Comprehensive care of type 1 and type 2 DM requires an emphasis on nutrition, exercise, and monitoring of glycemic control but also usually involves glucose-lowering medication(s). This chapter discusses classes of such medications but does not describe every glucose-lowering agent available worldwide. The initial step is to select an individualized, glycemic goal for the patient.
ESTABLISHMENT OF TARGET LEVEL OF GLYCEMIC CONTROL
Because the complications of DM are related to glycemic control, normoglycemia or near-normoglycemia is the desired, but often elusive, goal for most patients. Normalization or near-normalization of the plasma glucose for long periods of time is extremely difficult, as demonstrated by the DCCT and United Kingdom Prospective Diabetes Study (UKPDS). Regardless of the level of hyperglycemia, improvement in glycemic control will lower the risk of diabetes-specific complications (Chap. 25).
The target for glycemic control (as reflected by the HbA1c) must be individualized, and the goals of therapy should be developed in consultation with the patient after considering a number of medical, social, and lifestyle issues. The ADA calls this a patient-centered approach, and other organizations such as the IDF and American Association of Clinical Endocrinologists (AACE) also suggest an individualized glycemic goal. Important factors to consider include the patient’s age and ability to understand and implement a complex treatment regimen, presence and severity of complications of diabetes, known cardiovascular disease (CVD), ability to recognize hypoglycemic symptoms, presence of other medical conditions or treatments that might affect survival or the response to therapy, lifestyle and occupation (e.g., possible consequences of experiencing hypoglycemia on the job), and level of support available from family and friends.
In general, the ADA suggests that the goal is to achieve an HbA1c as close to normal as possible without significant hypoglycemia. In most individuals, the target HbA1c should be <7% (Table 24-2) with a more stringent target for some patients. For instance, the HbA1c goal in a young adult with type 1 DM may be 6.5%. A higher HbA1c goal may be appropriate for the very young or old or in individuals with limited life span or comorbid conditions. For example, an appropriate HbA1c goal in elderly individuals with multiple, chronic illnesses and impaired activities of daily living might be 8.0 or 8.5%. A major consideration is the frequency and severity of hypoglycemia, because this becomes more common with a more stringent HbA1c goal.
More stringent glycemic control (HbA1c of ≤6%) is not beneficial, and may be detrimental, in patients with type 2 DM and a high risk of CVD. Large clinical trials (UKPDS, Action to Control Cardiovascular Risk in Diabetes [ACCORD], Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation [ADVANCE], Veterans Affairs Diabetes Trial [VADT]; Chap. 25) have examined glycemic control in type 2 DM in individuals with low risk of CVD, with high risk of CVD, or with established CVD and have found that more intense glycemic control is not beneficial and, in some patient populations, may have a negative impact on some outcomes. These divergent outcomes stress the need for individualized glycemic goals based on the following general guidelines: (1) early in the course of type 2 diabetes when the CVD risk is lower, improved glycemic control likely leads to improved cardiovascular outcome, but this benefit occurs more than a decade after the period of improved glycemic control; (2) intense glycemic control in individuals with established CVD or at high risk for CVD is not advantageous, and may be deleterious, over a follow-up of 3–5 years; an HbA1c goal <7.0% is not appropriate in this population; (3) hypoglycemia in such high-risk populations (elderly, CVD) should be avoided; and (4) improved glycemic control reduces microvascular complications of diabetes (Chap. 25) even if it does not improve macrovascular complications like CVD.
The ADA recommendations for fasting and bedtime glycemic goals and HbA1c targets are summarized in Table 24-2. The goal is to design and implement insulin regimens that mimic physiologic insulin secretion. Because individuals with type 1 DM partially or completely lack endogenous insulin production, administration of basal insulin is essential for regulating glycogen breakdown, gluconeogenesis, lipolysis, and ketogenesis. Likewise, insulin replacement for meals should be appropriate for the carbohydrate intake and promote normal glucose utilization and storage.
Intensive diabetes management has the goal of achieving euglycemia or near-normal glycemia. This approach requires multiple resources, including thorough and continuing patient education, comprehensive recording of plasma glucose measurements and nutrition intake by the patient, and a variable insulin regimen that matches glucose intake and insulin dose. Insulin regimens usually include multiple-component insulin regimens, multiple daily injections (MDIs), or insulin infusion devices (each discussed below).
The benefits of intensive diabetes management and improved glycemic control include a reduction in the microvascular complications of DM and a reduction in diabetes-related complications. From a psychological standpoint, the patient experiences greater control over his or her diabetes and often notes an improved sense of well-being, greater flexibility in the timing and content of meals, and the capability to alter insulin dosing with exercise. In addition, intensive diabetes management prior to and during pregnancy reduces the risk of fetal malformations and morbidity. Intensive diabetes management is encouraged in newly diagnosed patients with type 1 DM because it may prolong the period of C-peptide production, which may result in better glycemic control and a reduced risk of serious hypoglycemia. Although intensive management confers impressive benefits, it is also accompanied by significant personal and financial costs and is therefore not appropriate for all individuals.
