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Which oral antihyperglycemics are most efficacious in reducing hemoglobin A1C in diabetic patients?
ABSTRACT
BACKGROUND: Many new oral medications have been developed to treat diabetes, but uncertainty remains regarding which are best for initial treatment and whether effectiveness rates differ. This review compares the available oral antihyperglycemics.
POPULATION STUDIED: A total of 63 randomized controlled clinical trials involving oral hypoglycemic drugs for type 2 diabetes was identified by a MED-LINE search and review of the bibliographies of articles found initially. Other inclusion criteria were study duration of at least 3 months, at least 10 subjects at the study’s conclusion, and hemoglobin A1C levels reported. Other search details, such as the year and key words of a study, were not mentioned. More than 15,000 subjects have been enrolled in the identified trials, but no information was given regarding important clinical characteristics such as age, ethnicity, body mass index, or medical conditions other than diabetes. Therefore, assessing generalizability of the data to typical patients of family practitioners is difficult.
STUDY DESIGN AND VALIDITY: The article lists available randomized clinical trials that evaluate sulfonylureas, metformin, α-glucosidase inhibitors (AGIs), thiazolidinediones (TZDs), and nonsulfonylurea secretagogues as monotherapy versus placebo, in head-to-head trials or in combination, and compares their outcomes in terms of hemoglobin A1C reduction. When multiple doses of a drug were tested, the results from the highest dose were used. There was no attempt to synthesize the data provided by the studies into a meta-analysis.
OUTCOMES MEASURED: The major outcome measured was percent hemoglobin A1C reduction. Side effects were mentioned but not quantified. Cost, patient satisfaction, and quality of life were not addressed.
RESULTS: Except for the UKPDS, all available studies of oral hypoglycemics are short term and are limited in focus to hemoglobin A1C. Each class of drugs achieved a similar initial reduction in hemoglobin A1C of 1% to 2% except for the AGIs and nateglinide, which were less effective. The results are remarkably consistent across studies. Head-to-head comparison of specific medications further supports this conclusion. When taken in combination, the effects on hemoglobin A1C are additive.
Despite the claims of pharmaceutical marketing, there is little difference among sulfonylureas, metformin, and thiazolidinediones in reduction of hemoglobin A1C. Each class achieves an average reduction of 1% to 2%. Alpha glucosidase inhibitors and nonsulfonylurea secretogogues are probably somewhat less efficacious; combinations of medications seem to be additive.
Clinicians should keep in mind that diet and exercise remain first-line treatment for type 2 diabetes. Initial drug therapy should be guided, however, by evidence about long-term outcomes, such as reduction in the risk of myocardial infarction, renal failure, and blindness; to date, only metformin and sulfonylureas have been shown to be beneficial in reducing microvascular complications. Only metformin has been shown to reduce macrovascular complications and all-cause mortality in obese patients with type 2 diabetes. Interestingly, this beneficial effect of metformin is totally independent of blood sugar control. Thus, metformin should be the pharmaceutical agent of first choice in the treatment of type 2 diabetes.
ABSTRACT
BACKGROUND: Many new oral medications have been developed to treat diabetes, but uncertainty remains regarding which are best for initial treatment and whether effectiveness rates differ. This review compares the available oral antihyperglycemics.
POPULATION STUDIED: A total of 63 randomized controlled clinical trials involving oral hypoglycemic drugs for type 2 diabetes was identified by a MED-LINE search and review of the bibliographies of articles found initially. Other inclusion criteria were study duration of at least 3 months, at least 10 subjects at the study’s conclusion, and hemoglobin A1C levels reported. Other search details, such as the year and key words of a study, were not mentioned. More than 15,000 subjects have been enrolled in the identified trials, but no information was given regarding important clinical characteristics such as age, ethnicity, body mass index, or medical conditions other than diabetes. Therefore, assessing generalizability of the data to typical patients of family practitioners is difficult.
