Diagnosis of type 2 diabetes mellitus
Although patients with type 2 diabetes mellitus may present with symptoms as florid as those of type 1 diabetes mellitus (but usually not exhibiting spontaneous ketonuria), most patients with type 2 disease have relatively mild polyuria and polydipsia, and many cases are diagnosed only by office screening or other health checks.
The preferred test for type 2 diabetes mellitus on the grounds of reproducibility, convenience, and cost is an FPG . Oral glucose tolerance testing (OGTT) is more sensitive than FPG but is not recommended for routine use, because it is less reproducible, more inconvenient, and more costly.1 Moreover, the recommended treatment for almost all overweight or obese patients who would be candidates for OGTT would be the same regardless of OGTT results: a combined regimen of nutrition therapy, weight loss, and exercise. OGTT may be considered in unusually high risk patients and in those with IFG.
Management of type 2 diabetes mellitus
The same glycemic goals discussed earlier are appropriate for type 2 diabetes mellitus. However, these goals may sometimes have to be modified if severe cardiovascular disease, concurrent life-shortening malignancy, hypoglycemia unaware-ness, or inadequate family or social support make intensive treatment of diabetes dangerous or unlikely to benefit the patient in the long run. Self-monitoring of blood glucose when patients with type 2 diabetes mellitus are treated with diet plus exercise or with oral drugs is of less well established utility in patients with type 2 diabetes mellitus than in patients with type 1 diabetes mel-litus. However, fasting and postprandial blood glucose levels both correlate with HbA1c levels, and postprandial values can help reveal inadequate attention to diet and insufficient effectiveness of certain oral agents.
Nutritional Therapy and Exercise
An excellent short-term glycemic response to caloric reduction in patients with type 2 diabetes mellitus who are even modestly overweight can be expected.175, 176 On the basis of the degree of obesity and with the help of a dietitian, the patient should be provided with individualized culturally appropriate instructions to reduce intake by at least 250 to 500 calories a day. Such a decrease generally leads to an overall weight loss of 0.5 to 1.0 lb a week. There should be periodic reinforcement by the dietitian and physician. In the absence of a dietitian, the patient’s basal metabolic rate can be estimated at 10 cal/lb (20 cal/kg) of ideal body weight. A caloric prescription less than this amount will perforce decrease energy intake below the total daily energy expenditure. Consensus guidelines recommend that the calories should consist of less than 30% total fat, less than 10% saturated fat, less than 10% polyunsaturated fat, 10% to 15% monounsatu-rated fat, 10% to 20% protein, and 50% to 55% carbohydrate.177 Table sugar and other concentrated forms of carbohydrates are allowable in small portions at any one time (e.g., 5 g or 1 tsp of table sugar). Adding high-fiber foods can also lower plasma glucose modestly.178 Teaching patients to count the contemplated grams of carbohydrate before each meal helps them limit elevation of postprandial plasma glucose (PPG).
In massively obese individuals with BMI greater than 40 who are very symptomatic from hyperglycemia, a very low calorie diet (400 to 800 total calories a day using special high-protein supplements) can be very effective for the initial 2 to 3 months, but this strategy requires close medical monitoring.179
Weight losses of 5% to 10% (10 to 20 lb) produce significant decreases in FPG and HbA1c over 1 to 3 months.176 In the UKPDS, mean HbA1c fell from 9% to 7% during the 3-month dietary run-in period before randomization of the study patients.180,181 However, many patients are unable to maintain a calorie-restricted diet and even their initial weight loss. Pharmacologic aids for weight loss can be considered in such cases, but their efficacy is limited. These drugs include orlistat,182 a gastrointestinal lipase inhibitor that causes malabsorption of fat calories, and sibutramine, an inhibitor of dopamine, norepinephrine, and serotonin reuptake. Even after the addition of a weight-loss drug to therapy, appropriate diet therapy is essential. The patient should not be blamed for recidivism, because inability to lower body weight to ideal and keep it there may well be a central nervous system manifestation of or contributor to type 2 diabetes mellitus and out of the patient’s consistent control.183 Surgical therapy for obesity by reduction of gastric volume184,185 can effectively control type 2 diabetes mellitus and is gaining acceptance in very obese individuals who are unresponsive to other therapy. Of great interest, such treatment may work by altering the concentrations of humoral signals from the gastrointestinal tract that regulate appetite.
