Diabetes mellitus (DM) is a heterogeneous chronic disorder of nutrient metabolism characterized by elevated levels of blood glucose and associated with numerous acute and chronic complications. Diabetes is among the most common disorders encountered in primary care medicine; if diagnosed and undiagnosed cases are included, approximately 6.3 percent of the population, or 16 million Americans have DM. ^1,2 Adult patients with DM have the highest incidence of blindness, renal failure and non-traumatic amputations in the United States.

The classification of diabetes has recently been revised based upon a better understanding of the pathophysiology of the disorder. The terms "insulin dependent" (IDDM) and "non-insulin dependent" (NIDDM) have been eliminated because they were confusing and resulted in patients being classified based upon their treatment rather than the etiology of the disorder. The terms Type 1 and Type 2 diabetes are still used to describe the two major types of diabetes – note that the Roman numerals have been dropped and the use of Arabic numerals has been adopted to avoid confusion. Type 1 diabetes is characterized by b -cell destruction usually leading to absolute insulin deficiency and Type 2 diabetes is characterized by insulin resistance with a variable degree of insulin secretory deficiency.

This disorder accounts for 5 to 10 percent of patients with DM and usually occurs in persons less than 30 years of age with a peak incidence around the age of puberty. Type 1 DM may occur at any age, however and about 20 percent of patients classified as Type 2 may actually be slowly evolving Type 1 patients. Type 1 DM is characterized by the destruction of islet beta cell mass with resultant absolute or near absolute deficiency of insulin secretory ability. Most cases of Type 1 DM are believed to be the result of an autoimmune process which leads to destruction of the beta cell as evidenced by the presence of islet cell antibodies (ICA), insulin autoantibodies (IAA); IA-2, IA-2b and antibodies to glutamic acid decarboxylase (GAD) which are frequently present early in the disease. Patients with Type 1 DM are typically lean, and in the absence of insulin therapy are prone to the development of potentially fatal ketosis. Certain HLA antigens, especially the Class II DR, D3 and D4 antigens appear to confer a higher risk for the subsequent development of the disease, as do a number of environmental factors such as antecedent viral infections (Coxsackie B), seasonal variation and early exposure to cow’s milk, among others. Race/ethnicity alters risk, with populations possessing significant Caucausian admixture at highest risk.

The majority of patients with DM (90 percent) have Type 2 DM, which usually presents at age greater than 30. Once believed to be rare, there has been a startling increase in the number of cases of Type 2 DM in children. The prevalence of Type 2 increases steadily with age from about 6 percent of the total population to more than 20 percent by age 65. Unlike Type 1 DM, this disorder is characterized by resistance to insulin action accompanied by a variable defect in pancreatic insulin secretory ability. Insulin levels may be low, normal or high, with hyperinsulinemia being most characteristic. The insulin resistance is manifested at the hepatic level by unrestrained hepatic glucose production despite hyperinsulinemia, which leads to fasting hyperglycemia. At the muscle level, it is manifested by decreased insulin-stimulated glucose uptake.

Unless severely stressed, these patients do not develop ketosis. Approximately 80 percent of patients with Type 2 DM are obese. The NHANES III study demonstrated that undiagnosed cases of Type 2 DM have decreased from 50 to 30 percent since NHANES II.³ Type 2 individuals frequently possess the attributes of the recently described "Syndrome X" or "Metabolic Syndrome," characterized by insulin resistance/hyperinsulinemia, hypertension, central obesity and dyslipidemia with an increased risk of atherosclerotic macrovascular disease. ⁴

The risk for development of Type 2 DM varies according to ethnicity/race, with African American, Latino and Native Americans being at two to three-fold greater risk than non-Hispanic white populations.^5,6 Additional risk factors for the development of Type 2 DM include advancing age, obesity (body weight > 130 percent of desirable), hypertension, dyslipidemia, family history, prior gestational diabetes, and frequent infections. Recently the Diabetes Prevention Program (DPP) published data demonstrating that instensive lifestyle changes including modes weight loss and exercise for 30 minutes 5-7 days per week could reduce the risk of diabetes by 58% while tretament with Metformin and conventional lifestyle reduced the risk by 31 %.⁷ The thiazolidinedione Troglitazone arm of the study was stopped due to the risk of liver disease and although the mean exposure was only 10 months this group also experienced a 20 decrease in the risk of developing diabetes.