STUDY DESIGN AND VALIDITY: The article lists available randomized clinical trials that evaluate sulfonylureas, metformin, α-glucosidase inhibitors (AGIs), thiazolidinediones (TZDs), and nonsulfonylurea secretagogues as monotherapy versus placebo, in head-to-head trials or in combination, and compares their outcomes in terms of hemoglobin A1C reduction. When multiple doses of a drug were tested, the results from the highest dose were used. There was no attempt to synthesize the data provided by the studies into a meta-analysis.
OUTCOMES MEASURED: The major outcome measured was percent hemoglobin A1C reduction. Side effects were mentioned but not quantified. Cost, patient satisfaction, and quality of life were not addressed.
RESULTS: Except for the UKPDS, all available studies of oral hypoglycemics are short term and are limited in focus to hemoglobin A1C. Each class of drugs achieved a similar initial reduction in hemoglobin A1C of 1% to 2% except for the AGIs and nateglinide, which were less effective. The results are remarkably consistent across studies. Head-to-head comparison of specific medications further supports this conclusion. When taken in combination, the effects on hemoglobin A1C are additive.
Despite the claims of pharmaceutical marketing, there is little difference among sulfonylureas, metformin, and thiazolidinediones in reduction of hemoglobin A1C. Each class achieves an average reduction of 1% to 2%. Alpha glucosidase inhibitors and nonsulfonylurea secretogogues are probably somewhat less efficacious; combinations of medications seem to be additive.
Clinicians should keep in mind that diet and exercise remain first-line treatment for type 2 diabetes. Initial drug therapy should be guided, however, by evidence about long-term outcomes, such as reduction in the risk of myocardial infarction, renal failure, and blindness; to date, only metformin and sulfonylureas have been shown to be beneficial in reducing microvascular complications. Only metformin has been shown to reduce macrovascular complications and all-cause mortality in obese patients with type 2 diabetes. Interestingly, this beneficial effect of metformin is totally independent of blood sugar control. Thus, metformin should be the pharmaceutical agent of first choice in the treatment of type 2 diabetes.
ABSTRACT
BACKGROUND: Many new oral medications have been developed to treat diabetes, but uncertainty remains regarding which are best for initial treatment and whether effectiveness rates differ. This review compares the available oral antihyperglycemics.
POPULATION STUDIED: A total of 63 randomized controlled clinical trials involving oral hypoglycemic drugs for type 2 diabetes was identified by a MED-LINE search and review of the bibliographies of articles found initially. Other inclusion criteria were study duration of at least 3 months, at least 10 subjects at the study’s conclusion, and hemoglobin A1C levels reported. Other search details, such as the year and key words of a study, were not mentioned. More than 15,000 subjects have been enrolled in the identified trials, but no information was given regarding important clinical characteristics such as age, ethnicity, body mass index, or medical conditions other than diabetes. Therefore, assessing generalizability of the data to typical patients of family practitioners is difficult.
STUDY DESIGN AND VALIDITY: The article lists available randomized clinical trials that evaluate sulfonylureas, metformin, α-glucosidase inhibitors (AGIs), thiazolidinediones (TZDs), and nonsulfonylurea secretagogues as monotherapy versus placebo, in head-to-head trials or in combination, and compares their outcomes in terms of hemoglobin A1C reduction. When multiple doses of a drug were tested, the results from the highest dose were used. There was no attempt to synthesize the data provided by the studies into a meta-analysis.
OUTCOMES MEASURED: The major outcome measured was percent hemoglobin A1C reduction. Side effects were mentioned but not quantified. Cost, patient satisfaction, and quality of life were not addressed.
RESULTS: Except for the UKPDS, all available studies of oral hypoglycemics are short term and are limited in focus to hemoglobin A1C. Each class of drugs achieved a similar initial reduction in hemoglobin A1C of 1% to 2% except for the AGIs and nateglinide, which were less effective. The results are remarkably consistent across studies. Head-to-head comparison of specific medications further supports this conclusion. When taken in combination, the effects on hemoglobin A1C are additive.
