Approach to the Patient with Diabetes Mellitus

David M. Slovik

Diabetes mellitus is the most prevalent endocrinologic problem encountered in primary care practice. It is a condition of emerging epidemic proportions, estimated to affect upward of 9% of the US population at present; incidence is projected to rise markedly worldwide in coming decades. As much as 40% of the US population is thought to be at risk for prediabetes or diabetes.

Diabetes mellitus is characterized by hyperglycemia, a relative or absolute deficiency of insulin, insulin resistance, and a propensity for the development of vascular and neurologic complications. The primary care physician, working with a multidisciplinary team, is uniquely positioned to coordinate comprehensive care for the diabetic patient. The ultimate goals of therapy are the prevention of complications that make diabetes a major risk factor for coronary artery disease, stroke, visual impairment, renal failure, impotence, peripheral neuropathy, foot ulcers, limb loss, and death.

Effective management requires thoughtful, meticulous care, incorporating intensive patient education and support by the entire health care team. Glycemic control, manifested by a target hemoglobin A1c of less than 7.0%, has emerged as a major treatment objective because of its association with significant reductions in microvascular complications and an emerging trend toward reduction in macrovascular risk. The challenge for the primary care physician is to design a comprehensive therapeutic program that is safe, effective, practical, and personalized. Important tasks for the primary care team include diagnosis (see Chapter 93), motivating and instituting a program of lifestyle modification, and designing and implementing a treatment plan capable of achieving target glycemic control and associated risk reductions without inducing hypoglycemia. Engaging the patient as a partner in care and monitoring is essential to achieving the best possible outcomes. Effective collaboration with consulting specialists in endocrinology, ophthalmology, nutrition, pharmacy, and podiatry and concurrent attention to and intensive treatment of all major cardiovascular risk factors round out the mission.

PATHOPHYSIOLOGY, CLINICAL PRESENTATION, AND COURSE (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 13)

Pathogenesis and Pathophysiology

The basic pathogenesis of diabetes is incompletely understood, but genetic and acquired factors have been identified. The principal lesion in type 1 disease is pancreatic beta-cell failure, usually due to autoimmune destruction of the beta cells, which leads to a loss of insulin production. Type 2 disease is characterized by impaired insulin secretion and insulin resistance. Inappropriate hepatic glucose production and decreased muscle glucose uptake are the pathophysiologic hallmarks of insulin resistance; they occur despite the secretion of insulin.

Type 1 Diabetes

Type 1 diabetes is characterized by autoimmune destruction of the pancreatic beta cells leading to an absolute deficiency of insulin. Patients are ketosis prone and require insulin to live. Onset is typically in youth, but it may occur at any age. Patients may have detectable serum autoantibodies to such pancreatic antigens as islet cells and glutamic acid dehydrogenase. Peripheral insulin resistance is less of a factor in type 1 disease than in type 2 disease, but may play a contributing role.

Type 2 Diabetes

Type 2 diabetes is characterized by variable degrees of insulin secretory deficiency and resistance. Insulin is present but in amounts insufficient to meet metabolic needs in a timely fashion. Because they have some insulin, these patients are not ketosis prone (except under severe stress, e.g., infections or surgery). They exhibit impaired insulin secretion at any plasma glucose concentration and insulin resistance (impaired insulin action at the level of the insulin receptor). Obesity, which is present in 60% to 80% of patients with type 2 diabetes, is believed to play a major role in insulin resistance. Type 2 diabetes is the most common type of diabetes.

Metabolic syndrome is a term used to denote the broader metabolic perturbations common in type 2 diabetes and often preceding it. Associated with caloric excess and inactivity, the syndrome’s clinical features include insulin resistance, obesity,
dyslipidemia (low HDL cholesterol, high triglycerides, high LDL cholesterol), hypertension, and a strongly increased risk for macrovascular atherosclerotic disease (coronary risk increased two- to fourfold)—coronary endothelial dysfunction is believed to contribute (see Chapter 30).

Weight gain is not the only contributor in type 2 disease to insulin resistance. Glucose intolerance in diabetic patients may also be worsened by infection, stress, thiazides, glucocorticoids, and pregnancy. Excess secretion of growth hormone, cortisol, catecholamines, or glucagon may contribute to glucose intolerance, as can diseases that destroy a substantial portion of the pancreas (e.g., chronic pancreatitis, hemochromatosis, cystic fibrosis).

Clinical Presentation and Course

Clinical presentation, like pathogenesis, varies by disease type. Type 1 disease may present emergently as ketoacidosis or less dramatically with the classic triad of polyuria, polydipsia, and polyphagia. Onset is usually in the first two decades of life but may occur later. Type 2 disease, by contrast, typically becomes evident later in life (incidence rises significantly starting in the fourth decade), often discovered as an incidental finding on screening urinalysis or blood sugar measurement. Sometimes, fatigue is the predominant symptom. In patients with more significant hyperglycemia, polyuria, polydipsia, and polyphagia with weight loss are encountered. Occasionally, the diagnosis is made during an evaluation for cardiovascular, renal, neurologic, or infectious disease. A complication such as myocardial ischemia, stroke, intermittent claudication, impotence, peripheral neuropathy, proteinuria, or retinopathy may be the initial manifestation. Erectile dysfunction is a common initial complaint in men.

The clinical course of untreated diabetes is one of progressive worsening of glycemic control due to the combination of pancreatic endocrine failure and peripheral insulin resistance. The rate of clinical decline in glycemic control may wax and wane, affected by the interplay of these two pathophysiologic factors. The rate of clinical failure is typically rapid and progressive in type 1 disease, following years of silent immunemediated islet cell destruction; however, early on, there may be a transient honeymoon period before beta-cell exhaustion sets in. In untreated type 2 disease, the overall clinical course is also progressive, but it is usually more indolent and more heavily influenced by the state of insulin resistance. Early clinical type 2 disease is characterized by impaired timing of insulin release producing postprandial hyperglycemia and the potential for episodes of hypoglycemia; total insulin production may actually rise. As the disease progresses and beta-cell reserve declines, hyperglycemia worsens. Initially, drugs that increase insulin production and release improve glucose tolerance, but with further beta-cell decline, hyperglycemia worsens and eventually becomes unresponsive to such agents. Complications set in over time at a rate and intensity related to the severity and duration of glucose intolerance.