These include gestational diabetes, diabetes secondary to or associated with pancreatic disease, hormonal disease, drug or chemical exposure, insulin receptor abnormalities and certain genetic syndromes, which are beyond the scope of this chapter.

The diagnosis of Type 1 DM is usually obvious, with the abrupt onset of classic symptoms of polyuria, polydipsia, weight loss, blurred vision and marked hyperglycemia frequently associated with ketosis or ketoacidosis. The diagnosis of Type 2 DM is frequently more subtle, and these patients may have few symptoms. In fact, up to 20 percent of patients with Type 2 DM already have evidence of microvascular complications such as neuropathy or retinopathy at the time of their diagnosis, suggesting the onset of disease seven to ten years prior to diagnosis ^8,9 The diagnostic criteria for diabetes were revised in 1997 and are as follows:

In the absence of unequivocal hyperglycemia with acute metabolic decompensation, these criteria should be confirmed by repeat testing on a different day. The third measure (OGTT) is not recommended for routine clinical use. At the present time, the American Diabetes Association (ADA) feels that glycosylated hemoglobin is insufficiently sensitive and inadequately standardized to be used as a diagnostic test. Many diabetologists, however, feel the OGTT should be abandoned in favor of glycosylated hemoglobin.

The microvascular complications of DM include retinopathy, neuropathy and nephropathy and occur in both forms of the disease. It is generally believed that chronic hyperglycemia is an important etiologic factor in the development of these small vessel complications. Potent pathogenic mechanisms by which hyperglycemia may induce these changes include (1) glycosylation of proteins with formation of advanced glycosylation endproducts (AGEs) with crosslinkage and disruption of normal protein function, including those found in arterial walls, nerves and glomerular basement membranes, (2) activation of the polyol pathway with elevation of intracellular sorbitol and fructose, (3) depletion of intracellular myoinositol and (4) increased oxidation and glycoxidation of proteins.

Diabetic retinopathy results in 25 percent of the cases of blindness in the US and DM is the most frequent cause of adult blindness in the country. Fifty percent of Type 1 patients have retinopathy after 10 years and 80 percent at 15 years. Retinopathy may be found at any time after diagnosis in the Type 2 patient. Type 1 patients should be referred for yearly retinal exam after five years of DM. Yearly retinal exams should begin at diagnosis in Type 2 diabetics because of the likelihood of disease prior to diagnosis. Early laser photocoagulation of vision-threatening retinopathy has been demonstrated to preserve vision.

Nephropathy eventually develops in 35-45 percent of Type 1 diabetics and in 10-20 percent of Type 2 diabetics. Clinically, it begins with renal enlargement and hyperfiltration. This progresses to a stage of microalbuminuria of 30-300 mg/24 hours (or mg/gm Cr). Patients with microalbuminuria will likely progress to clinical albuminuria (>300 mg/24 hours), with hypertension usually present at this stage. ACE inhibition has been demonstrated to retard the initial development or rate of progression of renal disease.¹⁰ Recently angiotensin receptor blocking agents (ARBs) have proven to be useful as well. ^11-13 Women of child-bearing age should be counseled that ACE-inhibitors are teratogenic and must be discontinued during pregnancy. Control of hypertension is essential, with a recommended goal of < 130/80.¹⁴ In those patients without overt proteinuria on dipstick, assessment of microalbumin should be performed at least yearly. In the setting of a stable serum creatinine, a spot albumin-to-creatinine ratio correlates well with a timed collection. A timed collection (24 hours or 8 hours overnight) should be performed if there is persistant albuminuria.

TABLE 1: Definitions of abnormalities in albumin excretion

Neuropathy is a frequent microvascular complication. It may be present in multiple forms, including a peripheral, symmetric, predominantly sensory neuropathy of the lower extremities, which may be asymptomatic or painful. Charcot joint and ulcers may result from the sensory loss, and neuropathy is a major risk factor for amputation in the patient with DM. Asymmetric forms, which may result from nerve infarct, include mononeuropathies involving the eye, face and extremities, as well as diabetic amyotrophy. Autonomic neuropathy may be manifested by orthostatic hypotension, gastroparesis, persistent diarrhea and impotence.

