 5-20mg (QD)

Glyburide(DiaBeta®)

2.5mg QD (1.25mg QD for elderly)

1.25-20mg (QD or BID)

Micronized Glyburide(Glynase®)

1.5mg QD 1-12mg (QD)

Glimepiride(Amaryl®)

1-2mg QD 1-8mg (QD)

Meglitinides Short-acting insulin secretagogues MOA:MOA: Stimulate pancreatic insulin secretion → ↓ glucose rise

after a meal, but insulin release is glucose dependent and diminishes at low blood glucose concentrations.

AE’s:AE’s: Hypoglycemia (less than SU due to glucose sensitive release of insulin), weight gain, headache, GI disturbances (nausea, vomitting, diarrhea) and arthralgia.

Pharmacokinetics:Pharmacokinetics: Rapidly absorbed after administration and short half life, metabolized by CYP 3A4 and CYP 2C9 to inactive metabolites and excreted renally and through bile.

Role of therapy:Role of therapy: Good choice for Pts who have postprandial hyperglycemia who are close to glycemic goals. Less efficacious than SUs with average HgA1C reduction

being 0.6 to 1%.

Meglitinides Advantages:Advantages: Flexible dosing with lifestyle, safe in renal

and liver failure, rapid onset Disadvantage:Disadvantage: Risk hypoglycemia (but less frequent and

severe than SU therapy) and weight gain. Dosing:Dosing: ↑ dose every 1-2 weeks. Take 1-30 min before

meals. If meal is skipped, skip dose.

Initial doseInitial dose Maintenance doseMaintenance dose

RepaglinideRepaglinide(Prandin®)

0.5-2mg before each meal

0.5-4mg TID-QID(Max. 16mg/d)

NateglinideNateglinide(Starlix®)

120mg TID (60mg TID if close to goal HA1c)

60 or 120mg TID

BiguanidesMetformin (Glucophage®)

MOA: ↓ hepatic glucose output, ↓ intestinal absorption of glucose, ↑ peripheral glucose uptake, ↑ insulin-mediated glucose utilization and sensitivity, and contains a antilypolytic effect (insulin must be present for metformin to work).

AE’s: GI disturbances (abdominal discomfort, stomach upset, diarrhea, nausea, vomiting, bloating, flatulence, anorexia—ER may reduce GI AE’s; mild, transient, and reversible after dose reduction and may be minimized by titrating dose slowly and taking with food), metallic taste, anorexia, and lactic acidosis (rare).

Pharmacokinetics: Not metabolized and excreted unchanged in urine. Antihyperglycemic effects > 24 hours, although t1/2 is 6 hours.

Contraindications: Renal dysfunction (SCr ≥ 1.5mg/dl in males and Scr ≥ 1.4mg/dl in females) CHF requiring pharmacologic treatment Withhold therapy w/ use of iodinated contrast therapy Known hypersensitivity to metformin Acute or chronic metabolic acidosis Surgical procedure


Caution: Pts in hypoxic states (e.g. shock, acute MI) Hepatic impairment Undergoing surgical procedure Alcoholics Dehydration Elderly debilitated or malnourished Pts Lactic acidosis due to accumulation of metformin

Role in therapy: Usual initial therapy in obese Pts. Good choice when SU are not producing desirable effects.

Reduce FPG by 60-80mg/dl. Reduce HgA1C by 1.5-2.0%. Reduction in TGs by 16%, LDL by 8%, and increases HDL by 2% ( good for insulin

resistance syndrome). Weight loss of 2-5 kg. Given in combination w/ a SU results in a synergistic effect. UKPDS → when compared to SUs or insulin, there was no significant difference in

reducing microvascular complications but reduced macrovascular complications significantly.


Advantages: No hypoglycemia or weight gain, weight loss possible, and beneficial effects on lipids (↓ TG, total cholesterol, and LDL).

Disadvantage: Risk of lactic acidosis, many GI AE’s (must titrate dose slowly), must monitor renal function on a regular basis and contraindicated when Pt is renally insufficient (SrCr ≥ 1.4mg/dl for women and ≥ 1.5 mg/dl in men).