Complications

Complications of diabetes occur with a very high frequency. Most correlate with the magnitude and duration of hyperglycemia; there does not appear to be any glycemic threshold for the development of such complications. The major complications of diabetes can be categorized as microvascular (retinopathy, neuropathy, nephropathy) and macrovascular (large-vessel atherosclerotic disease).

Microvascular Disease

Microvascular disease accounts for much of the morbidity of diabetes, causing nephropathy, retinopathy, and neuropathy. The risk for these microvascular complications can be markedly reduced by achieving tight glucose control (see later discussion).

Diabetic Nephropathy.

Diabetic nephropathy is one of the leading causes of end-stage renal failure in adults, accounting for 25% of cases (see Chapter 142). Characteristic renal changes include glomerular basement membrane thickening and mesangial proliferation. Mesangial proliferation correlates strongly with the onset of proteinuria and hypertension. Subclinical and histologic findings for diabetic nephropathy are present long before the stage of clinical proteinuria. An elevated glomerular filtration rate (hyperfiltration), genetic determinants, and hypertension contribute to the progression of renal impairment. With persistent proteinuria, hypertension becomes established, and glomerular filtration begins to decline at the rate of 1 mL/min/mo.

The risk for the development of nephropathy correlates with the duration of disease and the degree of hyperglycemia. Renal failure eventually develops in 30% to 50% of type 1 diabetics and 6% to 9% of type 2 patients. Tight control of the blood glucose can reduce the risk for renal failure, particularly as primary prevention and if instituted early. It can reverse mild proteinuria in type 1 diabetics who do not yet have renal insufficiency. In the presence of significant proteinuria (>500 mg/d), near normalization of the plasma glucose may not slow the rate of renal deterioration. Bladder dysfunction and resultant urinary tract infections can also contribute to renal impairment in patients with diabetic neuropathy.

Retinopathy.

The risk for retinopathic changes (see Chapter 209) is related to the duration and degree of hyperglycemia. After 20 years of diabetes, all age groups show a 75% to 80% prevalence of retinopathy. The cumulative incidence of retinopathy can be reduced by more than 50% with intensive insulin therapy. The greatest effect is in primary prevention and in those with mild to moderate nonproliferative retinopathy. Strict glycemic control is of little benefit in advanced retinopathy. Reversible changes in the lens configuration occur with wide fluctuations in plasma glucose and may cause transiently blurred vision. In addition, cataracts and glaucoma occur with increased frequency (see Chapters 207 and 208).

Neuropathy.

Neuropathy may develop in approximately 50% of diabetic patients and lead to a peripheral sensory deficit, autonomic dysfunction, or mononeuritis. Mechanisms include myo-inositol depletion in nerve cell membranes (which prolongs conduction time) and hyperglycemia-induced sorbitol accumulation in nerve tissues that have a polyol pathway for glucose metabolism (e.g., Schwann cells). Microangiopathic changes that decrease the blood supply to the myelin sheaths are believed to be responsible for the mononeuropathy. Independent risk factors include duration of diabetes, current level of glycosylated hemoglobin, body mass index (BMI), smoking, hypertension, and presence of cardiovascular disease.

The peripheral neuropathy is predominantly sensory; sensation is reduced in the lower extremities, and the condition may progress to cause pain and dysesthesias. Autonomic neuropathy most commonly presents as impotence. Gastrointestinal motility disturbances (delayed gastric emptying), orthostatic hypotension, and urinary retention are other potential manifestations. Autonomic neuropathy is almost always seen in association with distal polyneuropathy. Its presence is an important predictor of foot and other infections.

Diabetic mononeuropathy involves discrete cranial or peripheral nerves, singly or as a mononeuritis multiplex. Cranial nerves III and VI are most commonly affected. In contrast to other diabetic neuropathies, mononeuropathies resolve almost completely within 1 year of onset.

Macrovascular Disease

Premature atherosclerosis may develop in large and medium vessels, leading to coronary ischemia, stroke, and peripheral arterial insufficiency. Purported mechanisms include hyperglycemic alteration of lipid deposits to make them more atherogenic and insulin resistance resulting in increased blood pressure, reduced levels of high density lipoprotein (HDL) cholesterol, and increased levels of very low density lipoprotein (VLDL) cholesterol, an atherogenic phenotype termed syndrome X. These adverse vascular effects are enhanced by the presence of smoking, hypertension, and hyperlipidemia. While emerging evidence suggests the potential for significant reduction in macrovascular risk by achievement of tight glycemic control (see later discussion), maximal reduction in such risk still requires attention to and aggressive treatment of all major cardiovascular risk factors (see Chapters 18, 26, 27, 30, 31, and 54).

Increased Susceptibility to Infection

Increased susceptibility to infection in diabetics appears to result from impaired leukocyte function, compromised vascular supply, and neuropathy. Cellulitis and candidiasis occur, with infections of ischemic foot lesions especially serious because they may lead to osteomyelitis and may require amputation. Overall, the occurrence of perioperative infections correlates with end-organ involvement by diabetes and marked degrees of hyperglycemia. Recent studies show a sixfold increase in all perioperative complications (stroke, infection, and renal insufficiency) in patients with end-organ disease. Urinary tract infections are common in patients with an autonomic bladder (see Chapter 134). Risk of infection is reduced by improved glycemic control.