Reduction of microvascular complications appears to be possible with tight glycemic control. There are epidemiological studies which show correlation between hyperglycemia and complications, as well as intervention studies in both Type 1 and Type 2 DM which demonstrate that complications can be reduced with tight control.^15,16 The Diabetes Control and Complications Trial was a randomized clinical trial which compared conventional therapy to intensive treatment in Type 1 DM, aiming to achieve near normal glycemic control. The risk reduction for retinopathy, nephropathy and neuropathy was approximately 60 percent in the intensively treated subjects (mean HbA1c 7.2) compared with conventionally treated subjects (mean HbA1c 9.1). The Kumamoto Study¹⁷ looked at 110 Japanese subjects with adult onset DM and like the DCCT compared an intensively treated group to conventionally treated subjects. Their results were remarkably similar, with risk reductions for retinopathy, nephropathy and neuropathy of about 60 percent. The results of the 20 year United Kingdom Prospective Diabetes Study (UKPDS) confirmed the importance of intensive glycemic control (HbA1c 7.0) compared with conventional therapy (HbA1c 7.9) in the reduction of microvascular complication in patients with Type 2 diabetes.^18,19

Coronary artery atherosclerosis and ischemic heart disease is the most frequent cause of mortality in diabetic patients. The MRFIT study demonstrated that men with diabetes had a two to four-fold greater coronary heart disease mortality risk than non-diabetic men at any level of serum cholesterol. The protective effect of the premenopausal state on coronary heart disease risk is lost in women with diabetes.²⁰ The etiology of the increased level of macrovascular disease is likely multi-factorial, Epidemiological studies suggest that hyperglycemia is associated with increased macrovascular disease risk,²¹and elevated HbA1c has been associated with both coronary events and mortality.²²Both insulin resistance and endogenous hyperinsulinemia are predictors of ischemic heart disease.²³ The above mentioned UKPDS report described a 16 percent reduction in the risk of combined fatal and nonfatal myocardial infarction between the two groups which just missed statistical significance (p=0.052), however, in the obese metformin-treated subgroup there was a significant reduction in myocardial infarction.¹⁸ There was no evidence to support an increased risk with intensive insulin, sulfonylurea or biguanide therapy.

Dyslipidemia is common in patients with DM, with elevated triglycerides and low HDL levels being the most characteristic lipid abnormality. ²⁴ In addition, Type 2 DM is associated with an increase in the number of coagulation factors, increased platelet aggregability and thromboxane release, as well as decreased fibrinolytic activity with increased levels of plasminogen activator inhibitor (PAI-1) and Lp(a).²⁵DM is now considered a CHD risk equivalent Aggressive treatment of hyperlipidemia in diabetic patients is strongly recommended with an LDLc goal of <100 mg/dL.^26-29

Peripheral vascular disease (PVD) is four times more frequent in individuals with diabetes as in those without diabetes. ³⁰ Untreated disease can lead to gangrene and amputation of the foot or lower extremity. Almost 50 percent of nontraumatic lower extremity amputations occur in people with DM. Survival is dismal in diabetic patients after amputation, with five-year mortality between 39 and 68 percent. Up to 85 percent of lower extremity amputations could be prevented by improving prevention and treatment of foot ulcers, minimizing their recurrence and educating patients about proper foot care.

Cerebrovascular disease is also a more frequent complication in DM, with stroke two to four times more likely in patients with diabetes. The increased risk appears, however, to be related to the increased prevalence of hypertension in patients with DM. Patients with DM and normal blood pressure experience about the same risk for stroke as non-diabetic individuals.³⁰

The most effective management would be the prevention of diabetes and trials are on going for both Type1 and Type 2 diabetes. For established diabetes the ADA standards of medical care for patients with diabetes recommend at least quarterly visits with glycosylated hemoglobin measurement, individualized nutrition recommendations and instruction preferably by a registered dietician, recommendations for appropriate lifestyle changes (e.g. exercise, smoking cessation), self management instruction including self monitoring of blood glucose, yearly assessment of urinary protein/microalbumin excretion, lipid assessment, yearly dilated eye exam in all patients over the age of 30 as well as those with diabetes for 3 to 5 years, foot examination and podiatry consultations if appropriate.

TABLE 2: Goals for glycemic control

The American College of Endocrinology and the European Association for the Study of Diabetes are advocating even more aggressive glycemic control aiming for HgbA1c <6.5 percent.