Current insulin preparations are generated by recombinant DNA technology and consist of the amino acid sequence of human insulin or variations thereof. In the United States, most insulin is formulated as U-100 (100 units/mL). Regular insulin formulated as U-500 (500 units/mL) is available and sometimes useful in patients with severe insulin resistance. Human insulin has been formulated with distinctive pharmacokinetics or genetically modified to more closely mimic physiologic insulin secretion. Insulins can be classified as short-acting or long-acting (Table 24-4). For example, one short-acting insulin formulation, insulin lispro, is an insulin analogue in which the 28th and 29th amino acids (lysine and proline) on the insulin B chain have been reversed by recombinant DNA technology. Insulin aspart and insulin glulisine are genetically modified insulin analogues with properties similar to lispro. All three of the insulin analogues have full biologic activity but less tendency for self-aggregation, resulting in more rapid absorption and onset of action and a shorter duration of action. These characteristics are particularly advantageous for allowing entrainment of insulin injection and action to rising plasma glucose levels following meals. The shorter duration of action also appears to be associated with a decreased number of hypoglycemic episodes, primarily because the decay of insulin action corresponds to the decline in plasma glucose after a meal. Thus, insulin aspart, lispro, or glulisine is preferred over regular insulin for prandial coverage. Insulin glargine is a long-acting biosynthetic human insulin that differs from normal insulin in that asparagine is replaced by glycine at amino acid 21, and two arginine residues are added to the C terminus of the B chain. Compared to neutral protamine Hagedorn (NPH) insulin, the onset of insulin glargine action is later, the duration of action is longer (~24 h), and there is a less pronounced peak. A lower incidence of hypoglycemia, especially at night, has been reported with insulin glargine when compared to NPH insulin. The most recent evidence does not support an association between glargine and increased cancer risk. Insulin detemir has a fatty acid side chain that prolongs its action by slowing absorption and catabolism. Twice-daily injections of glargine or detemir are sometimes required to provide 24-h coverage. Regular and NPH insulin have the native insulin amino acid sequence.
TABLE 24-4PROPERTIES OF INSULIN PREPARATIONSa ||Download (.pdf) TABLE 24-4 PROPERTIES OF INSULIN PREPARATIONSa
| ||TIME OF ACTION |
|PREPARATION ||ONSET, H ||PEAK, H ||EFFECTIVE DURATION, H |
|Short-acting || || || |
| Aspart ||<0.25 ||0.5–1.5 ||2–4 |
| Glulisine ||<0.25 ||0.5–1.5 ||2–4 |
| Lispro ||<0.25 ||0.5–1.5 ||2–4 |
| Regular ||0.5–1.0 ||2–3 ||3–6 |
|Long-acting || || || |
| Detemir ||1–4 ||—b ||12-24c |
| Glargine ||2–4 ||—b ||20-24 |
| NPH ||2–4 ||4–10 ||10–16 |
|Insulin combinationsd || || || |
| 75/25–75% protamine lispro, 25% lispro ||<0.25 ||Duale ||10–16 |
| 70/30–70% protamine aspart, 30% aspart ||<0.25 ||Duale ||15–18 |
| 50/50–50% protamine lispro, 50% lispro ||<0.25 ||Duale ||10–16 |
| 70/30–70% NPH, 30% regular ||0.5–1 ||Duale ||10–16 |
Basal insulin requirements are provided by long-acting (NPH insulin, insulin glargine, or insulin detemir) insulin formulations. These are usually prescribed with short-acting insulin in an attempt to mimic physiologic insulin release with meals. Although mixing of NPH and short-acting insulin formulations is common practice, this mixing may alter the insulin absorption profile (especially the short-acting insulins). For example, lispro absorption is delayed by mixing with NPH. The alteration in insulin absorption when the patient mixes different insulin formulations should not prevent mixing insulins. However, the following guidelines should be followed: (1) mix the different insulin formulations in the syringe immediately before injection (inject within 2 min after mixing); (2) do not store insulin as a mixture; (3) follow the same routine in terms of insulin mixing and administration to standardize the physiologic response to injected insulin; and (4) do not mix insulin glargine or detemir with other insulins. The miscibility of some insulins allows for the production of combination insulins that contain 70% NPH and 30% regular (70/30), or equal mixtures of NPH and regular (50/50). By including the insulin analogue mixed with protamine, several combinations have a short-acting and long-acting profile (Table 24-4). Although more convenient for the patient (only two injections/day), combination insulin formulations do not allow independent adjustment of short-acting and long-acting activity. Several insulin formulations are available as insulin “pens,” which may be more convenient for some patients. Insulin delivery by inhalation has recently been approved but is not yet available. Other insulins, such as one with a duration of action of several days, are under development but are not currently available in the United States.
Representations of the various insulin regimens that may be used in type 1 DM are illustrated in Fig. 24-1. Although the insulin profiles are depicted as “smooth,” symmetric curves, there is considerable patient-to-patient variation in the peak and duration. In all regimens, long-acting insulins (NPH, glargine, or detemir) supply basal insulin, whereas regular, insulin aspart, glulisine, or lispro insulin provides prandial insulin. Short-acting insulin analogues should be injected just before (<10 min) or just after a meal; regular insulin is given 30–45 min prior to a meal. Sometimes short-acting insulin analogues are injected just after a meal (gastroparesis, unpredictable food intake).
Representative insulin regimens for the treatment of diabetes. For each panel, the y-axis shows the amount of insulin effect and the x-axis shows the time of day. B, breakfast; HS, bedtime; L, lunch; S, supper. *Lispro, glulisine, or insulin aspart can be used. The time of insulin injection is shown with a vertical arrow. The type of insulin is noted above each insulin curve. A. Multiple-component insulin regimen consisting of long-acting insulin (∧glargine or detemir) to provide basal insulin coverage and three shots of glulisine, lispro, or insulin aspart to provide glycemic coverage for each meal. B. Injection of two shots of long-acting insulin (NPH) and short-acting insulin analogue (glulisine, lispro, insulin aspart [solid red line], or regular insulin [green dashed line]). Only one formulation of short-acting insulin is used. C. Insulin administration by insulin infusion device is shown with the basal insulin and a bolus injection at each meal. The basal insulin rate is decreased during the evening and increased slightly prior to the patient awakening in the morning. Glulisine, lispro, or insulin aspart is used in the insulin pump. (Adapted from H Lebovitz [ed]: Therapy for Diabetes Mellitus. American Diabetes Association, Alexandria, VA, 2004.)