WORKUP (1,14, 15, 16, 17, 18, 19, 20, 21 and 22)

Screening (see also Chapter 93)

Despite the high prevalence of diabetes and practical means of diagnosis and treatment, there remains debate about the costeffectiveness of population-wide screening for detection and early treatment during the asymptomatic period. The lack of consensus results in part from limited data on the efficacy of early pharmacologic treatment for type 2 disease. The U.S. Preventive Services Task Force does not recommend population-wide screening of adults, whereas the American Diabetes Association does for those over the age of 45 years. Nonetheless, both agree on prescribing a healthy lifestyle for all adults and screening persons deemed at increased cardiovascular risk, especially where the finding of diabetes would significantly alter the overall approach to cardiovascular prevention (see Chapter 93 for detailed discussion).

Diagnosis

Consensus diagnostic criteria have undergone revision in recent years: The glucose level for “normal” has been lowered, a “prediabetes” range has been defined, and the diagnosis of diabetes can now be made on the basis of the glycosylated hemoglobin (hemoglobin A_1c [HbA_1c]) as well as on the more traditional plasma glucose level (for details, see Chapter 93). Of note, the hemoglobin A1c, which reflects the cumulative 2- to 3-month endogenous exposure to glucose and provides an estimate of its average level, is more predictive of cardiovascular risk than the fasting glucose and, when used in screening, equivalent with regard to predicting risk of developing diabetes.

The preferred approach to classification, as issued by the American Diabetes Association, is according to underlying pathophysiology. Consequently, the preferred terms for diabetes classification are type 1 and type 2. Older classification terms, such as insulin-dependent and non-insulin-dependent diabetes, are discouraged because exogenous insulin may be needed to treat either form of the disease. Similarly, juvenile-onset, maturityonset, adult-onset, and maturity-onset diabetes of the young are discouraged because age of onset is not always pathophysiologically meaningful. No distinction is made between primary and secondary causes of diabetes.

Diagnostic Criteria

Normal

Fasting plasma glucose less than 100 mg/dL; hemoglobin A1c less than or equal to 5.6%.

Prediabetes: Increased Risk for Diabetes and Cardiovascular Complications

Between “normal” and “diabetes” levels of plasma glucose and serum hemoglobin A1c exists a range of readings associated with an increased risk of developing diabetes, particularly type 2, sometimes referred to as prediabetes. The risk for the development of overt type 2 diabetes is increased (1% to 5% annually), as is the risk for cardiovascular disease. Such patients may be identified by an impaired fasting glucose (IFG, plasma glucose 100 mg/dL to 125 mg/dL), an impaired glucose tolerance (IGT, fasting glucose <126 mg/dL and a 2-hour glucose level 140 mg/dL to 199 mg/d after a 75-g oral glucose challenge [oral glucose tolerance test—2-hour OGTT]), or HbA_1c levels of 5.7% to 6.4%. Persons in this category typically present with manifestations of the metabolic syndrome (i.e., obesity, dyslipidemia, and hypertension—see Chapters 26 and 27). Microvascular complications generally do not develop in those who do not progress to frank diabetes.

Diabetes

Often requires confirmation by repeat measurements on a separate day.

HbA_1c 6.5% or higher; fasting plasma glucose 126 mg/dL or higher; random plasma glucose 200 mg/dL or higher in a person with classic diabetic symptoms (polyuria, polydipsia, or weight loss) or a hyperglycemic crisis; 2-hour postprandial plasma glucose level 200 mg/dL or higher after the administration of the equivalent of a 75-g oral glucose load.

Gestational Diabetes

Gestational diabetes mellitus (GDM) refers to glucose intolerance diagnosed during pregnancy that is not clearly overt diabetes. In pregnancy, even minor degrees of glucose intolerance can adversely affect outcomes (see later discussion). Risk assessment should occur at the first prenatal visit in conjunction with standard screening for undiagnosed diabetes using standard diagnostic criteria in those with diabetes risk factors deemed at high risk for having preexisting diabetes (see Chapter 93). In pregnant women not known to have diabetes, screening is suggested at 24 to 28 weeks of gestation using a 75-g 2-hour OGTT. Plasma glucose is measured at fasting, 1 and 2 hours. The diagnosis of GDM is made if fasting plasma glucose is greater than or equal to 92 mg/dL or on OGTT, 1-hour glucose is greater than or equal to 180 mg/dL,
or 2-hour glucose is greater than or equal to 153 mg/dL. Women with GDM have an increased risk for developing diabetes throughout their lifetime and should have lifelong screening.

Other Forms

Rare forms of diabetes include genetic defects of beta-cell function or insulin action, damage to pancreatic exocrine tissue (e.g., cystic fibrosis, pancreatitis, pancreatectomy), endocrinopathies (e.g., Cushing syndrome, hyperthyroidism, acromegaly), drugs (e.g., glucocorticoids, thiazide diuretics), infections (congenital rubella, cytomegalovirus), uncommon forms of immune-mediated diabetes (e.g., stiff-man syndrome and anti-insulin receptor antibodies), and other genetic syndromes associated with diabetes (e.g., Down syndrome and the diabetes insipidus, diabetes mellitus, optic atrophy, and deafness syndrome).

Screening for Other Cardiovascular Risk Factors

The diagnosis of diabetes confers substantial cardiovascular event risk, equivalent to that of persons with clinically evident atherosclerotic disease (see Chapter 18). This has raised the question of screening newly diagnosed persons with type 2 disease for asymptomatic coronary disease as a means of improving cardiovascular outcomes through early diagnosis and treatment. In a large randomized trial of such screening by adenosine-stress radionuclide scanning, there was no difference in cardiac event rates at 5 years, indicating that such screening was not productive. However, screening for other major cardiovascular risk factors (e.g., hypertension, hypercholesterolemia, smoking) is warranted because treatment significantly lowers coronary event risk (see later discussion and Chapters 14, 15, 26, 27, 30, 31, and 54).