Despite the claims of pharmaceutical marketing, there is little difference among sulfonylureas, metformin, and thiazolidinediones in reduction of hemoglobin A1C. Each class achieves an average reduction of 1% to 2%. Alpha glucosidase inhibitors and nonsulfonylurea secretogogues are probably somewhat less efficacious; combinations of medications seem to be additive.
Clinicians should keep in mind that diet and exercise remain first-line treatment for type 2 diabetes. Initial drug therapy should be guided, however, by evidence about long-term outcomes, such as reduction in the risk of myocardial infarction, renal failure, and blindness; to date, only metformin and sulfonylureas have been shown to be beneficial in reducing microvascular complications. Only metformin has been shown to reduce macrovascular complications and all-cause mortality in obese patients with type 2 diabetes. Interestingly, this beneficial effect of metformin is totally independent of blood sugar control. Thus, metformin should be the pharmaceutical agent of first choice in the treatment of type 2 diabetes.
What is the optimal protocol for diagnosis of ectopic pregnancy?
BACKGROUND: Ectopic pregnancy is a major cause of morbidity and mortality in women of reproductive age, but uncertainty remains about the best strategy for early diagnosis.
POPULATION STUDIED: This study used a hypothetical cohort of 10,000 women with first trimester pregnancies (positive pregnancy test result) who presented to an inner-city emergency department with abdominal pain or bleeding. Patients with any evidence of intra-abdominal hemorrhage were excluded. Their assumed prevalences of ectopic, intrauterine, and nonviable pregnancies were 9.4%, 61.1%, and 29.9%, respectively, based on a weighted average of 3 studies from inner-city teaching hospitals. The availability of 24-hour endovaginal ultrasound and human chorionic gonadotropin (HCG) testing was assumed. The results derived from this population are likely to be similar to those seen by family physicians, but caution should be exercised in generalizing this information to settings such as office practices or rural emergency departments.
STUDY DESIGN AND VALIDITY: The decision analysis defined 6 diagnostic algorithms: (1) transvaginal ultrasound (US) followed by quantitative HCG; (2) quantitative HCG followed by US; (3) progesterone followed by US and quantitative HCG; (4) progesterone followed by quantitative HCG and US; (5) US followed by repeat US; and (6) clinical examination. In practice, ultrasound and HCG are often done simultaneously, but otherwise the descriptions are appropriate. Strategies involving transabdominal US, serial HCGs, and methotrexate were not included. It was assumed that dilatation and curettage (D&C) and laparoscopy were 100% diagnostic and that US does not mistake intrauterine pregnancy for ectopic pregnancy. One- and two-way sensitivity analysis of test characteristics were performed using values obtained from the literature; prevalence of disease and performance of clinical examination were not included in the analysis.The methodologic strength of this study was fair. This clinical question is well suited to decision analysis; the different options are described well; and the analysis addresses appropriate outcomes, including unnecessarily interrupted pregnancies. The major weakness is a lack of information about the literature search and sensitivity analysis that makes it difficult to assess whether the authors’ underlying assumptions are valid. In addition, the authors assume that the highest priority is to avoid missed ectopic pregnancies. Although this is reasonable, no effort was made to query the literature, other professionals, or patients about what their preferred priorities would be, especially when the large majority of ectopic pregnancies are being detected by most of the strategies.
OUTCOMES MEASURED: The primary outcome was the number of missed ectopic pregnancies per 10,000 women. Secondary outcomes included the number of interrupted intrauterine pregnancies; the number of D&Cs, laparoscopies, USs, blood collections, and admissions; the days until diagnosis; and the hospital charges.
RESULTS: No ectopic pregnancies were missed with strategies that involved only US and HCG. Of those 2 strategies, US as the first step led to the fewest interrupted intrauterine pregnancies (70 vs 122). The progesterone algorithms missed more women with ectopic pregnancies (24) and required more surgeries but had the fewest number of interrupted pregnancies (25 and 39). US followed by US missed no ectopic pregnancies and had the shortest time until diagnosis but had the highest hospital charges. Clinical examination alone missed all ectopic pregnancies (940). Sensitivity analysis confirmed that the strategy of HCG followed by US was the most favorable, provided the sensitivity of the US for diagnosing intrauterine pregnancy was above 93%.