A shortcoming of current insulin regimens is that injected insulin immediately enters the systemic circulation, whereas endogenous insulin is secreted into the portal venous system. Thus, exogenous insulin administration exposes the liver to subphysiologic insulin levels. No insulin regimen reproduces the precise insulin secretory pattern of the pancreatic islet. However, the most physiologic regimens entail more frequent insulin injections, greater reliance on short-acting insulin, and more frequent capillary plasma glucose measurements. In general, individuals with type 1 DM require 0.5–1 U/kg per day of insulin divided into multiple doses, with ~50% of the insulin given as basal insulin.
Multiple-component insulin regimens refer to the combination of basal insulin and bolus insulin (preprandial short-acting insulin). The timing and dose of short-acting, preprandial insulin are altered to accommodate the SMBG results, anticipated food intake, and physical activity. Such regimens offer the patient with type 1 diabetes more flexibility in terms of lifestyle and the best chance for achieving near normoglycemia. One such regimen, shown in Fig. 24-1B, consists of basal insulin with glargine or detemir and preprandial lispro, glulisine, or insulin aspart. The insulin aspart, glulisine, or lispro dose is based on individualized algorithms that integrate the preprandial glucose and the anticipated carbohydrate intake. To determine the meal component of the preprandial insulin dose, the patient uses an insulin-to-carbohydrate ratio (a common ratio for type 1 DM is 1–1.5 units/10 g of carbohydrate, but this must be determined for each individual). To this insulin dose is added the supplemental or correcting insulin based on the preprandial blood glucose (one formula uses 1 unit of insulin for every 2.7 mmol/L [50 mg/dL] over the preprandial glucose target; another formula uses [body weight in kg] × [blood glucose – desired glucose in mg/dL]/1500). An alternative multiple-component insulin regimen consists of bedtime NPH insulin, a small dose of NPH insulin at breakfast (20–30% of bedtime dose), and preprandial short-acting insulin. Other variations of this regimen are in use but have the disadvantage that NPH has a significant peak, making hypoglycemia more common. Frequent SMBG (more than three times per day) is absolutely essential for these types of insulin regimens.
In the past, one commonly used regimen consisted of twice-daily injections of NPH mixed with a short-acting insulin before the morning and evening meals (Fig. 24-1B). Such regimens usually prescribe two-thirds of the total daily insulin dose in the morning (with about two-thirds given as long-acting insulin and one-third as short-acting) and one-third before the evening meal (with approximately one-half given as long-acting insulin and one-half as short-acting). The drawback to such a regimen is that it forces a rigid schedule on the patient, in terms of daily activity and the content and timing of meals. Although it is simple and effective at avoiding severe hyperglycemia, it does not generate near-normal glycemic control in individuals with type 1 DM. Moreover, if the patient’s meal pattern or content varies or if physical activity is increased, hyperglycemia or hypoglycemia may result. Moving the long-acting insulin from before the evening meal to bedtime may avoid nocturnal hypoglycemia and provide more insulin as glucose levels rise in the early morning (so-called dawn phenomenon). The insulin dose in such regimens should be adjusted based on SMBG results with the following general assumptions: (1) the fasting glucose is primarily determined by the prior evening long-acting insulin; (2) the pre-lunch glucose is a function of the morning short-acting insulin; (3) the pre-supper glucose is a function of the morning long-acting insulin; and (4) the bedtime glucose is a function of the pre-supper, short-acting insulin. This is not an optimal regimen for the patient with type 1 DM, but is sometimes used for patients with type 2 DM.
Continuous SC insulin infusion (CSII) is a very effective insulin regimen for the patient with type 1 DM (Fig. 24-1C). To the basal insulin infusion, a preprandial insulin (“bolus”) is delivered by the insulin infusion device based on instructions from the patient, who uses an individualized algorithm incorporating the preprandial plasma glucose and anticipated carbohydrate intake. These sophisticated insulin infusion devices can accurately deliver small doses of insulin (microliters per hour) and have several advantages: (1) multiple basal infusion rates can be programmed to accommodate nocturnal versus daytime basal insulin requirement; (2) basal infusion rates can be altered during periods of exercise; (3) different waveforms of insulin infusion with meal-related bolus allow better matching of insulin depending on meal composition; and (4) programmed algorithms consider prior insulin administration and blood glucose values in calculating the insulin dose. These devices require instruction by a health professional with considerable experience with insulin-infusion devices and very frequent patient interactions with the diabetes management team. Insulin-infusion devices present unique challenges, such as infection at the infusion site, unexplained hyperglycemia because the infusion set becomes obstructed, or diabetic ketoacidosis if the pump becomes disconnected. Because most physicians use lispro, glulisine, or insulin aspart in CSII, the extremely short half-life of these insulins quickly leads to insulin deficiency if the delivery system is interrupted. Essential to the safe use of infusion devices is thorough patient education about pump function and frequent SMBG. Efforts to create a closed-loop system in which data from continuous glucose measurement regulate the insulin infusion rate are under way.
Other agents that improve glucose control
The role of amylin, a 37-amino-acid peptide co-secreted with insulin from pancreatic beta cells, in normal glucose homeostasis is uncertain. However, based on the rationale that patients who are insulin deficient are also amylin deficient, an analogue of amylin (pramlintide) was created and found to reduce postprandial glycemic excursions in type 1 and type 2 diabetic patients taking insulin. Pramlintide injected just before a meal slows gastric emptying and suppresses glucagon but does not alter insulin levels. Pramlintide is approved for insulin-treated patients with type 1 and type 2 DM. Addition of pramlintide produces a modest reduction in the HbA1c and seems to dampen meal-related glucose excursions. In type 1 DM, pramlintide is started as a 15-μg SC injection before each meal and titrated up to a maximum of 30–60 μg as tolerated. In type 2 DM, pramlintide is started as a 60-μg SC injection before each meal and may be titrated up to a maximum of 120 μg. The major side effects are nausea and vomiting, and dose escalations should be slow to limit these side effects. Because pramlintide slows gastric emptying, it may influence absorption of other medications and should not be used in combination with other drugs that slow GI motility. The short-acting insulin given before the meal should initially be reduced to avoid hypoglycemia and then titrated as the effects of the pramlintide become evident. α-Glucosidase inhibitors are sometimes used with insulin in type 1 DM.
