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Oral Antidiabetic Agents: A Comparative Review

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Abstract

Type 2 diabetes mellitus is a chronic disease characterized by insulin resistance, impaired insulin secretion, and/or increased hepatic glucose production. The mainstays of drug treatment are the oral antidiabetic agents. Insulin is usually reserved for patients who do not achieve fasting plasma glucose or A1C goals with or cannot tolerate the oral antidiabetic agents. There are 5 classes of oral antidiabetic agents available in the United States: sulfonylureas, biguanides, alpha-glucosidase inhibitors, thiazolidinediones, and nonsulfonylurea secretagogues. They have differences and similarities with respect to their pharmacology and role in diabetes. This article reviews the pharmacology, efficacy, safety, and selection of the oral agents used to treat type 2 diabetes mellitus.

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... Ze stimuleren de opslag van vrije vetzuren in vetweefsel. Ook via indirecte effecten in vetweefsel wordt de insulinegevoeligheid bevorderd [Diamant 2003, Yki-Järvinen 2004, Koski 2004. In een review worden alle bekende effecten van rosi-en pioglitazon samengevat: vermindering van het hepatische vet, verhoging van de insulinegevoeligheid en reductie van de voortgaande intima-media-verdikking [Westerbacka 2004. ...
... Noot 49 Repaglinide (ook wel meglitinide of kortwerkende insulinesecretagogeen genoemd) verhoogt de insulinesecretie uit de bètacel [Koski 2004, Inzucchi 2002. Repaglinide werkt snel en kort in vergelijking met sulfonylureumderivaten. ...
... Bij inname vlak voor de maaltijd treedt het stimulerende effect op de insulinesecretie vooral tijdens de maaltijd op. Daardoor zijn de postprandiale glucosewaarden lager [Koski 2004, Inzucchi 2002; de klinische betekenis is onduidelijk [Heine 2002]. ...
... 3 En la actualidad se dispone de nueve nuevas clases de medicamentos antidiabéticos orales, entre ellos los secretagogos: sulfonilureas y glinidas que estimulan la liberación pancreática de insulina por diferentes receptores. 5 Estos medicamentos tienen diferentes efectos en el perfil de lípidos, pues las sulfonilureas no afectan de manera importante el perfil de lípidos, las glinidas disminuyen discretamente los triglicéridos. 5,6 La repaglinida tiene una vida media y duración de acción muy corta. ...
... 5 Estos medicamentos tienen diferentes efectos en el perfil de lípidos, pues las sulfonilureas no afectan de manera importante el perfil de lípidos, las glinidas disminuyen discretamente los triglicéridos. 5,6 La repaglinida tiene una vida media y duración de acción muy corta. Su principal acción es sobre la hiperglucemia postprandial, 7,12 su efecto de acción corta ayuda a disminuir la incidencia de hipoglucemia. ...
... Las glinidas disminuyen la glucosa en ayuno en 10 mg/dL y su efecto en las concentraciones de glucosa postprandial puede tener un efecto protector cardiovascular a largo plazo. 5,6,7 La seguridad cardiovascular de los medicamentos antidiabéticos es un tema de importancia actual. Los únicos agentes antidiabéticos orales que han demostrado disminuir las complicaciones cardiovasculares en ensayos clínicos son las sulfonilureas y la metformina, 8,9 aunque estudios recientes cuestionan la eficacia de las primeras. ...
... The α-glucosidase inhibitors obstruct the pathway of intestinal carbohydrate breakdown by inhibiting some enzymes responsible for it (DeFronzo 1999;Lebovitz 1997). Another hypoglycemic drug group, thiazolidinediones (TZDs), works by increasing the sensitivity of muscular and adipose tissues to insulin (DeFronzo 1999;Koski 2004). This class of drugs also helps in the reduction of glucose production by the liver. ...
... Nonsulfonylureas secretagogues and repaglinides are also known to be beneficial in reducing the blood glucose by somewhat same mechanism as used by sulfonylureas. Non-sulfonylureas secretagogues and repaglinides improve the insulin secretion from pancreatic β cells, however binding to different β-cell receptors (Koski 2004). ...
