overall age 25-44 BMI > 34.9
* Differed significantly from placebo "Differed significantly from metformin or placebo
FIGURE 11.5 Effects of metformin and intensive lifestyle intervention on rates of type 2 diabetes in adults with IGT. Data adapted from Knowler et al., Diabetes Prevention Program, N. Eng. J. Med., 346, 393, 2002. With permission.
development of severe hepatotoxicity in a small number of subjects. The experimental groups were studied for 1.8-4.6 years.
Daily energy and fat intake decreased only in the group randomized to intensive lifestyle modification. Nevertheless, patients in the metformin group also lost weight, though not as much as those in the intensive-lifestyle group. In both groups, weight loss was most significant in the first 6-12 months of the study. The changes in body weight were accompanied by reductions in the rates of progression from IGT to type 2 diabetes. The three-year cumulative incidence of diabetes was 28.9 percent in the placebo group, 21.7 percent in the metformin-treated group, and 14.4 percent in the intensive-lifestyle group. Overall, therefore, intensive-lifestyle intervention was more effective than metformin.
However, metformin was as effective as lifestyle change in subjects with BMI exceeding 34.9 and in those with highest fasting-glucose concentrations (Figure 11.5); these subgroups are at greatest risk for progression to type 2 diabetes. Metformin was also as effective as a lifestyle intervention in younger adults aged 25-44 years. On the other hand, treatment effects did not vary according to gender, race, or ethnic group. In addition to reducing the risk of development of type 2 diabetes, intensive-lifestyle intervention and metformin also had favorable, albeit small effects on blood pressure and serum lipids.
Metformin was well-tolerated by the majority of subjects, though many patients had transient abdominal discomfort which can be prevented by taking the medication with food. There were no instances of hepatic dysfunction or lactic acidosis; nevertheless, the drug should not be administered to patients with underlying cardiac, hepatic, renal, or gastrointestinal disease.
The major effects of lifestyle intervention and metformin were exerted within the first 12-18 months of the study. After the first year, fasting blood-glucose concentrations, HbA1c concentrations, and rates of diabetes increased in both the intensive-lifestyle and metformin groups, and the slopes of the intervention and treatment curves after the first year appeared to parallel the slope of the placebo group. This finding suggests that the interventions may delay, rather than truly prevent, the development of type 2 diabetes. Nevertheless, studies performed in nondiabetic subjects one to two weeks after the trial's conclusion showed that the protective effect of metformin persisted in three-fourths of the drug-treated subjects even after discontinuation of medication. The duration of this protective effect is unknown; prolonged treatment with metformin might be necessary to reduce the rate of progression to diabetes in high-risk subjects.
The thiazolidinediones (TZDs) regulate lipid and carbohydrate metabolism through binding to peroxisome proliferator-activated receptor (PPAR)-y. When activated by TZDs, PPAR-y heterodimerizes with the retinoid X receptor and binds to the promoters of target genes, including lipoprotein lipase, fatty-acid transport protein, acetyl-CoA-synthase, and aP2 . The major effects of the TZDs are exerted in adipose tissue and skeletal muscle (Figure 11.4) [19, 86]. The drugs induce the differentiation of small, insulin-sensitive adipocytes, increase adipose tissue insulin-receptor number, adiponectin expression, and glucose uptake, and reduce expression of TNF alpha and, in mice, resistin. Rates of lipolysis and FFA release are reduced, TG clearance is enhanced, and hepatic VLDL synthesis decreases. Circulating TG levels decline during treatment with pioglitazone and, to a lesser extent, with rosigl-itazone. With adipogenic and antilipolytic actions, the TZDs increase total body-fat mass and body weight; however, the ratio of lower body/subcutaneous (SQ) fat to upper-body/visceral fat may rise . TZDs potentiate the effects of insulin on skeletal-muscle glucose uptake through induction of glucose transporters (GLUTs)
1 and 4 . These actions require the presence of insulin and may be mediated by activation of phosphatidylinositol (PI) 3-kinase. Glucose tolerance improves in type
2 diabetic patients treated with TZDs; plasma insulin concentrations decline, while plasma adiponectin levels rise. The rise in adiponectin, in concert with direct effects of the TZDs on the vascular endothelium, reduces carotid intimal medial thickness and increases arterial distensibility. TZDs also reduce plasma C-reactive protein concentrations in diabetic patients and the percentage of small dense LDL levels in diabetic and nondiabetic hypertensive adults [81-83]. In theory, these changes reduce the risk of development and progression of atheromatous lesions.
A few studies have examined the effects of the TZDs on glucose tolerance, lipid profiles, and other cardiovascular risk factors in nondiabetic adults and in women with PCOS. No such investigations have been performed in children or adolescents.