The goals of glycemia-controlling therapy for type 2 DM are similar to those in type 1 DM. Whereas glycemic control tends to dominate the management of type 1 DM, the care of individuals with type 2 DM must also include attention to the treatment of conditions associated with type 2 DM (e.g., obesity, hypertension, dyslipidemia, CVD) and detection/management of DM-related complications (Fig. 24-2). Reduction in cardiovascular risk is of paramount importance because this is the leading cause of mortality in these individuals.
Essential elements in comprehensive care of type 2 diabetes.
Type 2 DM management should begin with MNT (discussed above). An exercise regimen to increase insulin sensitivity and promote weight loss should also be instituted. Pharmacologic approaches to the management of type 2 DM include oral glucose-lowering agents, insulin, and other agents that improve glucose control; most physicians and patients prefer oral glucose-lowering agents as the initial choice. Any therapy that improves glycemic control reduces “glucose toxicity” to beta cells and improves endogenous insulin secretion. However, type 2 DM is a progressive disorder and ultimately requires multiple therapeutic agents and often insulin in most patients.
Advances in the therapy of type 2 DM have generated oral glucose-lowering agents that target different pathophysiologic processes in type 2 DM. Based on their mechanisms of action, glucose-lowering agents are subdivided into agents that increase insulin secretion, reduce glucose production, increase insulin sensitivity, enhance GLP-1 action, or promote urinary excretion of glucose (Table 24-5). Glucose-lowering agents other than insulin (with the exception of amylin analogue and α-glucosidase inhibitors) are ineffective in type 1 DM and should not be used for glucose management of severely ill individuals with type 2 DM. Insulin is sometimes the initial glucose-lowering agent in type 2 DM.
TABLE 24-5AGENTS USED FOR TREATMENT OF TYPE 1 OR TYPE 2 DIABETES ||Download (.pdf) TABLE 24-5 AGENTS USED FOR TREATMENT OF TYPE 1 OR TYPE 2 DIABETES
| ||MECHANISM OF ACTION ||EXAMPLESa ||HBA1c REDUCTION (%)b ||AGENT-SPECIFIC ADVANTAGES ||AGENT-SPECIFIC DISADVANTAGES ||CONTRAINDICATIONS |
|Biguanidesc* ||↓ Hepatic glucose production ||Metformin ||1–2 ||Weight neutral, do not cause hypoglycemia, inexpensive, extensive experience, ↓ CV events ||Diarrhea, nausea, lactic acidosis ||Serum creatinine >1.5 mg/dL (men) >1.4 mg/dL (women) (see text), CHF, radiographic contrast studies, hospitalized patients, acidosis |
|α-Glucosidase inhibitorsc** ||↓ GI glucose absorption ||Acarbose, miglitol, voglibose ||0.5–0.8 ||Reduce postprandial glycemia ||GI flatulence, liver function tests ||Renal/liver disease |
|Dipeptidyl peptidase IV inhibitorsc*** ||Prolong endogenous GLP-1 action ||Alogliptin, Anagliptin, Gemigliptin, linagliptin, saxagliptin, sitagliptin, teneligliptin, vildagliptin ||0.5–0.8 ||Well tolerated, do not cause hypoglycemia || ||Reduced dose with renal disease; one associated with increase heart failure risk; possible association with ACE inhibitor–induced angioedema |
|Insulin secretagogues: Sulfonylureasc* ||↑ Insulin secretion ||Glibornuride, gliclazide, glimepiride, glipizide, gliquidone, glyburide, glyclopyramide ||1–2 ||Short onset of action, lower postprandial glucose, inexpensive ||Hypoglycemia, weight gain ||Renal/liver disease |
|Insulin secretagogues: Nonsulfonylureasc*** ||↑ Insulin secretion ||Nateglinide, repaglinide, mitiglinide ||0.5–1.0 ||Short onset of action, lower postprandial glucose ||Hypoglycemia ||Renal/liver disease |
|Sodium-glucose co-transporter 2 inhibitors*** ||↑ Urinary glucose excretion ||Canagliflozin, dapagliflozin, empagliflozin ||0.5–1.0 ||Insulin secretion and action independent ||Urinary and vaginal infections, dehydration, exacerbate tendency to hyperkalemia ||Limited clinical experience; moderate renal insufficiency |
|Thiazolidinedionesc*** ||↓ Insulin resistance, ↑ glucose utilization ||Rosiglitazone, pioglitazone ||0.5–1.4 ||Lower insulin requirements ||Peripheral edema, CHF, weight gain, fractures, macular edema ||CHF, liver disease |
|Amylin agonistsc,d*** ||Slow gastric emptying, ↓ glucagon ||Pramlintide ||0.25–0.5 ||Reduce postprandial glycemia, weight loss ||Injection, nausea, ↑ risk of hypoglycemia with insulin ||Agents that also slow GI motility |
|GLP-1 receptor agonistsc*** ||↑ Insulin, ↓ glucagon, slow gastric emptying, satiety ||Exenatide, liraglutide, dulaglutide ||0.5–1.0 ||Weight loss, do not cause hypoglycemia ||Injection, nausea, ↑ risk of hypoglycemia with insulin secretagogues ||Renal disease, agents that also slow GI motility; medullary carcinoma of thyroid |
|Insulinc,d**** ||↑ Glucose utilization, ↓ hepatic glucose production, and other anabolic actions ||See text and Table 24-4 ||Not limited ||Known safety profile ||Injection, weight gain, hypoglycemia || |
|Medical nutrition therapy and physical activityc* ||↓ Insulin resistance, ↑ insulin secretion ||Low-calorie, low-fat diet, exercise ||1–3 ||Other health benefits ||Compliance difficult, long-term success low || |
Metformin, representative of this class of agents, reduces hepatic glucose production and improves peripheral glucose utilization slightly (Table 24-5). Metformin activates AMP-dependent protein kinase and enters cells through organic cation transporters (polymorphisms of these may influence the response to metformin). Recent evidence indicates that metformin’s mechanism for reducing hepatic glucose production is to antagonize glucagon’s ability to generate cAMP in hepatocytes. Metformin reduces fasting plasma glucose (FPG) and insulin levels, improves the lipid profile, and promotes modest weight loss. An extended-release form is available and may have fewer gastrointestinal side effects (diarrhea, anorexia, nausea, metallic taste). Because of its relatively slow onset of action and gastrointestinal symptoms with higher doses, the initial dose should be low and then escalated every 2–3 weeks based on SMBG measurements. Metformin is effective as monotherapy and can be used in combination with other oral agents or with insulin. The major toxicity of metformin, lactic acidosis, is very rare and can be prevented by careful patient selection. Vitamin B12 levels are ~30% lower during metformin treatment. Metformin should not be used in patients with renal insufficiency (glomerular filtration rate [GFR] <60 mL/min), any form of acidosis, unstable congestive heart failure (CHF), liver disease, or severe hypoxemia. Some feel that that these guidelines are too restrictive and prevent individuals with mild to moderate renal impairment from being safely treated with metformin. The National Institute for Health and Clinical Excellence in the United Kingdom suggests that metformin be used at a GFR >30 mL/min, with a reduced dose when the GFR is <45 mL/min. Metformin should be discontinued in hospitalized patients, in patients who can take nothing orally, and in those receiving radiographic contrast material. Insulin should be used until metformin can be restarted.
