Type 2 Diabetes Mellitus

Current Management

Classifications of Glucose Intolerance

n Diabetes mellitus (to be discussed)

n Impaired fasting glucose

– FPG 110 mg/dL or above but < 126

n Impaired glucose tolerance

– @ 2-hr point of oral glucose tolerance test, glucose is 140 mg/dL or above but < 200

n Gestational diabetes

– At risk of developing Type 2 DM within 10 yrs.

Types of Diabetes Mellitus

n Type 1: characterized by insulin deficiency as a result of pancreatic islet cell loss.

n Type 2: characterized by insulin resistance,

– increased production of insulin early in illness in attempt to overcome insulin resistance

– usually followed by dysfunction of pancreatic beta cell

n Third type in relation to other diseases, drug or chemical use, etc.

Statistics

n In the United States:

– More than 16 million people currently have type 2 diabetes

– estimated that 50% may be undiagnosed

– An estimated cost of more than $92 billion/yr

n Much of the cost of diabetes, both personal and economic, can be traced to inadequate glycemic control and treatment of comorbidities.

Quality of Care: Good or Bad?

n In Canadian study of family physician compliance with clinical practice guidelines only 53% had Hgb A1c in prior 12 months

n California HMO study:

– no Hgb A1c documented in 56% of patients

– FPG not documented in 65%

– foot exams not conducted in 94% of patients

– urine protein not checked in 52%

– untreated lipid abnormalities

Underdiagnosis/Undertreatment

n Strong evidence that persistent aggressive control of blood glucose levels is the best way to prevent much of the considerable morbidity associated with the chronic “end-organ” complications of diabetes.

n So, why does undertreatment occur?

Pathophysiology

n 3 physiologic process that normally regulate glucose levels are altered:

– production of glucose by the liver

– secretion of insulin by beta cells of the pancreas

– uptake of glucose in peripheral tissues stimulated by insulin activity

n At early stage of disease, may develop resistance to insulin

n Pancreatic cells compensate by increasing insulin release, resulting in hyperinsulinemia

n This is associated with obesity and can exist undetected for many years (= prediabetes stage)

n Insulin levels may then diminish,

– does not allow for adequate compensation for insulin resistance

n Hyperglycemia then occurs

Insulin Resistance

n Abdominal obesity and physical inactivity greatly contribute

– especially in genetically predisposed patients

n Insulin resistance may contribute to development of CV risk factors (HTN, dyslipidemia, obesity, and atherosclerotic heart disease) years before onset of the hyperglycemia and diagnosis of DM.

Therefore...

n An improvement in insulin resistance in prediabetic patients may delay or prevent the development of diabetes

n Strongly encouraged to institute lifestyle changes such as diet and exercise to slow the progression to type 2 diabetes.

Primary Risk Factors for Type 2

n Family history

n Obesity (>20% over ideal body weight)

n Race (American Indian, Hispanic, Black)

n Age at or >45 years

n Previously identified impaired glucose tolerance

n HTN, hyperlipidemia

n Hx. of gestational diabetes or infant >9 lb.

Syndrome X (Insulin resistance syndrome)

n Abdominal obesity (intra-abdominal or visceral fat) = prevalent factor in development of type 2 diabetes

n Correlates strongly with glucose tolerance, hyperinsulinemia, dyslipidemia, and increases in BP (all contribute to development of CV disease)

n This constellation of sx. has been grouped into a specific diagnostic entity (syndrome)

Complications

n Driven by consistent or intermittent hyperglycemia

n Proteins are readily nonenzymatically glycosylated (glycation) in direct proportion to the amount of free glucose available.

n Hemoglobin protein may circulate in plasma for 60-90 days as part of the RBC

Microvascular Complications

n Diabetic retinopathy (visual loss, blindness)

n Diabetic nephropathy

– 15-20% of type 2 DM patients develop end-stage renal disease (ESRD)

n account for 1/3 of patients needing treatment for ESRD

n Diabetic neuropathy

– affects 50% of diabetic patients

– may be symmetrical or focal

Macrovascular Complications

n Atherosclerosis involving the arteries of the heart, lower extremities, and brain

– major cause of death from diabetes

– process is the same as that occurring in nondiabetic patients, but begins earlier in life and appears to be accelerated when compared to nondiabetic patients.

Glycated Hemoglobin Test

n Reflects metabolic control

n Reflect the state of the patient’s glycemia over the preceding 8-12 weeks.

n Perform at intervals of about 3-4 months to guide adjustment of therapy

– objective check on accuracy of patients monitoring of DM

Intensive Therapy: Studies

n Diabetes Control and Complications Trial

n Stockholm trial

n Veterans Affairs Cooperative Study on Glycemic Control and Complications in NIDDM

n United Kingdom Prospective Study 1977

n Wisconsin Epidemiologic Study of Diabetic Retinopathy

n Japanese 6-Year Trial

Implications of Clinical Trials Results: Early, Aggressive Tx.

n Intensive glycemic control was associated with a reduction in the incidence of microvascular complications of diabetes

n Also associated with delayed progression among patients presenting with these sequelae already in place.