In obese, non-diabetic subjects , troglitazone decreased insulin resistance and improved glucose tolerance. Rates of glucose disposal and the insulin-sensitivity index increased while glycemic responses to oral glucose declined. The mean fasting insulin concentrations decreased by 48 percent, and the plasma insulin responses to oral glucose and mixed meals decreased by 40 percent and 41 percent, respectively. Other studies showed that TZDs reduced blood pressure in nondiabetic obese adults. In women with PCOS, a three-month trial of troglitazone reduced fasting glucose and insulin concentrations and improved, but did not normalize, whole-body insulin sensitivity. Troglitazone also improved endothelial function as measured by leg blood flow.
The results of these studies indicate that the TZDs increase insulin sensitivity, improve glucose tolerance, and reduce cardiovascular risk in insulin-resistant adults and in women with PCOS. That the TZDs, like metformin, can reduce the risk of type 2 diabetes in target populations was established in the TRIPOD study , a randomized, placebo-controlled, double-blind investigation of women with IGT. The experimental group consisted of Latino women with a history of gestational diabetes and IGT at the time of initiation of the study. During the 30-month investigation, annual diabetes incidence rates were 12.1 percent in the placebo group and 5.4 percent in the troglitazone group. Those with an increase in whole-body insulin sensitivity following initiation of troglitazone were most likely to benefit.
Interestingly, protection from diabetes persisted for at least three to eight months after the drug was discontinued. This finding suggested that troglitazone may have altered the natural progression of diabetes and not simply masked progression through a pharmacologic action. As with metformin, the duration of this protective action is currently unknown.
Unfortunately, troglitazone was removed from the commercial market because the drug caused fatal hepatic failure in a small number of subjects. Nonlethal hepatotoxicity has also been reported with other currently available TZDs, though at a far lower frequency than with troglitazone. Hepatic dysfunction must be excluded before TZD therapy is initiated, and liver function tests should be measured monthly for the first six months of treatment, every two months for the remainder of the first year, and at regular intervals thereafter. Other potential complications of TZD therapy include edema and anemia, so the drug should not be administered to patients with underlying cardiac disease.
Pharmacologic agents currently in use indirectly target the complications of insulin resistance. Animal studies suggest that approaches that directly target metabolic signaling and cytokine production may prove useful in the prevention of type 2 diabetes and cardiovascular disease.
An appealing therapeutic candidate is the adipocytokine adiponectin. Adiponec-tin levels decline in obesity and other states accompanied by insulin resistance but rise following treatment with thiazolidinediones. Administration of recombinant adiponectin to obese mice reduces blood-glucose and insulin concentrations, increases insulin sensitivity and hepatic fatty-acid oxidation, reduces hepatic fatty-acid synthesis, reverses hepatic steatosis, and decreases body weight .
Targeting of oxygen radicals and PARP also shows promise. Activation of PARP by glucose-induced oxidative stress inhibits glyceraldehyde phosphate dehydrogenase activity and may thereby promote the formation of polyols, glucosamine, and advanced glycation end products and the activation of protein kinase C . These metabolites mediate glucose-dependent endothelial dysfunction. In animal models of diabetes, the pharmacological inhibition of PARP improves endothelial function.
It is likely that future investigations will identify new targets and pharmacothera-peutic agents that will prevent long-term complications in high-risk patients.
4. Recommendations Regarding Pharmacotherapy in Diabetes Prevention
In the opinion of the author, pharmacologic therapy should be considered for severely resistant or glucose-intolerant (IFG or IGT) children or adolescents who fail to respond to a 6- to 12-month trial of lifestyle intervention despite a good-faith effort. Good-faith effort means that the patient has attempted to follow a low-saturated-fat/low-calorie diet recommended by a dietary counselor and has increased his or her energy expenditure through regular exercise. Unsuccessful means that the elevations of fasting or postprandial glucose persist or worsen despite lifestyle intervention. The decision to initiate drug therapy relieves neither the child nor the physician of the commitment to long-term lifestyle change; thus, diet-and-exercise regimens should be maintained, even if they had not proven effective in the absence of medication.
Given its proven efficacy in treating insulin-resistant, as well as diabetic, adolescents, adults, and women with PCOS, its track record of safety in men and women, and its ability to limit weight gain, the author considers metformin the drug of choice for treating the obese child with severe insulin resistance, IFG, or IGT. Though lactic acidosis is extraordinarily rare in pediatric patients, metformin should not be administered to children with underlying cardiac, hepatic, renal, or gastrointestinal disease. Obese subjects with mild elevations in hepatic enzymes (less than threefold higher than established norms) may receive the drug; indeed, some studies suggest that metformin may be useful in treatment of hepatic steatosis. Concurrent use of a multivitamin seems reasonable, because metformin increases urinary excretion of vitamins B1 and B6.