PRINCIPLES OF MANAGEMENT

Prevention (23, 24, 25, 26, 27 and 28—see also Chapters 18, 27, 54, and 233)

Prevention of type 2 diabetes is an achievable and important goal that deserves attention regardless of whether or not formal screening is conducted. Lifestyle elements such as lack of exercise, obesity, smoking, and high dietary consumption of saturated fat and sugar constitute powerful but modifiable risk factors. Several large randomized studies an meta-analyses of lifestyle modification have shown up to a 58% reduction in the rate of conversion from prediabetes to diabetes. Measures of demonstrated efficacy include 150 minutes of moderate aerobic exercise (e.g., brisk walking) weekly, use of a Mediterranean-style diet, and modest (7%) weight reduction. Smoking cessation is also essential, since smoking is an independent risk factor for development of type 2 disease. Initiation of metformin therapy in persons with prediabetes has also proved effective in randomized trial, but less so than lifestyle modification, underscoring the importance of lifestyle in the genesis, prevention, and treatment of type 2 disease. Use of insulin glargine can also reduce incidence of diabetes in dysglycemic patients, but at a cost of hypoglycemia and weight gain and without improving cardiovascular outcomes.

Treatment Goals, Strategies, and Key Elements Including Lifestyle Modification (29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57 and 58)

Treatment goals for glycemic control are becoming increasingly ambitious as the benefits of tight metabolic control become more evident and the means to achieve them more readily available. However, with tight control comes increased risk of severe hypoglycemia. Awareness of the risks as well as the benefits of such tight control is essential to design of a safe and effective therapeutic program.

Benefits and Risks of Tight Glycemic Control

Landmark, large-scale randomized trials such as the Diabetes Control and Complications Trial (involving type 1 patients) and the United Kingdom Prospective Diabetes Study (UKPDS— involving type 2 patients) demonstrated both in initial reports and in long-term follow-up (10 to 17 years) that early initiation of intensive treatment of hyperglycemia aimed at achieving and maintaining blood glucose concentrations close to the normal range (HbA_1c <7.0%) delays the onset and limits the progression of the long-term microvascular complications of diabetes and significantly reduces the risk of adverse cardiovascular events and all-cause mortality.

These very encouraging results created considerable interest in even more intense glycemic control, stimulating large-scale randomized trials of patients treated to tighter glycemic control targets (HbA_1c <6.5% or <6.0%—ADVANCE and ACCORD trials, respectively). These trials uncovered the downside of tight control, not only failure to achieve significant reductions in cardiovascular risk but in the case of the ACCORD study (where the goal was an HbA_1c of <6.0%), an increase in the all-cause mortality rate. A subsequent analysis of the ACCORD data found a strong independent correlation between severity of hypoglycemia and risk of adverse cardiovascular events and death. Of note, both the ACCORD and ADVANCE study populations were composed of higher-risk patients, with over a third having a prior cardiovascular event and many having long-standing type 2 diabetes before initiation of a tight glycemic control regimen.

Another important risk-benefit consideration derives from the Danish Steno-2 trial, in which persons with type 2 diabetes and microalbuminuria were randomized to comprehensive, intensive treatment of all major cardiovascular risk factors versus usual care. Significant reductions in cardiovascular event risk, cardiovascular mortality, and all-cause mortality were achieved with intensive multifactorial treatment without risk of serious adverse effects.

The take-home lesson from these important trials is that early initiation of tight, but not overly tight, glycemic control along with attention to all major cardiovascular risk factors provides the best chance of achieving significant and safe reductions in microvascular and macrovascular complications, including all-cause mortality.

Glycemic Goals (Table 102-1)

Based on such findings and others, the American Diabetes Association recommends a treatment goal of HbA_1c less than 7.0% and as close to normal as possible without inducing significant hypoglycemia.

TABLE 102-1 Goals for Glycemic Control for Nonpregnant Adults^a

▪ HbA_1c <7.0%

▪ Preprandial plasma glucose 70-130 mg/dL

▪ Peak postprandial plasma glucose <180 mg/dL

^a“Less-stringent A1C goals (such as <8%) may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions, and those with long-standing diabetes in whom the general goal is difficult to attain despite DSME, appropriate glucose monitoring, and effective doses of multiple glucose-lowering agents including insulin.” American Diabetes Association. Standards of medical care in diabetes—2012: position statement. Diabetes Care 2012;35(Suppl 1):S11.

Goals should be individualized based on duration of diabetes, age, life expectancy, comorbid conditions, hypoglycemic unawareness, and other individual patient considerations.

Treating the patient rather than treating “to target” is essential to maximizing patient safety in diabetes management. An elderly person with type 2 diabetes and preexisting cardiovascular disease is likely to be better served by a less intense glycemic control program and a higher target HbA_1c, which minimizes the changes of severe hypoglycemia, compared to the more aggressive glucose-lowering regimen appropriate for a newly diagnosed obese 50-year-old with type 2 disease and no clinical evidence of atherosclerotic disease.

Nonetheless, normalization of carbohydrate metabolism stands as a major treatment objective for all diabetics. The challenge is how to accomplish normalization without increasing hypoglycemic risk, given treatment modalities and monitoring methods available. Strong patient engagement and close support by the primary care team are essential. Advances in treatment and monitoring promise to facilitate safe achievement of glycemic control (see later discussion).

Treatment Strategy: Overview

The approach is pathophysiologically based, with a focus on the importance of establishing euglycemia as quickly as possible because diabetic complications are mostly a function of the degree and duration of hyperglycemia. Because the fasting glucose level is the most important determinant of daily glycemia, efforts to normalize it are given top priority. A reduction in postprandial glucose is also important, but the postprandial glucose level is a lesser determinant of overall control.

In type 1 disease, the emphasis is on intensive insulin therapy to make up for the loss of insulin production. Diet and exercise also play key roles because there is an increasing appreciation for the contribution of insulin resistance to poor glycemic control in type 1 disease.