Clinical Management of Type 2 Diabetes

Nonpharmacologic Therapy

n Especially effective in obese, sedentary persons (90% of type 2 DM patients)

n Diet

– Even a modest weight reduction (5Kg) can dramatically improve glucose tolerance

– Also improves lipoprotein profiles and BP

n Exercise

– Improves insulin action in peripheral muscles

n Smoking cessation

n Treatment of HTN and hyperlipidemia

n Stress reduction

n Nonpharmacologic therapy = most challenging aspects of therapy to implement and maintain

n Produces acceptable results in < 10% of pts.

Pharmacotherapy

n Addition of an antidiabetic agent is usually required to control glucose levels

n Choice of one agent over others depends on mechanism of action, efficacy, side effects, ease of administration, cost, and pt. age

n If glycemic goals are not maintained with monotherapy, then 2 major options: insulin or combination therapies

n If combination does not work--> insulin

Sulfonylureas

n Act primarily by stimulating insulin release from beta cells

n Also reduce hepatic glucose output and potentiate insulin action

n Rational choice because of relative deficiency in insulin in patients at an early stage; few adverse effects, less cost

n Reduce A1c by 1.5-2% and FPG by 50-60 mg/L

n Concern: tendency toward weight gain and hypoglycemia, especially with long-acting drugs.

n First generation: tolbutamide (Orinase), acetohexamide (Dymelor), tolazamide (Tolinase) and chlorpropamide (Diabinese)

n Second generation: glipizide (Glucotrol), glyburide (DiaBeta, Micronase), and glimepiride (Amaryl)

n 2nd generation more potent without causing chronic elevation of insulin secretion

– induce fewer drug interactions

– inactive metabolites

– low reported alcohol flushing

n Chlorpropamide = longest 1/2 life, so higher hypoglycemic potential

n Glipizide-rapid absorption, distribution, elimination = less risk of hypoglycemia

n Glipizide now available in an extended-release GI therapeutic system (Glucotrol XL)

– low doses (5-10 mg) as effective as higher doses in immediate-release formulations

– no weight gain with XL form

New Generation Sulfonylurea

n Glimepiride

– recently licensed in the US

– lower risk of hypoglycemia due to its specific protein binding to the sulfonylurea receptor

Insulin secretagogues

n Act by stimulating insulin release from pancreatic beta cells in the presence of D-glucose

n Examples: Repaglinide (Prandin), nateglinide (Starlix)

n Rapidly absorbed and eliminated, T1/2<1hr

n Taken preprandially (with three meals)

n A1c decreased from 8.5 to 7.8%

n SE: mild/moderate hypoglycemia

Biguanides

n Example: Metformin (Glucophage)-only one in US

n Note: There are now combination medications available. For example: Glucovance = Glyberide + Metform

n Act by reducing hepatic gluconeogenesis

n Equal efficacy in initial monotherapy with sulfonylureas

n Tends to induce a mild weight loss (good for obese patients)

n Should not be used with renal, liver, or advanced CV disease (lactic acidosis)

Alpha-Glucosidase Inhibitors

n Action: competitive inhibition of intestinal alpha-glucosidases that hydrolyze complex CHO in the intestinal tract

n Results in delayed glucose absorption and reduction of postprandial hyperglycemia

n Examples: Acarbose (Precose) and miglitol (Glyset)

n Reduce A1c 0.5-1% (better reduction if with sulfonylureas or biguanides)

Thiazolidinediones

n Act by reducing insulin resistance in the peripheral tissues, primarily in the skeletal muscle and by inhibiting hepatic gluconeogenesis

n Troglitazone (Rezulin)-first one in US—removed from market

n Examples: pioglitazone (Actos), rosiglitazone (Avandia)

n Can reduce insulin requirements

n Decrease A1c 1%

n Check liver enzymes

Insulin

n Short-term and long-term tx. Options

n Supplements endogenous insulin

n Suppresses hepatic glucose production

n May improve insulin sensitivity

n Used first-line for nonobese, younger, severely hyperglycemic patients, during severe stress or in pregnancy

When oral therapy begins to fail:

n One possible approach:

– combine an intermediate-acting insulin at bedtime with a daytime sulfonylurea

– known as BIDS (bedtime insulin, daytime sulfonylurea)

– provides glucose control without inconvenience of multiple daily injections

When all other methods fail:

n Insulin therapy alone is finally required

n Consider regimens providing 24-hour coverage

– Twice-daily injections of intermediate-acting insulin and short-acting insulin

– Aggressive therapy involving long-acting insulin combined with regular insulin at meals

n Insulin pump

UK Prospective Diabetes Study

n Found that monotherapy with any agent will achieve comparable glycemic levels, but secondary failure appears to occur at the same frequency, regardless of which agent is used initially.