This decision analysis provides fair evidence that transvaginal US followed by quantitative HCG is the optimal strategy for diagnosing ectopic pregnancy. Obtaining HCG before ultrasound also performs very well, but strategies starting with progesterone miss a number of ectopic pregnancies. Clinicians should be cautious, however, about generalizing these results to patient populations with a different prevalence of ectopic pregnancy or with different values regarding the interruption of intrauterine pregnancies, and should look for information that incorporates the diagnostic and therapeutic options available in their settings.
BACKGROUND: Ectopic pregnancy is a major cause of morbidity and mortality in women of reproductive age, but uncertainty remains about the best strategy for early diagnosis.
POPULATION STUDIED: This study used a hypothetical cohort of 10,000 women with first trimester pregnancies (positive pregnancy test result) who presented to an inner-city emergency department with abdominal pain or bleeding. Patients with any evidence of intra-abdominal hemorrhage were excluded. Their assumed prevalences of ectopic, intrauterine, and nonviable pregnancies were 9.4%, 61.1%, and 29.9%, respectively, based on a weighted average of 3 studies from inner-city teaching hospitals. The availability of 24-hour endovaginal ultrasound and human chorionic gonadotropin (HCG) testing was assumed. The results derived from this population are likely to be similar to those seen by family physicians, but caution should be exercised in generalizing this information to settings such as office practices or rural emergency departments.
STUDY DESIGN AND VALIDITY: The decision analysis defined 6 diagnostic algorithms: (1) transvaginal ultrasound (US) followed by quantitative HCG; (2) quantitative HCG followed by US; (3) progesterone followed by US and quantitative HCG; (4) progesterone followed by quantitative HCG and US; (5) US followed by repeat US; and (6) clinical examination. In practice, ultrasound and HCG are often done simultaneously, but otherwise the descriptions are appropriate. Strategies involving transabdominal US, serial HCGs, and methotrexate were not included. It was assumed that dilatation and curettage (D&C) and laparoscopy were 100% diagnostic and that US does not mistake intrauterine pregnancy for ectopic pregnancy. One- and two-way sensitivity analysis of test characteristics were performed using values obtained from the literature; prevalence of disease and performance of clinical examination were not included in the analysis.The methodologic strength of this study was fair. This clinical question is well suited to decision analysis; the different options are described well; and the analysis addresses appropriate outcomes, including unnecessarily interrupted pregnancies. The major weakness is a lack of information about the literature search and sensitivity analysis that makes it difficult to assess whether the authors’ underlying assumptions are valid. In addition, the authors assume that the highest priority is to avoid missed ectopic pregnancies. Although this is reasonable, no effort was made to query the literature, other professionals, or patients about what their preferred priorities would be, especially when the large majority of ectopic pregnancies are being detected by most of the strategies.
OUTCOMES MEASURED: The primary outcome was the number of missed ectopic pregnancies per 10,000 women. Secondary outcomes included the number of interrupted intrauterine pregnancies; the number of D&Cs, laparoscopies, USs, blood collections, and admissions; the days until diagnosis; and the hospital charges.
RESULTS: No ectopic pregnancies were missed with strategies that involved only US and HCG. Of those 2 strategies, US as the first step led to the fewest interrupted intrauterine pregnancies (70 vs 122). The progesterone algorithms missed more women with ectopic pregnancies (24) and required more surgeries but had the fewest number of interrupted pregnancies (25 and 39). US followed by US missed no ectopic pregnancies and had the shortest time until diagnosis but had the highest hospital charges. Clinical examination alone missed all ectopic pregnancies (940). Sensitivity analysis confirmed that the strategy of HCG followed by US was the most favorable, provided the sensitivity of the US for diagnosing intrauterine pregnancy was above 93%.