... The α-glucosidase inhibitors obstruct the pathway of intestinal carbohydrate breakdown by inhibiting some enzymes responsible for it (DeFronzo 1999;Lebovitz 1997). Another hypoglycemic drug group, thiazolidinediones (TZDs), works by increasing the sensitivity of muscular and adipose tissues to insulin (DeFronzo 1999;Koski 2004). This class of drugs also helps in the reduction of glucose production by the liver. ...
... Nonsulfonylureas secretagogues and repaglinides are also known to be beneficial in reducing the blood glucose by somewhat same mechanism as used by sulfonylureas. Non-sulfonylureas secretagogues and repaglinides improve the insulin secretion from pancreatic β cells, however binding to different β-cell receptors (Koski 2004). ...
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In this chapter, we discussed and reread the use of two traditional medicinal plants Aloe barbadensis and Momordica charantia for the treatment of diabetes. The antidiabetic consequences of both the debated plants stand accredited to the phytochemical combinations or single constituents of the plant extracts. Alkaloids, phenolic acids, flavonoids, glycosides, and saponins are the main elements with antidiabetic properties. Various machineries have been brought forth by the researchers with regard to the phytochemicals and their antidiabetic regulations, for example, glucose regulation and fat metabolism, insulin secretion, β-cell stimulation, NF-kB-inducing kinase (NIK) pathway, etc. Further research and developments in the utilization of traditional treatments have considerably powered the drug progression of innovative effects intended for diabetes. Consequently, further effectual scientific examinations are necessary for supplementary authentication. Alternatively, the main antidiabetic principles of medicinal plants should be prioritized and explored to ensure the better outcomes.
... O aumento no influxo de cálcio promove a liberação dos grânulos de insulina pré- formados. Este mecanismo só funciona, portanto, se houver insulina disponível para ser liberada e é mais pronunciado na presença de glicemia elevada 257 . A eficácia das sulfoniluréias tende a se reduzir com o tempo de uso. ...
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Orientadora: Rosana Radominski Co-orientadores: Roberto Pantarolo e Fernando Ferández-Llimós Inclui apęndice Inclui bibliografia e anexos Área de concentraçăo: Cięncias da Saúde
... Currently available drugs for treatment of Diabetes mellitus have a number of limitations, such as adverse effects and high rate of secondary failure (Koski, 2004). As there is a growing trend towards using natural remedies as adjuncts to conventional therapy, traditionally used plants might provide a useful source of new hypoglycemic compounds (Bailey and Day, 1989 ). ...
Article
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The present research was made to investigate the potential hypoglycemic and hypolipidemic effect of Morus Indica and Asystasia gangetica in alloxan induced diabetes mellitus. Diabetes was induced by alloxan (150 mg/kg i.p) in to rats. Ethanolic extract of leaves of Morus Indica and Asystasia gangetica was administered to alloxan induced diabetic rats. Glibenclamide used as a reference standard. Blood glucose, triglycerides, cholesterol, HDL-cholesterol, LDL-cholesterol and total proteins were estimated from the serum by using standard kits. All groups show significant increase in the level of biochemical parameters were decreased by administration of ethanolic extract of leaves of Morus Indica and Asystasia gangetica. From this study it has been concluded that the ethanolic extracts of leaves of Morus Indica and Asystasia gangetica having good hypoglycemic and hypolipidemic effect.
... Glibenclamide is regularly used as an insulin stimulant in many studies and also used as a standard antidiabetic drug in STZinduced diabetes to relate the antidiabetic belongings of a variety of hypoglycemic compounds (Andrade Cetto A, et al., 2000). Now current drugs for the treatment of diabetes mellitus have numerous limits, such as unwanted effects and higher rate of secondary failure (Koski RR, 2004). As there is a rising tendency towards using usual medicines as adjuncts to conventional therapy, conservatively used plants might proposal a helpful source of new hypoglycemic compounds. ...
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Herbal medicines are commonly measured to be fewer toxic and also free from side effects, than synthetic ones. Therefore, the present study is an effort to study antihyperglycemic property of ethanolic remove of Sesbania grandifloria counter to streptozotocin encouraged diabetes. The outcome of ethanolic remove of Sesbania grandifloria on blood glucose and liver glycogen remained studied in the diabetic rats. The study also measured for the outcome of herbal extract for their outcome on SOD, catalase, GSH and LPO in the homogenates of the pancreas. The outcomes of the current study shows important antidiabetic and antioxidant possible for the selected plants alone and also in combination as a projecting reduction in blood glucose and liver glycogen remained experimental in the rats treated with the extracts of the particular plants. Likewise, the levels of the defensive antioxidant enzymes like SOD, catalase and GSH were improved along with fall in the LPO levels. The current study offers a systematic evidence for antidiabetic and antioxidant potential of Sesbania grandifloria. © JK Welfare & Pharmascope Foundation | International Journal of Research in Pharmaceutical Sciences.