Insulin secretagogues—agents that affect the ATP-sensitive K+ channel
Insulin secretagogues stimulate insulin secretion by interacting with the ATP-sensitive potassium channel on the beta cell (Chap. 23). These drugs are most effective in individuals with type 2 DM of relatively recent onset (<5 years) who have residual endogenous insulin production. First-generation sulfonylureas (chlorpropamide, tolazamide, tolbutamide) have a longer half-life, a greater incidence of hypoglycemia, and more frequent drug interactions, and are no longer used. Second-generation sulfonylureas have a more rapid onset of action and better coverage of the postprandial glucose rise, but the shorter half-life of some agents may require more than once-a-day dosing. Sulfonylureas reduce both fasting and postprandial glucose and should be initiated at low doses and increased at 1- to 2-week intervals based on SMBG. In general, sulfonylureas increase insulin acutely and thus should be taken shortly before a meal; with chronic therapy, though, the insulin release is more sustained. Glimepiride and glipizide can be given in a single daily dose and are preferred over glyburide, especially in the elderly. Repaglinide, nateglinide, and mitiglinide are not sulfonylureas but also interact with the ATP-sensitive potassium channel. Because of their short half-life, these agents are given with each meal or immediately before to reduce meal-related glucose excursions.
Insulin secretagogues, especially the longer acting ones, have the potential to cause hypoglycemia, especially in elderly individuals. Hypoglycemia is usually related to delayed meals, increased physical activity, alcohol intake, or renal insufficiency. Individuals who ingest an overdose of some agents develop prolonged and serious hypoglycemia and should be monitored closely in the hospital (Chap. 26). Most sulfonylureas are metabolized in the liver to compounds (some of which are active) that are cleared by the kidney. Thus, their use in individuals with significant hepatic or renal dysfunction is not advisable. Weight gain, a common side effect of sulfonylurea therapy, results from the increased insulin levels and improvement in glycemic control. Some sulfonylureas have significant drug interactions with alcohol and some medications including warfarin, aspirin, ketoconazole, α-glucosidase inhibitors, and fluconazole. A related isoform of ATP-sensitive potassium channels is present in the myocardium and the brain. All of these agents except glyburide have a low affinity for this isoform. Despite concerns that this agent might affect the myocardial response to ischemia and observational studies suggesting that sulfonylureas increase cardiovascular risk, studies have not shown an increased cardiac mortality with glyburide or other agents in this class.
Insulin secretagogues—agents that enhance GLP-1 receptor signaling
“Incretins” amplify glucose-stimulated insulin secretion (Chap. 23). Agents that either act as a GLP-1 receptor agonist or enhance endogenous GLP-1 activity are approved for the treatment of type 2 DM (Table 24-5). Agents in this class do not cause hypoglycemia because of the glucose-dependent nature of incretin-stimulated insulin secretion (unless there is concomitant use of an agent that can lead to hypoglycemia—sulfonylureas, etc.). Exenatide, a synthetic version of a peptide initially identified in the saliva of the Gila monster (exendin-4), is an analogue of GLP-1. Unlike native GLP-1, which has a half-life of >5 min, differences in the exenatide amino acid sequence render it resistant to the enzyme that degrades GLP-1 (dipeptidyl peptidase IV [DPP-IV]). Thus, exenatide has prolonged GLP-1-like action and binds to GLP-1 receptors found in islets, the gastrointestinal tract, and the brain. Liraglutide, another GLP-1 receptor agonist, is almost identical to native GLP-1 except for an amino acid substitution and addition of a fatty acyl group (coupled with a γ-glutamic acid spacer) that promote binding to albumin and plasma proteins and prolong its half-life. GLP-1 receptor agonists increase glucose-stimulated insulin secretion, suppress glucagon, and slow gastric emptying. These agents do not promote weight gain; in fact, most patients experience modest weight loss and appetite suppression. Treatment with these agents should start at a low dose to minimize initial side effects (nausea being the limiting one). GLP-1 receptor agonists, available in twice daily, daily, and weekly injectable formulations, can be used as combination therapy with metformin, sulfonylureas, and thiazolidinediones. Some patients taking insulin secretagogues may require a reduction in those agents to prevent hypoglycemia. The major side effects are nausea, vomiting, and diarrhea. Some formulations carry a black box warning from the FDA because of an increased risk of thyroid C-cell tumors in rodents and are contraindicated in individuals with medullary carcinoma of the thyroid or multiple endocrine neoplasia. Because GLP-1 receptor agonists slow gastric emptying, they may influence the absorption of other drugs. Whether GLP-1 receptor agonists enhance beta cell survival, promote beta cell proliferation, or alter the natural history of type 2 DM is not known. Other GLP-1 receptor agonists and formulations are under development.