Dosing: Take with food and ↑ by 500mg every 1-2 wks. Start with 500mg QD with the evening meal and if tolerated add a second 500mg dose with breakfast. Maximum daily dose is 2550mg or 2000mg for the XR release formulation. Little additional benefits documented with XR formulation.

Fortamet® Avandamet®

Initial Dose Maintenance TDD

Metformin 500mg QD or BID 0.5-2.5g (BID or TID)Metformin XR 500-1000mg QD 1.5-2g (QD over 2-3

doses)

Thiazolidinediones MOA: Activation of PPARу (fat and vascular) reduces

insulin resistance in the periphery, ↑ insulin sensitivity in muscle, liver and fat tissues, by increasing glucose utilization and ↓ hepatic glucose production (insulin must be present in significant quantities for these actions to work), and preserves pancreatic beta cell function.

AE’s: HA, edema, fluid retention, weight gain (average 1.5-4.0kg), dilutional anemia, hepatotoxicity. Several case reports on hepatotoxicity with TZDs, but ALT improved

after d/c of TZDs. Recommend ALT be checked prior to therapy and then periodically

at physicians discretion → ALT > 2.5 time the ULN; should not start TZDs and ALT > 3 times the ULN; should d/c TZD.

Pharmacokinetics: Extensively metabolized in liver to inactive metabolites, excreted in urine and feces. Antihyperglycemic effects greater than 24 hours.

Thiazolidinediones Role in therapy: Approved as monotherapy or in combination with SUs,

metformin, or insulin. Has been shown to be less effective as monotherapy when compared to SU

and metformin unless given early in disease course. Recommend use with other oral agents, where synergistic effects can lower

HgA1C by 1.5% and FPG by 60-70 mg/dL at maximal doses. Efficacy is dependent on sufficient insulinemia. Pts who are overweight or who gain weight on medication tend to have a ↑

reduction in HgA1C.

Advantages: No hypoglycemia Beneficial affects on lipids:

Pioglitazone ↓ TGs by 10-20%, whereas rosiglitazones has no effect. ↑ HDL by 10% in both. Rosiglitazone ↑ LDL by 8-16% and no significant increase with

pioglitazone. Can be used in renal failure; no dosage adjustment necessary.

Thiazolidinediones Disadvantages:

Risk of edema (4-5%); be cautious in CHF class I-II Pts and contraindicated in class III-IV Pts due to plasma volume expansion, when used with insulin risk of edema increases to 15%.

Risk of weight gain (fluid retention and fat accumulation), which is dose dependent, predicts a larger HgA1C reduction.

Anemia due to dilutional effects of increased plasma volume; must monitor CBC.

Hepatotoxicity; must monitor LFT’s at baseline, Q 2months during first year, then periodically, improvement in LFT’s upon d/c.

Many potential drug interactions (e.g., drugs metabolized by CYP450).

Onset of action is slow; may take up to 10-12 weeks for maximal effect.

Thiazolidinediones

Dosing: Titrate dose every 4 weeks. May take with or without food

Initial DoseInitial Dose Maintenance Dose Maintenance Dose TDDTDD

Rosiglitazone(Avandia®)

4mg QD 4-8mg (QD or BID)

Pioglitazone(Actos®)

15-30mg QD 15-45mg (QD)

α-Glucosidase Inhibitors MOA: Inhibit the upper GI enzymes α-glucosidases → unable to convert sucrose and

complex carbohydrates to glucose → slows absorption of glucose → slower rise in postprandial blood glucose concentrations.

AE’s: flatulence, diarrhea, bloating, abdominal cramps (Beano), ↑ LFT’s (only for acarbose in doses >50 mg TID), monitor serum transaminases Q 3 months for first year then periodically.

Pharmacokinetics: Acarbose → extensively metabolized to inactive product, half excreted unchanged in

feces and other half renally. Miglitol → eliminated renally as unchanged drug.

Role in therapy: For Pts who are near target HgA1C levels and near-normal FPG levels, but high postprandial levels, or Pts at risk for hypoglycemia.

Efficacy in glycemic control is modest → less potent than SUs and metformin, lowering HgA1C by only 0.5% to 1.0%.