Nonpharmacologic management is the first step in the management of the patient with Type 2 DM and is recommended for at least three months before embarking upon pharmacologic therapy. The cornerstone of the management of the Type 2 patient is behavior - diet, exercise and weight loss. There is no longer such a thing as an "ADA diet." Rather, the emphasis is on individualized meal plans taking into account patients’ personal and cultural preferences. There is still disagreement as to the optimal amount of carbohydrate and fat in the diet. The current recommended nutrient intake is:

Carbohydrate: 40-60 percent of calories

Protein: 10-20 percent of calories

Fat: < 30 percent of calories

Saturated fat: < 10 percent of calories

< 7 percent if patient has elevated LDL

Cholesterol: < 300 mg/day

Fiber: 20-35 g/day

A registered dietician or certified diabetes educator (CDE) can be of invaluable assistance in the preparation of a meal plan, and New York State requires all insurers (except Medicare) to cover this service. If the patient is overweight, the emphasis is on portion control and moderate calorie restriction to achieve a weight of < 120 percent of desired body weight (DBW). Even a weight loss of 10 to 20 pounds can make the difference between pharmacotherapy and diet control. DBW ranges can be rapidly estimated by the following calculation:

Women: 100 lb for 5 feet + 5 lb for each inch over 5 feet, +/- 10% for frame size

Men: 106 lb for 5 feet + 5 lb for each inch over 5 feet, +/- 10% for frame size

Exercise is recommended to maximize the effects of dietary modification, and can reduce cardiovascular risk factors, augment weight reduction diets, improve insulin sensitivity, reduce plasma glucose, reduce insulin or oral agent dose, raise HDL and improve quality of life. Care should be taken to rule out underlying coronary artery disease in patients with longstanding diabetes before giving an exercise prescription. An aerobic exercise program achieving 60 to 80 percent of maximum heart rate at least three times per week should be the goal. Aerobic exercise has been demonstrated to reduce the risk of development of Type 2 DM in high risk individuals.^7,31

Pharmacologic therapy is indicated in Type 2 DM when there is inadequate glycemic control with non-pharmacologic measures, and in all patients with Type 1 DM. Current pharmacologic options include insulin and oral agents, of which there are now several available classes. Recombinant human insulin has replaced animal insulin and should be specified on the prescription.

There are increasing options for insulin therapy with the availability of the newer insulin analogs which exhibit either very rapid onset and short durations of action (Insulin Lispro and Insulin Aspart) suitable for pre-meal therapy and pumps or peakless with long duration of action (Insulin Glargine) suitable for basal therapy. Insulin therapy is indicated in the Type 1 patient at all times, and in the Type 2 patient who has failed oral therapy or is significantly hyperglycemic at presentation. Insulin requirements in lean patients (within 120 percent of DBW) range from 0.5 to 1 unit/kg/24 hours and are usually about 0.7 units/kg/24 hours. In the past one shot per day of insulin rarely achieved acceptable glycemic control, however, some patients with Type 2 DM may achieve acceptable control with Glargine alone or in combination with oral agents.

When choosing an initial regimen for the Type1 or Type 2 diabetic, physicians need to estimate daily insulin requirements (based on weight) and then design a dose schedule that is as simple as possible and that minimizes the risk of hypoglycemia. One strategy is to start with 0.5 units/kg divided into a split dose regimen of NPH insulin, 2/3 in the morning and 1/3 at bedtime or Glargine 10units once per day at bedtime. Type 1 diabetics require regular insulin as well, and often require three doses a day (both NPH and regular in the morning, regular pre-supper and NPH at bedtime). If regular insulin is indicated, as it is in Type 1 DM, diabetologists recommend further dividing the morning dose into 2/3 intermediate-acting insulin (N or L) and 1/3 regular insulin given 30 minutes prior to the morning meal. The evening dose can be split into 1/2 regular given 30 minutes before supper and 1/2 intermediate-acting insulin given at bedtime. While this regimen requires a minimum of three injections, it best matches insulin action and reduces the risk of hypoglycemia. Alternatively, the evening R and N can be combined and given pre-supper, the so-called split-mixed regimen. Insulin Glargine may also be given as a single bedtime dose with a short acting insulin analog take before each meal to mimic the a physiologic state with basla and bolus insulin. Premixed 70/30 combinations of N/R can accomplish the same goal. These regimens are less than ideal, but are sometimes necessary to enhance patient compliance.