Additional benefits accrue from gradually increased aerobic exercise186 aimed at achieving at least 60% of maximal heart rate (220 minus age), such as walking 45 minutes at a brisk pace (approximately 3 to 5 miles an hour) three to five times a week. Exercise decreases insulin resistance and glycemia, contributes modestly to weight loss, reduces the risk of future cardiovascular disease, improves prognosis should a myocardial infarction occur, and enhances the patient’s sense of well-being and physical fitness. Conversely, physical inactivity predicts mortality in men with type 2 diabetes mellitus.187 In the presence of known coronary artery disease (CAD), the exercise should be prescribed with input from the patient’s cardiologist. If type 2 diabetes mel-litus has existed for more than 5 to 10 years or if the patient already has peripheral vascular or cerebral vascular disease, auto-nomic neuropathy, microalbuminuria, dyslipidemia, or a history of smoking, an electrocardiogram is essential and an electrocar-diographic exercise tolerance test is prudent before initiating a formal exercise program.
Pharmacologic Monotherapy
The array of pharmacologic agents available for treatment of type 2 diabetes mellitus is increasing steadily. Drugs can be specifically directed at the known pathophysiologic defects in type 2 diabetes mellitus [see Figure 15]. Although patient compliance favors initial use of monotherapy, none of the available agents can alone be expected to adequately control hyper-glycemia indefinitely.188 Therefore, diabetologists are beginning to consider using combinations of drugs from the outset of the need for any pharmacotherapy.189 Clinical trial data have established the efficacy and safety of various drugs [see Table 8] . The degrees to which these drugs lower HbA1c are fairly similar; the higher the initial dose of these agents, the greater the decrease in HbA1c.
Sulfonylurea agents SU agents, the oldest oral hypo-glycemic drugs, continue to have an important place in treatment.
Figure 15 Multiple drug classes with different predominant therapeutic effects are available for use singly or in numerous combinations. (1) Glitazones (thiazolidinediones) increase the sensitivity to insulin of glucose uptake by muscle and adipose tissue. (2) Metformin, the only approved biguanide drug, inhibits glucose production by the liver. (3) Sulfonylureas, repaglinide, and nateglinide stimulate insulin secretion, and insulin itself can be provided by injection. (4) a-Glucosidase inhibitors slow the digestion and absorption of carbohydrates from the diet. Plus signs indicate stimulation. Minus signs indicate inhibition.
Their primary mechanism of action is to close ATP-sensi-tive potassium channels in the beta cell (and other cell) membranes, which leads to an influx of calcium and stimulation of ex-ocytosis of insulin storage granules. They are most effective in normal-weight or modestly obese individuals who have had diabetes for less than 5 years and who can still secrete considerable amounts of insulin. The SU drugs in common use stimulate the beta cells more or less continuously and secondarily decrease insulin resistance. These effects [see Figure 14] result in decreases in FPG of 50 to 70 mg/dl and HbA1c of 1.0% to 2.0%.190 Peak PPG levels fall approximately as much as FPG. For most patients, treatment is initiated with the lowest recommended dose, and the dose is increased every 1 to 2 weeks until target blood glucose levels are attained or a practical maximal dose is reached [see Table 9]. Modern SU drugs can be taken as a single daily dose but occasionally are more effective when split into twice-daily doses. In symptomatic patients with FPG greater than 250, the patient may begin with half the maximal recommended dose. Hypo-glycemia, in particular, and weight gain are adverse effects of SU drugs. The highest prevalence of hypoglycemia occurs with gly-buride and chlorpropamide,191 drugs with long biologic half-lives. Elderly patients who live alone and lack concerned family, friends, or neighbors are at a special risk for severe, even fatal, hy-poglycemia.192 The shortest-acting SU drug, tolbutamide, may be the safest to use in such cases.