DPP-IV inhibitors inhibit degradation of native GLP-1 and thus enhance the incretin effect. DPP-IV, which is widely expressed on the cell surface of endothelial cells and some lymphocytes, degrades a wide range of peptides (not GLP-1 specific). DPP-IV inhibitors promote insulin secretion in the absence of hypoglycemia or weight gain and appear to have a preferential effect on postprandial blood glucose. The levels of GLP-1 action in the patient are greater with the GLP-1 receptor agonists than with DPP-IV inhibitors. DPP-IV inhibitors are used either alone or in combination with other oral agents in type 2 DM. Reduced doses should be given to patients with renal insufficiency. Initial concerns about the pancreatic side effects of GLP-1 receptor agonists and DPP-IV inhibitors (pancreatitis, possible premalignant lesions) appear to be unfounded.
α-Glucosidase inhibitors reduce postprandial hyperglycemia by delaying glucose absorption; they do not affect glucose utilization or insulin secretion (Table 24-5). Postprandial hyperglycemia, secondary to impaired hepatic and peripheral glucose disposal, contributes significantly to the hyperglycemic state in type 2 DM. These drugs, taken just before each meal, reduce glucose absorption by inhibiting the enzyme that cleaves oligosaccharides into simple sugars in the intestinal lumen. Therapy should be initiated at a low dose with the evening meal and increased to a maximal dose over weeks to months. The major side effects (diarrhea, flatulence, abdominal distention) are related to increased delivery of oligosaccharides to the large bowel and can be reduced somewhat by gradual upward dose titration. α-Glucosidase inhibitors may increase levels of sulfonylureas and increase the incidence of hypoglycemia. Simultaneous treatment with bile acid resins and antacids should be avoided. These agents should not be used in individuals with inflammatory bowel disease, gastroparesis, or a serum creatinine >177 μmol/L (2 mg/dL). This class of agents is not as potent as other oral agents in lowering the HbA1c but is unique because it reduces the postprandial glucose rise even in individuals with type 1 DM. If hypoglycemia from other diabetes treatments occurs while taking these agents, the patient should consume glucose because the degradation and absorption of complex carbohydrates will be retarded.
Thiazolidinediones (Table 24-5) reduce insulin resistance by binding to the PPAR-γ (peroxisome proliferator–activated receptor γ) nuclear receptor (which forms a heterodimer with the retinoid X receptor). The PPAR-γ receptor is found at highest levels in adipocytes but is expressed at lower levels in many other tissues. Agonists of this receptor regulate a large number of genes, promote adipocyte differentiation, reduce hepatic fat accumulation, and promote fatty acid storage. Thiazolidinediones promote a redistribution of fat from central to peripheral locations. Circulating insulin levels decrease with use of the thiazolidinediones, indicating a reduction in insulin resistance. Although direct comparisons are not available, the two currently available thiazolidinediones appear to have similar efficacy. The prototype of this class of drugs, troglitazone, was withdrawn from the U.S. market after reports of hepatotoxicity and an association with an idiosyncratic liver reaction that sometimes led to hepatic failure. Although rosiglitazone and pioglitazone do not appear to induce the liver abnormalities seen with troglitazone, the FDA recommends measurement of liver function tests prior to initiating therapy.
Rosiglitazone raises low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides slightly. Pioglitazone raises HDL to a greater degree and LDL a lesser degree but lowers triglycerides. The clinical significance of the lipid changes with these agents is not known and may be difficult to ascertain because most patients with type 2 DM are also treated with a statin.
Thiazolidinediones are associated with weight gain (2–3 kg), a small reduction in the hematocrit, and a mild increase in plasma volume. Peripheral edema and CHF are more common in individuals treated with these agents. These agents are contraindicated in patients with liver disease or CHF (class III or IV). The FDA has issued an alert that rare patients taking these agents may experience a worsening of diabetic macular edema. An increased risk of fractures has been noted in women taking these agents. Thiazolidinediones have been shown to induce ovulation in premenopausal women with polycystic ovary syndrome. Women should be warned about the risk of pregnancy because the safety of thiazolidinediones in pregnancy is not established.
Concerns about increased cardiovascular risk associated with rosiglitazone led to considerable restrictions on its use and to the FDA issuing a “black box” warning in 2007. However, based on new information, the FDA has revised its guidelines and categorizes rosiglitazone similar to other drugs for type 2 DM. Because of a possible increased risk of bladder cancer, pioglitazone is part of an ongoing FDA safety review.