In type 2 disease, insulin resistance is treated with diet, weight reduction, exercise, and, if necessary, drug therapy that improves insulin responsiveness. Impaired insulin secretion is countered by pharmacologic measures that increase endogenous insulin secretion or provide it exogenously. Combination programs that include insulin administration are often necessary to attain treatment goals, especially as the disease advances and pancreatic reserve declines.

Lifestyle modification (diet and exercise) remains the cornerstone of management. Traditionally, it has been initiated before starting drug therapy in type 2 disease, but recent expert consensus calls for more aggressive early intervention in hyperglycemic type 2 patients. Recommendations include treating with metformin in combination with lifestyle modification as the initial approach, followed by the early addition of other oral drugs or insulin if glycemic control is not readily achieved. Early drug therapy is also indicated if it is unlikely that the patient can lose weight or if the patient is pregnant.

Insulin remains the agent of first choice in persons with severe hyperglycemia, whether from type 1 or type 2 disease. For controlling mild-to-moderate hyperglycemia (fasting glucose between 140 and 240 mg/dL) in persons with type 2 disease, the biguanides (e.g., metformin) and to a lesser extent the second-generation sulfonylureas (e.g., glimepiride, glipizide, glyburide) are the agents of first choice. Compared to the newer and more expensive agents, metformin and the secondgeneration sulfonylureas demonstrate equivalent or superior efficacy at lower cost in control of hyperglycemia, lipids, and other intermediate treatment endpoints. Moreover, they have an established record of improving long-term outcomes (see later discussion).

A host of new drugs have appeared in recent years adding opportunity for mild-to-moderate enhancement of glycemic control, particularly in type 2 disease through a range of alternative mechanisms. Included are the thiazolidinediones (e.g., pioglitazone), α-glucosidase inhibitors (e.g., acarbose), meglitinides (e.g., repaglinide, nateglinide), amylin analogues (e.g., pramlintide), glucagon-like peptide-1 (GLP-1) analogues (e.g., exenatide), and dipeptidyl peptidase-4 (DPP-4) inhibitors (e.g., sitagliptin). Their use is heavily promoted and often costly. Cost-effectiveness, effects on long-term outcomes, and safety of long-term use remain to be determined (increased cardiovascular risk has emerged in postmarketing surveillance of one agent). Nonetheless, these drugs offer new avenues and additional approaches to glycemic control, some of which may complement first-line treatments or, in special circumstances, substitute for them. Clinically, they differ largely in terms of side effects, especially with regard to effects on weight and risk of hypoglycemia.

Coordination of care is essential because successful diabetes care requires a multifaceted collaborative approach involving the complementary inputs of many health care professionals (e.g., primary care physician, endocrinologist, nurse practitioner, nurse, clinical diabetic educator, dietitian, podiatrist, ophthalmologist, pharmacist, mental health professional). The ability to deliver and coordinate this care (whether orchestrated by a well-organized primary care practice, a diabetes specialty practice, or a commercial managed care program) demonstrably improves outcomes. Enhanced communication between patients and health care professionals reduces the need for avoidable hospitalizations and improves glycemic control.

Patient engagement and empowerment are also critical to achieving best outcomes in diabetes care. Diabetes self-management education (DSME) is an essential element. It is an approach that places the person with diabetes and their family at the center of the care model working along with health care professionals.

Lifestyle Modification: Diet and Exercise

Weight reduction through calorie restriction and exercise remains the cornerstone of therapy for all overweight patients with type 2 diabetes. Working toward attainment of ideal body weight is the best approach to achieving metabolic control. Even modest weight loss can improve glycemic control. A substantial reduction in blood glucose can be seen even within several days of instituting a low-calorie diet, as weight loss enhances the sensitivity of peripheral insulin receptors to endogenous insulin and reduces the requirements for administered insulin. Hepatic glycogen stores are depleted rapidly with caloric restriction.

It is not possible to predict the exact improvement in glucose control from each pound lost, but a reduction of body weight typically leads to an improvement in glucose tolerance. The glycemic response to weight loss is related to the initial fasting blood glucose. Patients who start off with lower fasting blood glucose levels will tend to normalize their blood glucose with less weight loss than those who start off with higher values.

The hyperglycemia of most type 2 diabetics can be controlled by achieving an ideal body weight; however, such weight reduction is often difficult to maintain because a permanent restriction in caloric intake is required. Rigidly developed and prescribed diets should be avoided in favor of diets adapted to the patient’s lifestyle. The goal is gradual, sustained weight reduction of approximately 1 to 2 lb each week (see Chapter 233). Consultation with a registered dietitian may be very helpful.

An effective exercise program (see Chapter 18) is another cornerstone of treatment. Exercise enhances weight loss by increasing caloric consumption, which is important in obese persons, who may require fewer calories to maintain their body weight. In addition, aerobic exercise facilitates glycemic control
independent of its effect on weight, reducing insulin resistance in liver and muscle in patients with type 2 disease.

Diet Composition.

Diet composition for type 2 diabetics is controversial and less critical than caloric restriction in achieving an ideal body weight. The best mix of carbohydrate, protein, and fat varies depending on individual circumstances. However, no matter what the macronutrient mix is, total caloric intake must be appropriate to weight management goals. The American Diabetes Association recommends diets low in calories, low in saturated fat, and liberal in complex carbohydrates, with as much as 60% of total calories allowed from such carbohydrates. Use of a Mediterranean-style diet, which has a high proportion of monounsaturated fat (mostly from fish and olive oil), a high ratio of polyunsaturates to saturated fat, and less than 50% of calories from carbohydrate, is associated with a significant reduction in cardiovascular risk (see Chapters 18, 27, 31, and 233). In randomized comparison with a low-fat diet in newly diagnosed patients with type 2 diabetes, the Mediterranean-style diet led to more favorable changes in weight, glycemic control, and cardiac risk factors and delay in need for pharmacologic therapy. Long-term daily use of an n-3 (omega-3) fatty acid supplement has no effect on rates of adverse cardiovascular events in high-risk patients with diabetes or glucose intolerance.