In some Type 2 patients, a single bedtime dose of NPH insulin can control fasting blood sugar. This strategy addresses the major defect of hepatic insulin resistance with unrestrained hepatic glucose production in the fasting state. The so-called Dawn phenomenon associated with increased early morning secretion of the counter-regulatory hormones (growth hormone, cortisol, glucagon and epinephrine) will further contribute to fasting hyperglycemia. If one shot of bedtime insulin is to be used, a reasonable starting place is a dose of 0.2 units/kg of NPH. This can be titrated up until satisfactory fasting blood glucose values are attained. Insulin Glargine can also be used. If taget FBS has been achieved and Hgb A1c remains high than 2 hour post prandial glucose levels should be checke and if elevated indicate the need for pre-meal short acting insulin.

Very large doses of insulin, frequently > 1.5 units/kg are sometimes necessary in order to overcome insulin resistance and control the blood glucose in Type 2 individuals. Insulin therapy is usually accompanied by weight gain, not uncommonly as great as 10 kg. Some patients may need as simple a regimen as possible, and glycemic targets may need to be modified. Insulin therapy may be needed initially in some Type 2 patients, but can frequently be withdrawn or reduced when better glycemic control is attained. This leads to resolution of glucose toxicity, with improved insulin sensitivity and restoration of insulin secretory ability.

There are now five classes of oral anti-diabetic pharmacotherapy available in the U.S. They differ in their mechanism of action and allow the possibility of complimentary combination therapy or combination with insulin. It is now possible to avoid or postpone the need for insulin therapy in Type 2 diabetics while achieving ADA glycemic goals.

Sulfonylureas are the oldest class of oral antidiabetic therapy, and there are many available agents to choose from, including both first and second generation agents. These differ in terms of half-life, route of elimination/metabolism, side effects and cost. They all share the ability to stimulate insulin secretion and therefore require intact pancreatic beta cells for therapeutic effect. They bind to a "sulfonylurea receptor" (closely related to an ATP-sensitive potassium channel), leading to insulin release. They may also impair ischemia-induced vasodilation by this mechanism. Commonly used second-generation sulfonylureas include glyburide (Micronase^TM, Diabeta^TM, Glynase^TM) and glipizide (Glucotrol^TM). The new sulfonylurea, glimeperide (Amaryl^TM) is also a second-generation agent; it binds to a unique site of this receptor and does not appear to impair this response. Any apparent improvement in insulin sensitivity is likely to be a result of overall improvement in glycemic control and resolution of glucose toxicity, rather than a direct action of the drug.

When used as a single agent, sulfonylureas lower the fasting blood glucose an average of 60 mg/dL and HbA1c by 1.5 percent. Insulin levels are increased after sulfonylurea therapy and, as a result, there is a tendency toward weight gain. Approximately 50 percent of patients with Type 2 DM are initially adequately controlled with sulfonylureas. About 15-25 percent of patients have little or no response and may actually be insulin deficient. There is a 3-5 percent per year secondary failure rate with sulfonylureas. Glimeperide is the only sulfonylurea with FDA approval to be used with insulin. It has been demonstrated to improve glycemic control and decrease insulin requirements. Other drugs have been used successfully for this purpose as well. The administration of Bedtime Insulin and Daytime Sulfonylurea therapy (BIDS) has been successfully used to improve glycemic control and decrease insulin dose, but it is used less frequently now that there are other oral agents which can be combined with sulfonylureas. The sulfonylureas can cause hypoglycemia, which has been fatal in rare cases. Providers should be aware that several commonly-used medications (including NSAIDS, salicylates, coumarins, b -blockers and sulfonamides) can potentiate the hypoglycemic effect of sulfonylureas.

TABLE 3: Second-generation sulfonylureas

Meglitinides are substituted benzoic acid or amino acid derivatives, which act similarly to the sulfonylureas although they bind to a different site on the same receptor and lead to increased insulin release. Repaglinide (Prandin^TM) and Nateglinide (Starlix ^TM ) are the available members of this class. They have a very short half-life and must be dosed with meals. If a meal is skipped so is the dose. They are safe in renal insufficiency and may be associated with less hypoglycemia than sulfonylureas.³² The can be particulary useful in the elderly who skip meals but the tradeoff is increased complexity of therapy with multiple doses.