Sodium-glucose co-transporter 2 inhibitors (SLGT2)
These agents (Table 24-5) lower the blood glucose by selectively inhibiting this co-transporter, which is expressed almost exclusively in the proximal, convoluted tubule in the kidney. This inhibits glucose reabsorption, lowers the renal threshold for glucose, and leads to increased urinary glucose excretion. Thus, the glucose-lowering effect is insulin independent and not related to changes in insulin sensitivity or secretion. Because these agents are the newest class to treat type 2 DM (Table 24-5), clinical experience is limited. Due to the increased urinary glucose, urinary or vaginal infections are more common, and the diuretic effect can lead to reduced intravascular volume. As part of the FDA approval of canagliflozin in 2013, postmarketing studies for cardiovascular outcomes and for monitoring bladder and urinary cancer risk are under way.
Other therapies for type 2 DM
Evidence indicates that bile acids, by signaling through nuclear receptors, may have a role in metabolism. Bile acid metabolism is abnormal in type 2 DM. The bile acid–binding resin colesevelam has been approved for the treatment of type 2 DM (already approved for treatment of hypercholesterolemia). Because bile acid–binding resins are minimally absorbed into the systemic circulation, how bile acid–binding resins lower blood glucose is not known. The most common side effects are gastrointestinal (constipation, abdominal pain, and nausea). Bile acid–binding resins can increase plasma triglycerides and should be used cautiously in patients with a tendency for hypertriglyceridemia. The role of this class of drugs in the treatment of type 2 DM is not yet defined.
A formulation of the dopamine receptor agonist bromocriptine (Cycloset) has been approved by the FDA for the treatment of type 2 DM. However, its role in the treatment of type 2 DM is uncertain.
Insulin therapy in type 2 DM
Insulin should be considered as the initial therapy in type 2 DM, particularly in lean individuals or those with severe weight loss, in individuals with underlying renal or hepatic disease that precludes oral glucose-lowering agents, or in individuals who are hospitalized or acutely ill. Insulin therapy is ultimately required by a substantial number of individuals with type 2 DM because of the progressive nature of the disorder and the relative insulin deficiency that develops in patients with long-standing diabetes. Both physician and patient reluctance often delay the initiation of insulin therapy, but glucose control and patient well-being are improved by insulin therapy in patients who have not reached the glycemic target.
Because endogenous insulin secretion continues and is capable of providing some coverage of mealtime caloric intake, insulin is usually initiated in a single dose of long-acting insulin (0.3–0.4 U/kg per day), given in the evening (NPH) or just before bedtime (NPH, glargine, detemir). Because fasting hyperglycemia and increased hepatic glucose production are prominent features of type 2 DM, bedtime insulin is more effective in clinical trials than a single dose of morning insulin. Glargine given at bedtime has less nocturnal hypoglycemia than NPH insulin. Some physicians prefer a relatively low, fixed starting dose of long-acting insulin (5–15 units) or a weight-based dose (0.2 units/kg). The insulin dose may then be adjusted in 10% increments as dictated by SMBG results. Both morning and bedtime long-acting insulin may be used in combination with oral glucose-lowering agents. Initially, basal insulin may be sufficient, but often prandial insulin coverage with multiple insulin injections is needed as diabetes progresses (see insulin regimens used for type 1 DM). Other insulin formulations that have a combination of short-acting and long-acting insulin (Table 24-4) are sometimes used in patients with type 2 DM because of convenience but do not allow independent adjustment of short-acting and long-acting insulin dose and often do not achieve the same degree of glycemic control as basal/bolus regimens. In selected patients with type 2 DM, insulin-infusion devices may be considered.
Choice of initial glucose-lowering agent
The level of hyperglycemia and the patient’s individualized goal (see “Establishment of Target Level of Glycemic Control”) should influence the initial choice of therapy. Assuming that maximal benefit of MNT and increased physical activity has been realized, patients with mild to moderate hyperglycemia (FPG <11.1–13.9 mmol/L [200–250 mg/dL]) often respond well to a single, oral glucose-lowering agent. Patients with more severe hyperglycemia (FPG >13.9 mmol/L [250 mg/dL]) may respond partially but are unlikely to achieve normoglycemia with oral monotherapy. A stepwise approach that starts with a single agent and adds a second agent to achieve the glycemic target can be used (see “Combination therapy with glucose-lowering agents,” below). Insulin can be used as initial therapy in individuals with severe hyperglycemia (FPG <13.9–16.7 mmol/L [250–300 mg/dL]) or in those who are symptomatic from the hyperglycemia. This approach is based on the rationale that more rapid glycemic control will reduce “glucose toxicity” to the islet cells, improve endogenous insulin secretion, and possibly allow oral glucose-lowering agents to be more effective. If this occurs, the insulin may be discontinued.
Insulin secretagogues, biguanides, α-glucosidase inhibitors, thiazolidinediones, GLP-1 receptor agonists, DPP-IV inhibitors, SLGT2 inhibitors, and insulin are approved for monotherapy of type 2 DM. Although each class of oral glucose-lowering agents has advantages and disadvantages (Table 24-5), certain generalizations apply: (1) insulin secretagogues, biguanides, GLP-1 receptor agonists, and thiazolidinediones improve glycemic control to a similar degree (1–2% reduction in HbA1c) and are more effective than α-glucosidase inhibitors, DPP-IV inhibitors, and SLGT2 inhibitors; (2) assuming a similar degree of glycemic improvement, no clinical advantage to one class of drugs has been demonstrated; any therapy that improves glycemic control is likely beneficial; (3) insulin secretagogues, GLP-1 receptor agonists, DPP-IV inhibitors, α-glucosidase inhibitors, and SLGT2 inhibitors begin to lower the plasma glucose immediately, whereas the glucose-lowering effects of the biguanides and thiazolidinediones are delayed by weeks; (4) not all agents are effective in all individuals with type 2 DM; (5) biguanides, α-glucosidase inhibitors, GLP-1 receptor agonists, DPP-IV inhibitors, thiazolidinediones, and SLGT2 inhibitors do not directly cause hypoglycemia; (6) most individuals will eventually require treatment with more than one class of oral glucose-lowering agents or insulin, reflecting the progressive nature of type 2 DM; and (7) durability of glycemic control is slightly less for glyburide compared to metformin or rosiglitazone.