Simple carbohydrates are discouraged due to their adverse effects on glycemic control. Eating of potatoes causes greater increases in blood glucose than does eating beans or wheat, yet even inclusion of sucrose or ice cream in mixed meals does not necessarily adversely affect glucose control. Nonetheless, there is a trend toward tightening carbohydrate allowances in type 2 diabetics due to studies showing worsening glycemic control and increases in VLDL triglyceride and total cholesterol when carbohydrate intake is high. Type 2 patients may benefit from a diet that is lower in total carbohydrates and higher in unsaturated fat and fiber. Hypertriglyceridemia secondary to the increase in carbohydrates has not been a problem, and in several studies, triglycerides and cholesterol levels have fallen substantially. Saturated fat intake should be less than 7% of total calories. Reducing intake of trans fat lowers low density lipoprotein (LDL) cholesterol and increases HDL cholesterol (see Chapter 27).

Increasing fiber content, which occurs with a higher intake of complex carbohydrates and a decreased intake of refined carbohydrates and animal fats, is associated with a low prevalence of diabetes mellitus. Increased intake of unprocessed foods (e.g., cereals, grains, fruits, and vegetables) improves glucose tolerance in type 2 diabetics and decreases insulin requirements in type 1 diabetics. Vitamin supplements, particularly those with purported antioxidant action (see Chapter 31), have not demonstrated cardiovascular benefit in randomized, controlled trials, nor have B-vitamin supplements (folate, B₁₂, B₆) that lower homocysteine been found effective in reducing progression of diabetic nephropathy.

Low-carbohydrate diets (e.g., Atkins diet—see also Chapters 27 and 233) have become popular among obese persons interested in achieving weight loss. Short-term improvements in weight and glycemic control have been observed, but such diets are hard to maintain and do not appear to confer any advantages with regard to longer-term glycemic control or cardiovascular outcomes.

Special Dietary Considerations for Patients on Insulin.

For type 1 insulin-requiring diabetics who are at ideal body weight, the essential aspect of dietary therapy is the regularity of caloric intake and the spacing of meals. Three meals, supplemented by snacks midmorning, midafternoon, and before bed, are needed to provide a source of glucose during the sustained presence of exogenously administered insulin. The commonly used American Diabetic Association diets recommend 2/9 of calories at breakfast, 2/9 at lunch, 4/9 at dinner, and 1/9 as snacks. The timing of meals must match peak insulin effects and activity schedules; increased activity requires increased food intake or a decrease in insulin dose to prevent hypoglycemia. Simple sugars are generally restricted because they worsen postprandial hyperglycemia; however, patients should carry a source of simple sugar, such as fruit juice or sugar candy, to limit an insulin reaction. Patients who are not taking insulin do not require elaborate exchange systems, careful timing of meals, or other special dietary accommodations.

Exercise.

Exercise has important effects on glucose control in diabetes. It increases glucose consumption, reduces insulin resistance, and improves glycemic control. As noted, its benefits extend beyond those attributable to weight loss alone. All forms of aerobic exercise, even walking and other forms of nonvigorous activity, improve insulin sensitivity and significantly lower overall cardiovascular risk (see Chapters 18 and 31). Consensus guidelines that maximize cardiovascular benefit include 150 minutes per week of moderate intensity aerobic exercise or 75 minutes per week of vigorous aerobic physical activity or a combination of the two in conjunction with 2 or 3 days per week of muscle-strengthening activities that involve all major muscle groups. The combination of aerobic and resistance training has proven better than either alone in lowering glycosylated hemoglobin levels.

Despite the guidelines, a customized exercise program that takes into account patient preferences and overall medical condition helps maximize compliance and desired outcomes while limiting risk. A careful preexercise examination that includes cardiovascular, pulmonary, musculoskeletal, and neurologic assessments should precede implementation of an exercise program, especially in someone who has been sedentary or who might have underlying disease that would limit exercise capacity (see Chapter 18). Finding clinical evidence of coronary heart disease (CHD), inadequately controlled hypertension, proliferative or severe nonproliferative retinopathy, peripheral neuropathy, foot ulcers, or autonomic neuropathy would require significant program adjustment.

A few specific precautions are worth noting as regards the exercise prescription in diabetic patients: (a) Patients with diabetes are at markedly increased cardiovascular risk, which should be taken into account in the design of an exercise program; starting with a low-intensity program and building up gradually as tolerated maximizes safety, especially if there is the probability of preexisting CHD (see Chapters 18 and 31). (b) Injecting insulin into a limb that will be engaged in exercise may precipitate hypoglycemia due to increased absorption; the abdomen is the preferred site. (c) Doses of insulin and insulin secretagogues may need to be reduced with implementation of an exercise program that enhances glycemic control and thus increases the risk of hypoglycemia; carbohydrate consumption may need to be increased. (d) In type 1 diabetics, exercise should be avoided in the setting of ketosis due to its potential to exacerbate ketone formation.

Smoking Cessation (see Chapter 54)

Smoking increases the risk of developing type 2 diabetes by up to 50%. It has been found to be an independent risk factor. Achievement of smoking cessation in diabetes is not only worthwhile from the perspective of reducing diabetes risk but also essential to lowering cardiovascular risk (see later discussion). However, in community-based study, successful cessation efforts have been paradoxically associated with a shortterm increase in incidence of type 2 diabetes, linked to the weight gain typically seen in conjunction with smoking cessation (see Chapter 54). A program of weight reduction should accompany smoking cessation efforts in patients with type 2 disease.