This decision analysis provides fair evidence that transvaginal US followed by quantitative HCG is the optimal strategy for diagnosing ectopic pregnancy. Obtaining HCG before ultrasound also performs very well, but strategies starting with progesterone miss a number of ectopic pregnancies. Clinicians should be cautious, however, about generalizing these results to patient populations with a different prevalence of ectopic pregnancy or with different values regarding the interruption of intrauterine pregnancies, and should look for information that incorporates the diagnostic and therapeutic options available in their settings.
BACKGROUND: Ectopic pregnancy is a major cause of morbidity and mortality in women of reproductive age, but uncertainty remains about the best strategy for early diagnosis.
POPULATION STUDIED: This study used a hypothetical cohort of 10,000 women with first trimester pregnancies (positive pregnancy test result) who presented to an inner-city emergency department with abdominal pain or bleeding. Patients with any evidence of intra-abdominal hemorrhage were excluded. Their assumed prevalences of ectopic, intrauterine, and nonviable pregnancies were 9.4%, 61.1%, and 29.9%, respectively, based on a weighted average of 3 studies from inner-city teaching hospitals. The availability of 24-hour endovaginal ultrasound and human chorionic gonadotropin (HCG) testing was assumed. The results derived from this population are likely to be similar to those seen by family physicians, but caution should be exercised in generalizing this information to settings such as office practices or rural emergency departments.
STUDY DESIGN AND VALIDITY: The decision analysis defined 6 diagnostic algorithms: (1) transvaginal ultrasound (US) followed by quantitative HCG; (2) quantitative HCG followed by US; (3) progesterone followed by US and quantitative HCG; (4) progesterone followed by quantitative HCG and US; (5) US followed by repeat US; and (6) clinical examination. In practice, ultrasound and HCG are often done simultaneously, but otherwise the descriptions are appropriate. Strategies involving transabdominal US, serial HCGs, and methotrexate were not included. It was assumed that dilatation and curettage (D&C) and laparoscopy were 100% diagnostic and that US does not mistake intrauterine pregnancy for ectopic pregnancy. One- and two-way sensitivity analysis of test characteristics were performed using values obtained from the literature; prevalence of disease and performance of clinical examination were not included in the analysis.The methodologic strength of this study was fair. This clinical question is well suited to decision analysis; the different options are described well; and the analysis addresses appropriate outcomes, including unnecessarily interrupted pregnancies. The major weakness is a lack of information about the literature search and sensitivity analysis that makes it difficult to assess whether the authors’ underlying assumptions are valid. In addition, the authors assume that the highest priority is to avoid missed ectopic pregnancies. Although this is reasonable, no effort was made to query the literature, other professionals, or patients about what their preferred priorities would be, especially when the large majority of ectopic pregnancies are being detected by most of the strategies.
OUTCOMES MEASURED: The primary outcome was the number of missed ectopic pregnancies per 10,000 women. Secondary outcomes included the number of interrupted intrauterine pregnancies; the number of D&Cs, laparoscopies, USs, blood collections, and admissions; the days until diagnosis; and the hospital charges.
RESULTS: No ectopic pregnancies were missed with strategies that involved only US and HCG. Of those 2 strategies, US as the first step led to the fewest interrupted intrauterine pregnancies (70 vs 122). The progesterone algorithms missed more women with ectopic pregnancies (24) and required more surgeries but had the fewest number of interrupted pregnancies (25 and 39). US followed by US missed no ectopic pregnancies and had the shortest time until diagnosis but had the highest hospital charges. Clinical examination alone missed all ectopic pregnancies (940). Sensitivity analysis confirmed that the strategy of HCG followed by US was the most favorable, provided the sensitivity of the US for diagnosing intrauterine pregnancy was above 93%.
This decision analysis provides fair evidence that transvaginal US followed by quantitative HCG is the optimal strategy for diagnosing ectopic pregnancy. Obtaining HCG before ultrasound also performs very well, but strategies starting with progesterone miss a number of ectopic pregnancies. Clinicians should be cautious, however, about generalizing these results to patient populations with a different prevalence of ectopic pregnancy or with different values regarding the interruption of intrauterine pregnancies, and should look for information that incorporates the diagnostic and therapeutic options available in their settings.