Biguanides are an older class of antihyperglycemics. The previously available phenformin was removed from the American market in the late 1970’s as a result of a number of cases of fatal lactic acidosis. A related agent, metformin (Glucophage^TM) has been available in Europe and the Caribbean for 40 years and was recently approved for use in the U.S. It differs from phenformin in that it is not protein-bound, undergoes no hepatic metabolism and is excreted unchanged in the urine. It requires intact renal function for elimination. Its mechanism of action is not completely understood, but it improves insulin sensitivity at the hepatic and muscle level. Metformin inhibits hepatic glucose output by inhibiting gluconeogenesis and glycogenolysis.

Rare cases of lactic acidosis (0.3 cases/1000 patient-years) have occurred with metformin, usually when the drug has been used in inappropriate patients. It does not produce hypoglycemia when used as a single agent. Metformin lowers fasting glucose by an average of 60 mg/dL and HbA1c about 1.5 percent (an effect similar to the sulfonylureas’). It may also be combined with sulfonylureas in patients with inadequate glycemic control for a further decrease of 60-70 mg/dL glucose and 1.5 percent glycosylated hemoglobin. Insulin levels are lower after therapy and patients tend to either lose weight or remain stable. In addition, triglyceride levels tend to fall about 15 percent and there is a small decrease in total and LDL cholesterol and a small increase in HDL cholesterol.

Metformin is contraindicated in patients with renal insufficiency (men with sCr>1.5 mg/dL and women with sCr > 1.4 mg/dL), patients with congestive heart failure requiring pharmacologic treatment, and patients > 80 years old unless creatinine clearance has been documented. It should not be used in conditions predisposing to hypoxia, liver dysfunction, alcohol abuse or binge drinking or acute or chronic metabolic acidosis. When radiologic contrast material is given, metformin should be held and restarted 48 hours after the procedure if the creatinine has remained stable. Forty years of experience with this agent have convinced diabetologists that it can be used safely with the proper precautions.³³ Metformin is available in 500 mg, 1000 mg and 850 mg tablets and should be given with meals to minimize GI side effects (such as diarrhea or bloating) which are usually self-limited if present. The maximum dose is 2500 mg/day although a recent dose response study suggested that maximum efficacy was reached at 2000 mg/day. A new combination form of metformin and glyburide is available and approved for use as initial therapy for Type2 DM. It has been associated with better glucose control at lower doses of each of the component monotherapies and few gastrointestinal and hypoglycemic side effects.

Alpha-glucosidase inhibitors competitively inhibit the digestion of polysaccharides and delay the digestion and absorption of complex carbohydrates, leading to lower post-prandial blood glucose levels. They are most useful in patients with predominantly post-prandial hyperglycemia, usually in combination with other OHAs or insulin. There are currently two agents available, acarbose (Precose^TM) and miglitol (Glyset^TM). The major side effects are gastrointestinal (predominantly flatulence) and can be minimized by beginning at a low dose and titrating slowly. They must be given with the first bite of a meal.

Thiazolidinediones (TZD) act to decrease insulin resistance, decrease hepatic glucose output and increase insulin-dependent glucose disposal in muscle. The exact mechanism of this class of drugs is unknown, but they require insulin for their effect. Troglitazone (Rezulin^TM) was the first of this class to be approved, and was withdrawn from the market due to its association with idiosyncratic fulminant hepatic failure resulting in liver transplantation and death. Two new thiazolidinediones, rosiglitazone (Avandia^TM) and pioglitazone (Actos^TM) appear to have less risk for hepatic toxicity and there have been no cases of fulminant hepatic failure. Monitoring of liver function if these agents are used (bi-monthly liver function tests for the first 12 months, periodicaly thereafter). Pioglitazone but not Rosiglitazone is indicated to be used in combination with insulin. These agents are associated with weight gain especially in combination therapy with insulin or insulin secretagogues. They can also cause edema, dilutional anemia and have been associated with congestive heart failure. They are not inidcated in patients with class III or IV heart failure. The TZD’s may also have a b -cell sparing effect which is being explored in ongoing clinical trials.

Combination therapy is becoming increasingly important in the ability to achieve and maintain glycemic control. The availability of multiple oral agents with different mechanisms of action has resulted in the potential for numerous combinations of oral therapy and insulin. Which regimens will be most beneficial for various types of patients remains to be determined and is the subject of ongoing investigation. The availability of these newer oral agents has the potential to dramatically improve the physician’s ability to achieve glycemic control and minimize side effects including hypoglycemia since several of the newer agents do not stimulate insulin secretion.