... Currently available drugs for the treatment of Diabetes mellitus have a number of limitations, such as adverse effects and a high rate of secondary failure. 21 As there is a growing trend towards using natural remedies adjunct to conventional therapy, traditionally used plants might provide a useful source of new hypoglycemic compounds. 22 Although Asystasia gangetica may be described as a medicinal plant 5 The hypoglycemic and antioxidant effect of mulberry leaves or shoot culture extract has been demonstrated using streptozotocin induced diabetic animals. ...
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R Pradeep Kumar,1 D Sujatha,2 TS Mohamed Saleem,1 C Madhusudhana Chetty,1 D Ranganayakulu21Department of Pharmacology, Annamacharya College of Pharmacy, Rajampet, India; 2Department of Pharmacology, Sri Padmavathi School of Pharmacy, Tirupathi, IndiaAbstract: Herbal drugs are frequently considered to be less toxic and also free from side effects, than synthetic ones. Hence, the present study was designed to investigate one such combination of herbal drugs, Asystasia gangetica and Morus indica for their antidiabetic and antioxidant potential against alloxan-induced diabetes in albino rats. The effect of both individual and a combination of Asystasia gangetica and Morus indica on blood glucose and liver glycogen were studied in the diabetic rats. The study also assessed for the effect of selected plant extracts for their effect on Superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH) and Lipid peroxidation (LPO) in the homogenates of the pancreas. The results of the present study attests significant antidiabetic and antioxidant potential for the selected plants individually and also in combination as a prominent decrease in blood glucose and liver glycogen was observed in the rats treated with the extracts of the selected plants. Similarly, the levels of the protective antioxidant enzymes like SOD, CAT and GSH were increased along with decrease in the LPO levels. The present study provides a scientific evidence for antidiabetic and antioxidant potential of Asystasia gangetica and Morus indica. Further studies to isolate bioactive compounds will pave the way to identify potential lead compounds for developing safe and efficacious antidiabetic agents.Keywords: hypoglycemic effect, herbal drugs, lipid peroxidation, hyperglycemia, diabetic animals
... Stimulation of such receptors controls the transcription of insulin-responsive genes involved in the regulation of transportation, production and glucose utilization. Moreover, it was shown that TZDs can enhance β-cell function by lowering free fatty acids levels that play an ultimate role in β-cell death [24]. ...
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De richtlijnen voor medicamenteuze behandeling zijn aangepast; metformine is de eerste stap in de behandeling voor alle patiënten en wordt ook na instelling op insuline gecontinueerd; voor thiazolidinedionen is beperkt plaats.
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To compare the effect of repaglinide in combination with metformin with monotherapy of each drug on glycemic control in patients with type 2 diabetes. A total of 83 patients with type 2 diabetes who had inadequate glycemic control (HbA1c > 7.1%) when receiving the antidiabetic agent metformin were enrolled in this multicenter, double-blind trial. Subjects were randomized to continue with their prestudy dose of metformin (n = 27), to continue with their prestudy dose of metformin with the addition of repaglinide (n = 27), or to receive repaglinide alone (n = 29). For patients receiving repaglinide, the optimal dose was determined during a 4- to 8-week titration and continued for a 3-month maintenance period. In subjects receiving combined therapy, HbA1c was reduced by 1.4 +/- 0.2%, from 8.3 to 6.9% (P = 0.0016) and fasting plasma glucose by 2.2 mmol/l (P = 0.0003). No significant changes were observed in subjects treated with either repaglinide or metformin monotherapy in HbA1c (0.4 and 0.3% decrease, respectively) or fasting plasma glucose (0.5 mmol/l increase and 0.3 mmol/l decrease respectively). Subjects receiving repaglinide either alone or in combination with metformin, had an increase in fasting levels of insulin between baseline and the end of the trial of 4.04 +/- 1.56 and 4.23 +/- 1.50 mU/l, respectively (P < 0.02). Gastrointestinal adverse events were common in the metformin group. An increase in body weight occurred in the repaglinide and combined therapy groups (2.4 +/- 0.5 and 3.0 +/- 0.5 kg, respectively; P < 0.05). Combined metformin and repaglinide therapy resulted in superior glycemic control compared with repaglinide or metformin monotherapy in patients with type 2 diabetes whose glycemia had not been well controlled on metformin alone. Repaglinide monotherapy was as effective as metformin monotherapy.