Pharmacologic Measures: Overview

Insulin remains the principal pharmacologic approach to treatment of type 1 disease, given the condition’s underlying pathophysiology of absolute loss of insulin production capacity. Type 2 disease, with its altered insulin release and marked tissue resistance, allows for a wider array of approaches to treatment. Orally administered drugs have been popular among patients and physicians for initial treatment for type 2 diabetes, particularly for mild to moderate degrees of hyperglycemia, because they can delay the need for parenteral insulin. Traditionally, insulin secretagogues (exemplified by the sulfonylureas) served as first-line agents for this purpose, but their failure to improve cardiovascular outcomes has increasingly relegated them to a second-line role, though still widely prescribed. The prevalence of obesity and appreciation for the importance of insulin resistance in type 2 disease had led to the advent and ascendancy of the biguanides, particularly metformin, as first-line pharmacologic intervention. They achieve about the same degree of glycemic control as the sulfonylureas, but with better cardiovascular outcomes.

An array of new oral and parenterally administered drugs has emerged in recent years as alternative first- and second-line agents for treatment of type 2 diabetes. Most are oral drugs, including the thiazolidinediones (“TZDs,” “glitazones”), alpha-glucosidase inhibitors, incretin-based agents (DDP-4 enzyme inhibitors, “gliptins”), nonsulfonylurea secretagogues (“glinides”), and even a reformulation of bromocriptine. The parenteral agents are GLP1 analogues. These operate along a spectrum of pathophysiologic mechanisms; they provide similar degrees of added glycemic control, but differ in their associations with weight gain and hypoglycemia. Their specific contributions to treatment of type 2 diabetes and precise roles in therapy remain to be fully established due to uncertainty about their effects on long-term outcomes such as macrovascular complications and survival. For example, postmarketing surveillance has revealed adverse cardiovascular effects for one of the TZDs (see later discussion). At the same time, advances in insulin preparations and delivery systems are making possible earlier initiation of insulin in type 2 disease, being easier and more convenient to administer and more predictable in effect.

How these developments will turn out remains to be seen, but available information from major studies provides guidance for now on a reasonably safe and effective way to proceed with pharmacologic intervention, pending new data that will be forthcoming. The literature should be followed closely, because new treatment paradigms are likely to continue emerging.

First-Line Orally Active Agents (30,32,43,55, 56, 57, 58, 59, 60,62,64,65,67,71,72)

The biguanide metformin and, to a lesser extent, the sulfonylureas constitute the orally active first-line agents.

Biguanides (e.g., Metformin)

Metformin has become a cornerstone of drug treatment for type 2 disease, based on its proven efficacy not only in controlling glucose intolerance but also in significantly reducing risk of important macro- and microvascular outcomes, especially in overweight and obese patients (as found in the UKPDS study referred to earlier and below). In glycemic treatment algorithms for type 2 disease, initiation of metformin is recommended at the time of diagnosis along with diet and exercise. Comparative review finds it to have the best risk-benefit profile of available drugs for type 2 diabetes.

Mechanism of Action.

Metformin differs from the traditional oral hypoglycemics (i.e., the sulfonylureas) in that it does not stimulate endogenous insulin secretion; rather, drugs of this class enhance tissue responsiveness to insulin. Consequently, biguanides are less likely to induce hypoglycemia and are particularly effective in the treatment of overweight patients with tissue resistance to insulin. Biguanides facilitate insulin uptake by peripheral tissue, especially muscle and liver, and decrease hepatic gluconeogenesis and basal glucose output, thereby helping to lower fasting glucose levels. Glucose utilization also improves in adipose and intestinal tissues. The net result is an improvement in fasting and postprandial hyperglycemia. Insulin demand declines as glucose utilization improves. Serum lipid abnormalities also improve.

Preparations.

Metformin is the only biguanide approved in the United States for the treatment of type 2 diabetes. The drug is rapidly and well-absorbed in the small intestine, with peak plasma concentrations in 2 hours. It is rapidly excreted unchanged by the kidneys. Impaired renal function (creatinine >1.5 mg/dL in men and >1.4 mg/dL in women) is a contraindication for use, especially at full doses. The drug is not metabolized by the liver. The original biguanide, phenformin, is no longer marketed because of its associated risk for lactic acidosis and an excess cardiovascular mortality (see later discussion).

Dosing.

The starting dose of metformin is 500 mg once daily with dinner. After 1 week, the dose is increased to twice daily, given with the two largest meals of the day (usually breakfast and dinner) to minimize gastrointestinal upset. The dose can be increased by 500 mg every 1 to 2 weeks until treatment goals are met or the maximum dose of 2,000 to 2,500 mg/d is reached. An extended-release formulation is also available, which can help to improve compliance.

Efficacy.

When used as monotherapy in an obese person with moderate glucose intolerance, metformin’s efficacy in terms of glycemic control (i.e., lowering fasting glucose and glycosylated hemoglobin levels) is about the same as that of a second-generation sulfonylurea. Incidence of monotherapy treatment failure is less for metformin than for glyburide (21% vs. 34% at 5 years). A synergistic effect is achieved when combined with sulfonylurea therapy in patients who do not respond well to metformin alone. Unlike the sulfonylureas, metformin is effective even in severe fasting hyperglycemia (>300 mg/dL), indicative of poor beta-cell responsiveness. Plasma triglycerides and LDL cholesterol levels are decreased.

In the UKPDS trial noted earlier, obese patients (>120% of ideal weight) with type 2 diabetes treated with metformin and attaining target glycemic control achieved clinically important, statistically significant, sustained long-term reductions in risks of microvascular disease and macrovascular complications (i.e., myocardial infarction, stroke, and cardiovascular death); all-cause mortality was also significantly reduced. These findings make metformin one of the few antihyperglycemic drugs with demonstrated ability to reduce macrovascular risk, the holy grail of diabetes management.

Adverse Effects.