Patients who present to an emergency room in hypoglycemic coma from any SU drug should be given restorative treatment with intravenous boluses of glucose and then admitted to the hospital because SU drugs can have durations of biologic action for up to 7 days. A blood glucose should be maintained at 150 to 200 mg/dl on intravenous glucose, oral carbohydrate, or both until this level can be sustained by administration of only 5 g/hr of one of the therapeutic agents. In the UKPDS, SU drugs did not increase cardiovascular disease events or mortality.37 This observation relieves much of the concern previously raised by the University Group Diabetes Program trial in 1970, which found that tolbutamide was associated with an excess of cardiovascular and total deaths.193 However, interactions of even modern SU drugs with cardiac muscle are reported, particularly inhibition of ischemic preconditioning, a cardioprotective mechanism.194 SU drugs are contraindicated in hepatic insufficiency and are dangerous when combined with alcohol ingestion. Glimepiride, the newest SU drug,195 has been given safely to patients with renal insufficiency, although these patients are susceptible to hypoglycemia for other reasons. SU drugs are subject to interactions with other drugs that can either exaggerate or interfere with their effects.
Beta cell stimulants Repaglinide and the phenylalanine derivative nateglinide represent a new class of beta cell stimulants [see Figure 15] that differ in structure and timing of action from those of SU drugs.196 Although they may act in part through SU drug mechanisms in the beta cells,197 they do so rapidly, with a peak effect at about l hour, and transiently, with a duration of about 4 hours. Their major action is the decrease of PPG by 50 to 60 mg/dl, although FPG also declines somewhat as glucose toxicity is relieved. As monotherapy, these new beta cell stimulants are most logically used early in type 2 diabetes mellitus, when FPG is not greatly elevated. They lower HbA1c by about 1.0%. Repaglinide and nateglinide must be taken 15 to 30 minutes before a meal and should never be taken without eating. Their short half-lives and the fact that, unlike SU drugs, they are active only in the presence of glucose are expected to reduce the likelihood of severe prolonged hypo-glycemic episodes.196 Weight gain may occur secondary to improved glycemic control.
Table 8 Oral Drugs for Type 2 Diabetes Mellitus
|
Drugs |
Lowest Effective Single Dose (mg) |
Practical Maximum Daily Dose (mg) |
Hypoglycemia with Monotherapy |
|
Sulfonylureas* |
|||
|
Glyburide |
1.25 |
10 |
Yes |
|
Micronized glyburide |
1.5 |
6 |
Yes |
|
Glipizide |
5 |
20 |
Yes |
|
Glipizide (gastrointestinal therapeutic system) |
5 |
20 |
Yes |
|
Glimepiride |
0.5 |
8 |
Yes |
|
Meglitinides^ |
|||
|
Repaglinide |
0.5 |
4* |
Yes |
|
Biguanides |
|||
|
Metformin |
500 |
2,000 |
No |
|
Thiazolidinediones§ |
|||
|
Rosiglitazone |
2 |
8 |
No |
|
Pioglitazone |
15 |
45 |
No |
|
a-Glucosidase inhibitors |
|||
|
Acarbose |
25 |
100* |
No |
|
Miglitol |
25 |
100* |
No |
*Tolbutamide, chlorpropamide, and acetohexamide are also still available.
^Nateglinide has a similar action to meglitinides but is technically phenylalanine derivative.
*This maximal dose must be taken each time with meals.