Reduces postprandial glucose levels by 40 to 50 mg/dl. Beneficial in Type I and Type 2 diabetes. No beneficial effects seen on lipids. May be taken alone or in combination with other agents. STOP-NIDDM → acarbose can decrease the conversion rate of IGT to diabetes and

also reduce risk of CV events; preventative medication ?

α-Glucosidase Inhibitors Advantages: No risk in hypoglycemia or weight gain (if

used alone), flexible dosing with lifestyle, less risk of systemic toxicity b/c of local GI effects.

Disadvantage: Intolerable AE’s: titration of dose to minimize AE’s.

Contraindications: Inflammatory bowel disease and short bowel syndrome, and in Pts with SrCr > 2 mg/dl.

Dosing: Must be taken with first bite of each meal. If meal is skipped, must

skip dose. Initiated with low dose (25mg w/ one meal a day) and increased

dose by 25mg/meal every 4-8 weeks Max: 50mg TID for Pts weighing 60kg or less Max: 100mg TID for Pts weighing more than 60kg

α-Glucosidase Inhibitors

Initial Dose Maintenance DoseAcarbose(Precose®)

25mg QD Min: 25mg TIDMax: 100mg TID

Miglitol(Glyset®)

25mg QD Min: 25mg TIDMax: 100mg TID

Note: In case of hypoglycemia → treat with glucose tablets (parenteral glucose or glucagon), complex carbohydrate will not be absorbed b/c of inhibition of α-Glucosidase.

How Supplied: Oral tablet: 25mg, 50mg, 100mg

Combination MedicationsBrand Doses Initial Dose Maximum Dose

Glucovance® Glyburide/ metformin

1.25/2502.5/5005/500

2.5-5/500 20 of glyburide, 2000 of metforminFDA- initial therapy

Metaglip® Glipizide/ metformin

2.5/2502.5/5005/500

2.5-5/500 20 of glipizide, 2000 of metforminFDA- initial therapy

Avandamet® Rosiglitazone/ metformin

1/5002/5004/5002/10004/1000

1-2/500 twice a day

8 of rosiglitazone, 2000 of metforminFDA- 2nd line, but can be used as initial

So Which Drugs Should Be Used?

Pharmacotherapy for Type 2 DM, has changed dramatically in the last few years. Several new drug classes. Recommendations to achieve more stringent

glycemic control. Texas Diabetes Council Recommendations

on glycemic control.


Symptomatic Pts (FPG ≥ 260 mg/dl) → reduce glucose toxicity with insulin treatment or combination oral therapy.

Pts with HgA1C of 7% or less → therapeutic lifestyle changes with or without an insulin sensitizer.

Pts with HgA1C of > 7% but <8% → initially treated with single oral agent.

Pts with ↑ HgA1C, 9 to 10%, will likely require initially therapy with two oral agents.

Best initial oral therapy is widely debated. UKPDS → obese Pts (>120% ideal body weight) without contraindications,

should be started on metformin and titrated upto 2000mg/d. Near normal weight Pts can be treated with insulin secretagogue.

Failure of initial therapy should lead to addition, rather than substitution of agent. Reserve substitution for intolerance to a drug.

Cost and efficacy have also lead to metformin and insulin secretagogues being 1st and 2nd line in therapy.


TZDs may substitute for metformin in Pts who are intolerant, as a insulin sensitizer.

Short term studies have shown TZDs to preserve beta cell function. UKPDS → insulin, metformin, and SUs did not stop beta cell failure. Long term studies in TZDs showing similar results may lead to TZDs becoming

first line. If Pt is inadequate on dual therapy → consider a third class of oral agent ,

usually TDZs (triple therapy is not FDA approved). Alternative → add on a intermediate or long acting insulin at bedtime to initial

oral agent or two-drug combination. SUs are often stopped when insulin is added → may be permissible until

multiple daily injections.All Pts with Type 2 DM will become insulinopenic → requiring insulin

therapy. Pts are usually transitioned to insulin → intermediate or long acting insulin

injections at bedtime and oral agents primarily for glycemic control during the day.