The most common side effect of biguanide therapy is dose-related gastrointestinal upset (nausea, diarrhea, bloating, abdominal discomfort). The risk for serious prolonged hypoglycemia is minimal. Lactic acidosis represents the most potentially serious adverse effect. One of the original biguanides—phenformin—was taken off the market by the U.S. Food and Drug Administration (FDA) in 1977 because of its association with fatal episodes of lactic acidosis. The risk for lactic acidosis associated with metformin is greatest in the setting of hypoxemia, hypovolemia, and states with decreased tissue perfusion and in renal insufficiency (creatinine >1.5 mg/dL). Accumulation of the drug secondary to reduced excretion results in impaired hepatic metabolism of lactate. Other risk factors include binge drinking, use of intravenous radiologic contrast agents, hepatic failure (lactate is metabolized by
the liver), and serious underlying illness, particularly heart failure.

Long-term data on safety have yet to be accumulated. Because insulin secretion is not increased with metformin use, weight gain does not occur; some patients may even lose weight. Patients who are to undergo a radiologic procedure that requires intravenous iodinated contrast should have their metformin therapy held for a few days prior to the procedure and remain well hydrated.

Patient Selection.

Based on the landmark results of the UKPDS, obese patients should be considered especially good candidates for metformin therapy. The drug helps to reverse their insulin resistance, peripheral responsiveness to insulin improves, and insulin needs decrease, so hyperinsulinism and its adverse effects, including weight gain, are minimized. The typical candidate is a moderately obese person with type 2 diabetes who has persistent moderate hyperglycemia (fasting glucose between 140 and 240 mg/dL, glycosylated hemoglobin >7.0%) despite a full program of diet and exercise. Early addition of metformin is suggested. Other candidates for metformin include obese patients who do not achieve tight control while taking a sulfonylurea at maximal doses. In this setting, metformin is added to the oral hypoglycemic program to improve control through its complementary mode of action. The sulfonylurea dose is reduced to lessen the risk for hypoglycemia. Combination therapy is most effective when initiated before the onset of symptomatic hyperglycemia (fasting glucose >250 mg/dL). Nonobese patients are also reasonable candidates for metformin. Typically, metformin lowers fasting blood glucose by approximately 20%.

Patients who started drug therapy with a sulfonylurea and become unresponsive to maximal doses have likely exhausted their beta-cell reserve and can be switched to metformin or considered for exogenous insulin therapy (sometimes in conjunction with metformin). The same pertains to the severely hyperglycemic obese patient (fasting glucose >300 mg/dL). Some diabetologists use metformin to supplement an insulin program in obese type 2 diabetics who require large insulin doses and have difficulty losing weight. The combined program helps to reduce insulin requirements and the appetite stimulation and weight gain that accompany hyperinsulinism. Caution and careful patient monitoring are required when a patient taking exogenous insulin is started on metformin; the insulin requirement may drop considerably, putting the patient at risk for hypoglycemia. Use in pregnancy is not associated with major congenital malformations.

Sulfonylureas

The sulfonylureas have been around for almost 50 years. With the advent of potent, long-acting, second-generation preparations and evidence of their efficacy and safety, the sulfonylureas continue to be a mainstay of treatment for mild to moderately severe type 2 disease (fasting glucose between 140 and 240 mg/dL). However, their primary role in treatment is undergoing reconsideration as metformin emerges as the more effective in terms of reducing cardiovascular risk (see later discussion). From 80% to 90% of newly treated type 2 diabetics respond to therapy. An absolute average reduction in HbA_1c of 1.5 to 2.0 percentage points, along with a reduction in fasting glucose of 60 to 70 mg/dL, is achieved in most cases. However, the secondary failure rate is high, and with time, despite continued therapy, glucose control worsens and a second oral agent or insulin is required. In addition, hypoglycemia is the most common side effect and is more concerning with the long-acting preparations.

Mechanism of Action.

The sulfonylureas acutely increase the sensitivity of beta cells to glucose and stimulate endogenous insulin release, probably by binding to a specific beta-cell receptor. This action can lead to hypoglycemia—hence the term oral hypoglycemic agents. These agents are effective in persons who require additional insulin secretion and have an adequate betacell reserve; they are ineffective in patients with type 1 diabetes. Enhancement of basal insulin secretion inhibits basal hepatic glucose production and improves the fasting glucose level. Efficacy declines with time as beta-cell function deteriorates; glycemic control worsens despite the use of maximum doses. Although these agents also increase insulin receptor binding and enhance tissue sensitivity to insulin, such effects are minor compared with the stimulation of insulin release and are insufficient to sustain glycemic control when insulin release declines.

Preparations and Pharmacology.

The first-generation sulfonylureas (e.g., chlorpropamide, tolbutamide, tolazamide) have given way to second-generation agents (e.g., glyburide, glipizide, glimepiride) in the treatment of type 2 diabetes, with the latter being more potent and some longer acting. All second-generation agents are available generically and of equal efficacy; bound nonionically to plasma proteins, they are less variable in bioavailability than first-generation oral agents. Duration of action is 12 to 24 hours. Drug metabolism is hepatic, necessitating caution and dose reduction in patients with liver disease. Glipizide releases insulin slightly more rapidly than the others, but this feature provides no special long-term advantage. In contrast to chlorpropamide, the second-generation agents do not cause inappropriate secretion of antidiuretic hormone and only rarely cause disulfiram (Antabuse)-like effects. Like those of their predecessors, the effects of these agents may be potentiated by sulfonamides, salicylates, and clofibrate or inhibited by warfarin.

Dosing Schedules (See Table 102-2).

Convenient once- or twicedaily dosing schedules are made possible by the 12- to 24-hour duration of action. A sustained-release glipizide preparation allows for once-daily dosing, which is a marginal convenience benefit but a means of reducing the cost of therapy if used in place of a twice-daily program. Because of the risk of hypoglycemia with long-acting sulfonylureas, in the elderly, it may be best to use a short-acting one like glipizide. The duration of action of glimepiride is slightly longer than that of other preparations (16 to 24 hours), so once-a-day dosing is also possible. A lower-dose formulation is available for glimepiride than for sustained-release glipizide, which facilitates its use in the elderly and those with mild hyperglycemia.

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