§Troglitazone was the initial drug approved in this class but was later withdrawn because of serious liver toxicity.
|
Table 9 Combination Oral Drug Therapy for Type 2 Diabetes Mellitus |
|
Combinations reported in the literature |
|
Sulfonylurea + metformin |
|
Sulfonylurea + thiazolidinedione |
|
Metformin + thiazolidinedione |
|
Metformin + repaglinide |
|
Repaglinide + thiazolidinedione |
|
Sulfonylurea + metformin + thiazolidinedione |
|
Acarbose + any other drug except repaglinide |
|
Miglitol + sulfonylurea |
|
Insulin + any other drug |
|
Potentially useful combination |
|
Repaglinide + metformin + thiazolidinedione |
|
Nateglinide + metformin + thiazolidinedione |
a-Glucosidase inhibitors a-Glucosidase inhibitors197,198 are a class of drugs represented by acarbose and miglitol, which are poorly absorbed but act within the gut to inhibit the digestion of polysaccharides [see Figure 15]. This action results in a slow release of glucose from food and therefore slow absorption from the GI tract. PPG levels decrease by 60 to 70 mg/dl, but FPG decreases by only 15 to 20 mg/dl.199 HbA1c generally falls 0.5% to 0.8%.198,199 These drugs are useful only as monotherapy when postprandial hyperglycemia is the main problem. They must be taken at the start of a meal. Flatulence, abdominal cramping, and diarrhea are frequent side effects that result from undigested carbohydrate reaching bacteria in the lower bowel. These side effects often limit patient acceptance of treatment with a-glucosi-dase inhibitors. Treatment should start with the smallest dose, and doses should be raised very gradually to enhance tolerance. With the exception of rare elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, these agents are nontoxic. Although hypoglycemia does not occur with monotherapy, it can do so when a-glucosidase inhibitors are added to SU drugs or insulin. In those instances, patients must be warned to treat hypoglycemia only with pure glucose (e.g., glucose tablets) because the therapeutic benefits of complex carbohydrates and even sucrose will be delayed by slow digestion.
Biguanide agents Metformin,200 the only drug approved in the biguanide class, acts primarily by decreasing excessive hepatic glucose production [see Figure 15],201,202 most likely through inhibiting gluconeogenesis. Because insulin also inhibits gluconeo-genesis [see Figure 1]20 and metformin requires the presence of insulin to be effective, metformin may be considered a hepatic insulin sensitizer. During metformin treatment, plasma insulin levels tend to decrease relative to glucose levels as a result of the decrease in insulin resistance. The chief action of this drug is to lower FPG by 50 to 70 mg/dl, with peak PPG levels following suit.203 Hypoglycemia almost never occurs with metformin monotherapy. Weight is not gained and may even be lost.200 Met-formin also decreases plasma triglyceride and low-density lipoprotein (LDL) cholesterol levels, and it increases HDL cholesterol levels to some degree. In addition, plasma plasminogen activator inhibitor-1 (PAI-1) activity declines.204 The weight loss, the improvement in the dyslipidemia typical of type 2 diabetes melli-tus, and the reduction in antifibrinolytic activity could explain one of the most interesting UKPDS observations. Compared with conventional diet treatment, metformin monotherapy substantially decreased the incidence of myocardial infarction, diabetes-related death, and all-cause mortality in an obese type 2 subco-hort of the trial.38
The most common side effects of metformin therapy are diarrhea, which may be severe; abdominal cramps; and gastric upset. To reduce the likelihood of these symptoms, the starting dose should not exceed 500 mg twice a day, and the drug should be used with special caution, if at all, in patients who have inflammatory GI disease. The maximum effective dose is 2,000 mg/day.205 The most feared, although rare, adverse effect is lactic acidosis.206 This often fatal complication occurs in 30 per million patients a year, and it usually occurs when the drug is used inappropriately, such as when the serum creatinine level is elevated or the patient is dehydrated. Hemodialysis along with bicarbonate administration can be effective therapy for metformin-induced lactic acidosis.207 The following are contraindications to use of metformin: serum creatinine level greater than 1.4 mg/dl in women and greater than 1.5 mg/dl in men; intravenous administration of radiographic iodinated contrast media; acute my-ocardial infarction; congestive heart failure; and any ischemic condition. Nausea, vomiting, tachypnea, and change in mental status call for measurements of serum electrolytes and lactate to rule out lactic acid metabolic acidosis. Although metformin monotherapy can be effective in both normal-weight and obese patients with type 2 diabetes mellitus, obese patients especially benefit from metformin therapy because of the absence of weight gain as glucose levels gradually fall.