Considerable clinical experience exists with metformin and sulfonylureas because they have been available for several decades. It is assumed that the α-glucosidase inhibitors, GLP-1 agonists, DPP-IV inhibitors, thiazolidinediones, and SLGT2 inhibitors will reduce DM-related complications by improving glycemic control, but long-term data are not yet available. The thiazolidinediones are theoretically attractive because they target a fundamental abnormality in type 2 DM, namely insulin resistance. However, all of these agents are currently more costly than metformin and sulfonylureas.
Treatment algorithms by several professional societies (ADA/European Association for the Study of Diabetes [EASD], IDF, AACE) suggest metformin as initial therapy because of its efficacy, known side effect profile, and low cost (Fig. 24-3). Metformin’s advantages are that it promotes mild weight loss, lowers insulin levels, and improves the lipid profile slightly. Based on SMBG results and the HbA1c, the dose of metformin should be increased until the glycemic target is achieved or maximum dose is reached. If metformin is not tolerated, then initial therapy with an insulin secretagogue or DPP-IV inhibitor is reasonable.
Glycemic management of type 2 diabetes. See text for discussion of treatment of severe hyperglycemia or symptomatic hyperglycemia. Agents that can be combined with metformin include insulin secretagogues, thiazolidinediones, α-glucosidase inhibitors, DPP-IV inhibitors, GLP-1 receptor agonists, SLGT2 inhibitors, and insulin. HbA1c, hemoglobin HbA1c.
Combination therapy with glucose-lowering agents
A number of combinations of therapeutic agents are successful in type 2 DM (metformin + second oral agent, metformin + GLP-1 receptor agonist, or metformin + insulin), and the dosing of agents in combination is the same as when the agents are used alone. Because mechanisms of action of the first and second agents should be different, the effect on glycemic control is usually additive. There are little data to support the choice of one combination over another combination. Medication costs vary considerably (Table 24-5), and this often factors into medication choice. Several fixed-dose combinations of oral agents are available, but evidence that they are superior to titration of single agent to a maximum dose and then addition of a second agent is lacking. If adequate control is not achieved with the combination of two agents (based on reassessment of the HbA1c every 3 months), a third oral agent or basal insulin should be added (Fig. 24-3). Treatment approaches vary considerably from country to country. For example, α-glucosidase inhibitors are used commonly in South Asian patients (Indian), but infrequently in the United States or Europe. Whether this reflects an underlying difference in the disease or physician preference is not clear.
Treatment with insulin becomes necessary as type 2 DM enters the phase of relative insulin deficiency (as seen in long-standing DM) and is signaled by inadequate glycemic control with one or two oral glucose-lowering agents. Insulin alone or in combination should be used in patients who fail to reach the glycemic target. For example, a single dose of long-acting insulin at bedtime is often effective in combination with metformin. In contrast, insulin secretagogues have little utility once insulin therapy is started. Experience using incretin therapies and insulin is limited. As endogenous insulin production falls further, multiple injections of long-acting and short-acting insulin regimens are necessary to control postprandial glucose excursions. These insulin regimens are identical to the long-acting and short-acting combination regimens discussed above for type 1 DM. Because the hyperglycemia of type 2 DM tends to be more “stable,” these regimens can be increased in 10% increments every 2–3 days using the fasting blood glucose results. Weight gain and hypoglycemia are the major adverse effects of insulin therapy. The daily insulin dose required can become quite large (1–2 units/kg per day) as endogenous insulin production falls and insulin resistance persists. Individuals who require >1 unit/kg per day of long-acting insulin should be considered for combination therapy with metformin or a thiazolidinedione. The addition of metformin or a thiazolidinedione can reduce insulin requirements in some individuals with type 2 DM, while maintaining or even improving glycemic control. Insulin plus a thiazolidinedione promotes weight gain and is associated with peripheral edema. Addition of a thiazolidinedione to a patient’s insulin regimen may necessitate a reduction in the insulin dose to avoid hypoglycemia. Patients requiring large doses of insulin (>200 units/day) can be treated with a more concentrated form of insulin, U-500.
Whole pancreas transplantation (performed concomitantly with a renal transplant) may normalize glucose tolerance and is an important therapeutic option in type 1 DM with end-stage renal disease, although it requires substantial expertise and is associated with the side effects of immunosuppression. Pancreatic islet transplantation has been plagued by limitations in pancreatic islet supply and graft survival and remains an area of clinical investigation. Many individuals with long-standing type 1 DM still produce very small amounts of insulin or have insulin-positive cells within the pancreas. This suggests that beta cells may slowly regenerate but are quickly destroyed by the autoimmune process. Thus, efforts to suppress the autoimmune process and to stimulate beta cell regeneration are being tested both at the time of diagnosis and in years after the diagnosis of type 1 DM. Closed-loop pumps that infuse the appropriate amount of insulin in response to changing glucose levels are potentially feasible now that CGM technology has been developed. Bi-hormonal pumps that deliver both insulin and glucagon are under development. New therapies under development for type 2 DM include activators of glucokinase, inhibitors of 11 β-hydroxysteroid dehydrogenase-1, GPR40 agonists, monoclonal antibodies to reduce inflammation, and salsalate.
Bariatric surgery for obese individuals with type 2 DM has shown considerable promise, sometimes with dramatic resolution of the diabetes or major reductions in the needed dose of glucose-lowering therapies (Chap. 21). Several large, unblinded clinical trials have demonstrated a much greater efficacy of bariatric surgery compared to medical management in the treatment of type 2 DM; the durability of the diabetes reversal or improvement is uncertain. The ADA clinical guidelines state that bariatric surgery should be considered in individuals with DM and a body mass index >35 kg/m2.