Given the lack of studies of TZDs in insulin-resistant children or adolescents, their potential, albeit rare, for severe hepatic complications, and their tendency to cause weight gain, the author would limit the use of TZDs to adolescents who fail to respond to, or cannot tolerate, metformin. Since the danger of hepatic dysfunction with combined therapy in pediatric patients is unknown, the TZDs should not be used in conjunction with metformin in nondiabetic children pending demonstration in long-term studies that the drug combination is safe. TZDs are contraindicated in patients with preexisting hepatic or cardiac disease. Orlistat, acarbose, and other inhibitors of nutrient absorption are not tolerated by many adolescents, but may be useful in highly motivated subjects.
It is not possible at this time to provide firm or uniform guidelines regarding the duration of pharmacologic intervention. A trial off medication may be warranted if glucose tolerance is normalized, particularly if there has been a decline in BMI z score. If IGT persists despite compliance with the medical/pharmacologic regimen, it may be necessary to intensify lifestyle intervention and to increase the dose of medication. If glucose tolerance declines or the patient develops overt diabetes, it may be necessary to add insulin or another pharmacologic agent to the therapeutic regimen.
Some have argued that the pharmacologic treatment of type 2 diabetes in children and adolescents should be similar to that of type 2 diabetes in adults. However, differences in disease presentation and course argue for a distinct approach to treatment of childhood type 2 diabetes. Many adults with type 2 diabetes are diagnosed after a prolonged course characterized by mild or moderate symptomatology. At the time of diagnosis, many have beta-cell failure, insulin deficiency, and established vascular complications. In contrast, most children and adolescents with type 2 diabetes are identified before beta-cell function is exhausted. In such cases, it is essential to rapidly normalize blood-glucose concentrations and correct dyslipidemia in order to prevent beta-cell glucotoxicity and lipotoxicity; in theory, this should prolong beta-cell lifespan, enhance glycemic stability, and limit long-term complications.
Rapid normalization of blood-glucose concentrations generally requires insulin administration, particularly if there is ketosis at diagnosis. Once near-normoglycemia is established, it is useful to begin metformin, increasing the dose gradually until maximal tolerated levels are achieved. The dose of insulin can then be reduced, facilitating weight loss in combination with lifestyle intervention. This author maintains low-level insulin therapy indefinitely if plasma C-peptide concentrations are marginal or low. Insulin corrects the insulin deficiency observed in patients with long-standing disease and can prevent the ketosis that may recur in some children and adolescents with type 2 diabetes.
Clinical studies in adults suggest that blood-glucose control in type 2 diabetes may be facilitated by the addition of amylin at mealtimes . Amylin is a beta-cell hormone that reduces postprandial hyperglucagonemia, slows gastric emptying, and reduces food intake. Amylin may reduce postprandial glucose excursions and limit weight gain, but the hormone increases the risk of severe hypoglycemia, nausea, and headache.
Metformin is not tolerated in a minority of subjects. In such cases, a thiazo-lidinedione may prove useful. However, thiazolidinediones are not approved for use in children and may cause weight gain, edema, and hepatic dysfunction. Ongoing studies will assess the benefits and risks of TZDs and combination therapy (met-formin plus TZD) in children with type 2 diabetes.
Sulfonylureas are mainstays of therapy in adults with type 2 diabetes. Their use as primary agents for treatment of type 2 diabetic children is currently under investigation. However, sulfonylureas increase the risk of weight gain and severe hypogly-cemia; in the opinion of the author, the preferred hypoglycemic agent in (particularly obese) children is insulin itself.
VIII. A MULTIFACETED APPROACH TO PREVENTION OF COMPLICATIONS
The major causes of death in adults with type 2 diabetes are myocardial infarction and stroke. Although cardiovascular risk in patients with type 2 diabetes varies with glycemic control, other factors play equal or more important roles. These include obesity, hypertension, smoking, dyslipidemia, ethnic background, and family history. In theory, aggressive lifestyle intervention in children and adolescents should include abolition of smoking and reduction in the intake of caffeine, which may raise blood pressure and postprandial glucose concentrations. Pharmacologic therapy may be necessary to reduce blood pressure, control microalbuminuria, and treat dyslipi-demia. A multifaceted approach that combined dietary counseling, statins, angio-tensin-converting enzyme inhibitors, and low-dose aspirin reduced by 50 percent to 60 percent the long-term (eight-year) risks of nephropathy, retinopathy, autonomic neuropathy, and cardiovascular end points (myocardial disease, stroke, and amputation) in diabetic adults with microalbuminuria . Such an approach may be necessary in the management of obese, insulin-resistant, and glucose-intolerant adolescents, who are commonly hypertensive and hyperlipidemic. The age and intensity of intervention may depend upon the family history of cardiovascular disease, as well as the severity of problems in the individual teenager under the physician's care.
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