Thiazolidinediones The newest class of oral drugs are thia-zolidinediones (TZDs) [see Table 8],208 which were exemplified by the no longer available but best studied drug, troglitazone . These agents work predominantly in muscle and adipose tissue to decrease insulin resistance [see Figure 15].202,209 Because insulin resistance is seen in almost all patients with type 2 diabetes mellitus, the advent of the TZDs raised expectations that they might be singularly effective. Like metformin, TZD drugs need the presence of insulin and are especially effective in obese patients. They also decrease hepatic glucose production to some extent.202 As monotherapy, they decrease FPG by 50 to 70 mg/dl and PPG by slightly more than that.209 HbA1c decreases by about 1.0% to 1.5%. Plasma insulin levels also decrease as glucose levels fall.209 TZD drugs act by binding to a metabolically important receptor, the peroxisome proliferator-activated receptor (PPAR), and they thereby regulate the expression of multiple genes.210 Their clinical effects take 4 to 12 weeks to become evident. In patients with marked elevation of FPG, a midrange dose is appropriate to start with (e.g., 4 mg rosiglitazone or 30 mg pioglitazone). Otherwise, the lowest dose is appropriate, and dose changes should be made at 4- to 12-week intervals.
TZD drugs can cause weight gain, which is partly fat tissue and partly extracellular fluid.208 The accumulation of extracellular fluid presents as edema, which can be troublesome when concurrent congestive heart failure exists, and a small dilutional fall in hemoglobin and hematocrit. Some findings suggest that the adipose tissue gain is largely subcutaneous rather than visceral.211 In clinical research trials, troglitazone therapy was accompanied by elevations of ALT and AST to more than three times the upper limit of normal in 2% of treated patients, compared with 0.6% of patients given placebo. However, after troglitazone was approved by the FDA, more than 60 cases of hepatic failure that necessitated liver transplantation or resulted in death, or both, were reported out of a user base of about one million persons. The FDA eventually withdrew approval, first for the prescription of troglitazone as mono-therapy and later for all indications. In clinical research trials, neither rosiglitazone nor pioglitazone caused AST and ALT elevations in excess of those caused by placebo, but these drugs have not been used enough to provide a guarantee that they will never cause idiosyncratic liver toxicity similar to that caused by troglitazone. Therefore, the FDA has mandated that these drugs be monitored by ALT measurements every 2 months for the first year of use. Neither rosiglitazone nor pioglitazone should be prescribed if the ALT level is greater than 2.5 times the upper limit of normal, and the drugs should be stopped if such levels are reached.
TZD drugs have exhibited effects in addition to glucose lowering that may be beneficial for treating cardiovascular compli-cations.212-219 Troglitazone and pioglitazone suppress formation of PAI-1, an action that enhances fibrinolysis.213,214 TZD drugs tend to decrease serum triglyceride levels and increase serum HDL cholesterol levels, but they also increase serum LDL cholesterol levels.208 In addition, troglitazone has been reported to shift the LDL spectrum from small, dense atherogenic particles to larger, more buoyant, less atherogenic particles.219 Endothelial function also likely improves.216,217 A decrease in carotid artery intimal-me-dial thickness217—a marker of atherosclerosis—as well as decreases in vasospastic angina215 and in recurrence of intimal hy-perplasia after coronary angioplasty218 have been reported in small series of patients treated with troglitazone for only 6 months.216,217 Whether TZD drugs will decrease rates of cardiovascular events through such actions remains to be seen.