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This multicenter open-label clinical trial compared the efficacy and safety of repaglinide/troglitazone combination therapy, repaglinide monotherapy, and troglitazone monotherapy in type 2 diabetes that had been inadequately controlled by sulfonylureas, acarbose, or metformin alone. Patients with type 2 diabetes (n = 256) who had inadequate glycemic control (HbA1c > or =7.0%) during previous monotherapy were randomly assigned to receive repaglinide (0.5-4.0 mg at meals), troglitazone (200-600 mg once daily), or a combination of repaglinide (1-4 mg at meals) and troglitazone (200-600 mg once daily). After a 4-6 week washout period, the trial assessed 22 weeks of treatment: 3 weeks (weeks 0-2) of forced titration, 11 weeks of fixed-dose treatment (weeks 3-13), and 8 weeks (weeks 14-21) of titration to maximum dose. Changes in HbA1c and fasting plasma glucose (FPG) values were measured. The combination therapy showed a significant reduction in mean HbA1c values (-1.7%) that was greater than with either type of monotherapy Repaglinide monotherapy resulted in a reduction of HbA1c values that was significantly greater than troglitazone (-0.8 vs. -0.4%) (P < 0.05). Combination therapy was more effective in reducing FPG values (-80 mg/dl) than either repaglinide (-43 mg/dl) or troglitazone (-46 mg/dl) monotherapies. Adverse events were similar in all groups. Combination therapy with repaglinide and troglitazone leads to better glycemic control than monotherapy with either agent alone. Repaglinide monotherapy was more effective in lowering HbA1c levels than troglitazone monotherapy Repaglinide/troglitazone combination therapy was effective and did not show unexpected adverse events.
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To evaluate the efficacy and tolerability of nateglinide and metformin alone and in combination in type 2 diabetic patients inadequately controlled by diet, focusing on changes in HbA1c, fasting plasma glucose (FPG), and mealtime glucose excursions. In this randomized double-blind study, patients with an HbA1c level between 6.8 and 11.0% during a 4-week placebo run-in received 24 weeks' treatment with 120 mg nateglinide before meals (n = 179), 500 mg metformin three times a day (n = 178), combination therapy (n = 172), or placebo (n = 172). HbA1c and FPG were evaluated regularly, and plasma glucose levels were determined after Sustacal challenge at weeks 0, 12, and 24. Hypoglycemia and other adverse events were recorded. At study end point, HbA1c was reduced from baseline with nateglinide and metformin but was increased with placebo (-0.5, -0.8, and +0.5%, respectively; P < or = 0.0001). Changes in FPG followed the same pattern (-0.7, -1.6, and +0.4 mmol/l; P < or = 0.0001). Combination therapy was additive (HbA1c -1.4% and FPG -2.4 mmol/l; P < or = 0.01 vs. monotherapy). After Sustacal challenge, there was a greater reduction in mealtime glucose with nateglinide monotherapy compared with metformin monotherapy or placebo (adjusted area under the curve [AUC]0-130 min -2.1, -1.1, and -0.6 mmol x h(-1) x l(-1); p < or = 0.0001). An even greater effect was observed with combination therapy (AUC0-130 min -2.5 mmol x h(-1) x l(-1); P < or = 0.0001 vs. metformin and placebo). All regimens were well tolerated. Nateglinide and metformin monotherapy each improved overall glycemic control but by different mechanisms. Nateglinide decreased mealtime glucose excursions, whereas metformin primarily affected FPG. In combination, nateglinide and metformin had complementary effects, improving HbA1c, FPG, and postprandial hyperglycemia.