Less hyperinsulinemia during the day. Less weight gain than traditional insulin regimens.


Insulin sensitizers used commonly with insulins → due to most diabetic Pts being insulin resistant.

Failure of bedtime insulin plus daytime oral agents → leads to conventional multiple daily dose insulin regimen; continuing insulin sensitizers should be tried.

Insulin doses in Type 2 DM may range due to variability of insulin resistance.

Glycemic control is a function of fasting and preprandial glycemia and postprandial glycemic excursions.

Postprandial glycemic control may need more emphasis if HgA1C is near glycemic goal; postprandial excursions proportionally contribute more than fasting glucose to HgA1C percentage as HgA1C nears goal.

Still unknown if postprandial glycemic control has more off an effect on complications risk as compared to conventional strategies.

American College of Endocrinology / American Association of Clinical Endocrinologists → post-glucose challenge glucose measurements are a better predictor of macrovascular disease risk.

Lipase Inhibitors

Xenical® (Orlistat) MOA: Inhibits pancreatic and gastric lipases →

blocks absorption of 30% of ingested fat, weight loss is associated with improvement in glycemic control.

Studies HgA1C levels ↓ in both groups (orlistat group and

placebo) and was related to extent of weight loss. There was significantly greater ↓ in TC and LDL than

placebo, independent of degree of weight loss. Role in therapy: May be a useful adjunct, but not

primary, therapy for Pts with Type 2 diabetes.

Lipase Inhibitors AE’s: Abdominal discomfort and pain, urgent need

to have a BM, oily or fatty stools, oily discharge , increased number of BMs, inability to control BMs.

Contraindications: cholestasis, chronic malabsorption syndrome

Administration: Should be taken during or up to one hour after meals, Pts should take MV containing A, D, E, K and Beta carotene at least two hours before or after orlistat use.

Dosing: 120mg TID for DM Type 2 (non FDA labeled indication).

Symlin®(Pramlintide)

MOA: Amylin is a peptide hormone secreted by pancreatic beta cells in conjunction with insulin; Pramlintide is a synthetic analog of human amylin → slows gastric emptying, reduces postprandial rise in blood glucose concentrations, and improves HgA1C levels in Type 1 and Type 2 diabetes when given SC.

Role in therapy: FDA approved for use in Pts with diabetes tx with mealtime insulin therapy (Type 1 or 2) or in Pts with Type 2 diabetes with a concurrent SU or metformin. Shown to modestly improve HgA1C levels without causing increased hypoglycemia or weight gain and even promoting weight loss.

AE’s: Abdominal pain, loss of appetite, nausea (improves over time), vomiting, HA, dizziness, cough, hypoglycemia

Symlin®(Pramlintide)

Dosing: Type 1 adjunctive treatment: initial 15mcg and increase to 30 to

60mcg (titrate in 15mcg increments).. Type 2 adjunctive treatment: initail 30mcg and increase to 120mcg. Recommend reducing preprandial, rapid acting or short acting

insulin dosages by 50% when Pramlintide is started. Administration: SQ, to abdomen or thigh, with or just prior

to meal; should not be mixed with insulin; if meal is skipped dose should be skipped.

Note: slows gastric emptying → can decrease rate of absorption of oral medications; should be administered one hour before or two hours after injection and Pts taking drugs that stimulate GI motility should not be considered for Pramlintide therapy.

GLP-1 Receptor AgonistsByetta® (Exenatide)

MOA: GI peptides (incretin mimetics) that stimulate glucose-dependent insulin secretion and inhibit glucagon release and gastric emptying.

Role in therapy: Adjunct therapy to Pts (Type 2) who are not controlled on a SU or metformin or a combination of both.

Studies: Modestly improved fasting glucose and HgA1C levels and does dependent weight loss was observed.

AE’s: nausea (diminished over time), vomiting, diarrhea, dose dependent hypoglycemia when taken with a SU.

Administration: SQ, in the thigh, abdomen, or upper arm, anytime within 60 minute period before the morning and evening meals.