Insulin About 40% of patients with type 2 diabetes mellitus in the United States are estimated to be taking insulin. A small proportion of these patients may have delayed-onset type 1 diabetes mellitus and may offer serologic evidence of beta cell au-toimmunity. However, most of these patients represent the end stage of type 2 diabetes mellitus. A small number of such patients, some of whom are even obese, present initially with clear-cut biologic evidence of insulin deficiency. This evidence includes marked recent loss of weight and muscle mass, debilitating fatigue and weakness, severe polyuria and polydypsia, considerable hypertriglyceridemia, ketonuria, and FPG often exceeding 300 mg/dl. These patients should be started on insulin immediately—as in patients with type 1 diabetes mellitus. After usually rapid clinical and biochemical improvement, insulin-dose requirements may decrease progressively. Patients can sometimes be tapered off insulin and be given a trial of an SU drug. This sequence has been reported in certain groups of African Americans.
Much more commonly, the need for insulin treatment has arisen because of eventual failure of oral drug therapy, particularly SU drugs. For normal-weight individuals in this situation, it is best to simply switch them to insulin. Some patients may still be managed on a single dose of intermediate- or long-acting insulin (starting dose of NPH, Lente, or glargine of 0.15 to 0.20 U/kg) in the morning222 or at bedtime if the FPG is being specifically target-ed.223 The latter is a particularly attractive way to lessen glycemia without stimulating weight gain.224 Other patients may need intermediate- or long-acting insulin twice a day, usually in a ratio of breakfast dose to bedtime dose of from 1:1 to 2:1. As endogenous postprandial insulin secretion declines further, regular or lispro insulin or insulin aspart [see Type 1 Diabetes Mellitus, above] must be added before meals. To approach normal glycemia, the doses of rapid, short-acting insulin are best adjusted according to the premeal blood glucose level, the carbohydrate content of the meal, or both. For all practical purposes, some patients with type 2 diabetes mellitus closely resemble patients with type 1 diabetes mellitus in the insulin regimens they require.
For stable patients incapable of accurately mixing different insulins in one syringe because of visual or cognitive impairment, premixed combinations of NPH with regular or lispro insulin are available in varying proportions; these combinations include 70% NPH/30% regular, 50% NPH/50% regular, and 75% NPH/25% lispro. These mixtures all suffer from the inflexibility of neither the dose of NPH nor the dose of the regular or lispro insulin being able to be altered individually. For example, a patient with satisfactory postbreakfast or prelunch blood glucose levels but elevated predinner blood glucose levels would benefit from an increase in the morning NPH insulin dose but not necessarily from an increase in the morning regular or lispro insulin dose. Premixed insulins are not suitable for bedtime use unless an uncommonly large snack is eaten. Despite the above objections, premixed insulins are convenient for patients and for family members who have therapeutic responsibilities.
Whatever insulin regimens are chosen, obese patients with type 2 diabetes mellitus often need large daily doses, which many practitioners are unaccustomed to prescribing. Doses of 1 U/kg body weight are not unusual, and doses of up to 400 U daily have been required to achieve glycemic targets in morbidly obese indi-viduals.225,226 Concern has been raised in the past that insulin might have atherogenic effects because epidemiologic studies (mostly in nondiabetic individuals) have shown an association between insulin resistance, fasting or postprandial plasma insulin levels, and future risk of cardiovascular disease.227 In the UKPDS37 and in the University Group Diabetes Program,228 exogenous insulin did not increase the rate of myocardial infarction or of cardiovascular death. It can be argued that the insulin doses used in those trials were not very large or that an adverse effect from an atherogenic property of insulin was offset by a beneficial effect resulting from a decrease in glycemia. In any event, there is not enough evidence of cardiovascular danger from exogenous insulin to justify withholding doses necessary to achieve near-normal glycemia. In two randomized clinical trials37,229 and in a large retrospective study,192 the incidence of serious hypoglycemic episodes was about two to three events per 100 patient-years. In elderly patients, however, one out of 20 severe hypoglycemic events can be accompanied by such complications as stroke, transient ischemic attack, myocardial infarction, injury, and death.190 Weight gain—in rare cases, even to degrees that have resulted in sleep apnea—is a major adverse effect of insulin therapy and is one justification for combining insulin with a drug such as met-formin, which can restrict weight gain to some extent.