GLP-1 Receptor Agonists Dosing:

Initial, 5mcg SC twice daily Maintenance, 10mcg SC twice daily after one month therapy. Dose reduction of SU may be needed to reduce risk of

hypoglycemia (not needed w/ Metformin). Not recommended in Pts with end stage renal disease or receiving

dialysis or severe renal impairment (CrCl < 30ml/min). Note: Slows gastric emptying → can decrease rate of

absorption of oral medications; should be administered one hour before or two hours after injection.

Liraglutide: longer acting GLP-1 analog given once a day rather than twice a day is in clinical trails.

Self Blood Glucose Testing

Examples of testing methods 4 times daily: before breakfast, lunch, dinner, and

bedtime snack → best method, but not practical for many Pts.

Combination 4 times/ 2 times daily: test 4 times on certain days and 2 times on other days of the week.

Alternating 2 times daily: test before breakfast and dinner one day, and before lunch and bedtime snack next time day. Repeat pattern.

Daily testing before meal and 2 hrs after same meal.

Drugs That Can Alter Blood Glucose Levels

↑ ↑ Blood GlucoseBlood Glucose ↓ ↓ Blood GlucoseBlood GlucoseBeta blockers Beta blockersDiuretics ACE inhibitorsCorticosteroids EthanolProtease inhibitors Insulin, SUPentamidine (later on) Pentamidine (initially)Phenytoin Quinine, quinidineSympathomimeticsNicotinic acid

Hypoglycemia Signs & Symptoms:Signs & Symptoms: Blurred vision, generalized sweating

(especially palms), tremors, hunger, confusion, anxiety, tachycardia. If severe → seizures, unconsciousness. Nocturnal hypoglycemia S&S include nightmares, restless sleep, profuse sweating, and headaches.

Cause:Cause: Blood glucose < 50mg/dl due to not eating at proper times, excessive exercise, drugs (exogenous insulin, SUs), and defective counter-regulatory responses (e.g. ↓ glucagon secretion)

Treatment:Treatment: If conscious, provide 10-20g carbohydrate (e.g. ½ cup orange juice, 6-8 lifesavers, 2-3 glucose tabs, etc..) If unconscious, give 1mg glucagon SC. If hospitalized, 50 ml of D5W provides rapid reversal of symptoms.

Monitoring Patients With Diabetes

FPG every visit and at home

Renal function (SCr, BUN)

HbA1C Q 3 months Opthalmologic exam Q year

Urinalysis for glucose, protein, and ketone content

Confirm adherence to diet and exercise regimens

BP Q 3-6 months Foot exam Q year

Fasting lipid profile Q 6 months

Adverse effects of medications

References American Diabetes Assocaition: Aspirin therapy in diabetes

(Position statement). Diabetes Care. 2002;25:S78-79. American Diabetes Association: Diabetic nephropathy (Position

statement). Diabetes Care. 2002;25:S85-89. American Diabetes Association: Evidence based nutrition

principles and recommendations for the treatment and prevention of diabetes and realted complications (Position statement). Diabetes Care. 2002;25:S50-60.

American Diabetes Association: Management of dyslipidemia in adults with diabetes (Position statement). Diabetes Care. 2002;25:S74-7.

Hardman Joel, Limbird lee, editors. Goodman&Gilman’s the pharmacological basis of therapeutics. New York: McGraw-hill companies,inc

Dipiro J, Talbert R, editors. Pharmacotherapy: A Pathophysiologic Approach. McGraw-Hill Companies, Inc. New York: 2002

References UptoDate. http://

uptodateonline.com/application/topic.asp?file=diabetes/25035

http://uptodateonline.com/application/topic.asp?file=diabetes/25035

http://guidelines.gov/summary/summary.aspx?doc_id=7212&nbr=004306&string=diabetes

http://online.statref.com/Document.aspx?FxID=27&DocID=344&QueryID=21476&SessionID=5541B0ANAKYVMKCH

http://guidelines.gov/algorithm/3306/NGC3306_1.pdf










dm 1 1

Health & Medicine

slows gastric emptying

american diabetes association

postprandial glycemic control

relative insulin deficiency

lipid lowering agents

normal ldl levels

initial drug therapy

25mg tid max