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Metformin is an insulin-sensitizing agent with potent antihyperglycemic properties. Its efficacy in reducing hyperglycemia in type 2 diabetes mellitus is similar to that of sulfonylureas, thiazolidinediones, and insulin. Metformin-based combination therapy is often superior to therapy with a single hypoglycemic agent. The antihyperglycemic properties of metformin are mainly attributed to suppressed hepatic glucose production, especially hepatic gluconeogenesis, and increased peripheral tissue insulin sensitivity. Although the precise mechanism of hypoglycemic action of metformin remains unclear, it probably interrupts mitochondrial oxidative processes in the liver and corrects abnormalities of intracellular calcium metabolism in insulin-sensitive tissues (liver, skeletal muscle, and adipocytes) and cardiovascular tissue.
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Decreased insulin sensitivity plays a major role in various human diseases, particularly type 2 diabetes mellitus, and is associated with a higher risk of atherosclerosis and cardiovascular complications. Thiazolidinediones, more commonly termed glitazones, are the first drugs to specifically target muscular insulin resistance. They have proven efficacy for reducing plasma glucose levels in patients with type 2 diabetes mellitus treated with diet alone, sulphonylureas, metformin or insulin. In addition, they are associated with some improvement of the cardiovascular risk profile. However, troglitazone, the first compound approved by the Food and Drug Administration in the US, proved to be hepatotoxic and was withdrawn from the market after the report of several dozen deaths or cases of severe hepatic failure requiring liver transplantation. It remains unclear whether or not hepatotoxicity is a class effect or is related to unique properties of troglitazone. Rosiglitazone and pioglitazone, two other glitazones, appear to have similar efficacy with regard to blood glucose control in patients with type 2 diabetes mellitus as compared with troglitazone. In controlled clinical trials, the incidence of significant (≥3 × upper limit of normal) increases in liver enzyme levels (ALT in particular) was similar with rosiglitazone or pioglitazone as compared with placebo, whereas troglitazone was associated with a 3-fold greater incidence. In contrast to the numerous case reports of acute liver failure in patients receiving troglitzone, only a few case reports of hepatotoxicity have been reported in patients treated with rosiglitazone until now, with a causal relationship remaining uncertain. Furthermore, no single case of severe hepatotoxicity has been reported yet with pioglitazone. It should be mentioned that troglitazone, unlike pioglitazone and rosiglitazone, induces the cytochrome P450 isoform 3A4, which is partly responsible for its metabolism, and may be prone to drug interactions. Importantly enough, obesity, insulin resistance and type 2 diabetes mellitus are associated with liver abnormalities, especially non-alcoholic steatohepatitis, independent of any pharmacological treatment. This association obviously complicates the selection of patients who are good candidates for a treatment with glitazones as well as the monitoring of liver tests after initiation of therapy with any thiazolidinedione compound. While regular monitoring of liver enzymes is still recommended and more long term data are desirable, current evidence from clinical trials and postmarketing experience in the US supports the conclusion that rosiglitazone and pioglitazone do not share the hepatotoxic profile of troglitazone.
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PREVIEWIncreasingly, type 2 diabetes takes a toll on public health and healthcare costs in the United States. Although the remedy for this growing problem is very complex, two critical components of its control are prevention and effective therapy. Progress in diabetes prevention is likely to take decades. But fortunately, growth in our understanding of what occurs in this chronic disease has led to advances in the pharmacologic options aimed at decreasing hyperglycemia, the main clinically measurable metabolic consequence of diabetes. In this article, Drs Ahmann and Riddle provide an overview of the oral agents now available for the treatment of diabetes and discuss the clinical factors that help determine when to use which medication and what outcome to expect.
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Combination therapy is logical for patients with non-insulin-dependent (type 2) diabetes mellitus, because they often have poor responses to single-drug therapy. We studied the efficacy and physiologic effects of metformin and troglitazone alone and in combination in patients with type 2 diabetes. We randomly assigned 29 patients to receive either metformin or troglitazone for three months, after which they were given both drugs for another three months. Plasma glucose concentrations during fasting and postprandially and glycosylated hemoglobin values were measured periodically during both treatments. Endogenous glucose production and peripheral glucose disposal were measured at base line and after three and six months. During metformin therapy, fasting and postprandial plasma glucose concentrations decreased by 20 percent (58 mg per deciliter [3.2 mmol per liter], P<0.001) and 25 percent (87 mg per deciliter [4.8 mmol per liter], P<0.001), respectively. The corresponding decreases during troglitazone therapy were 20 percent (54 mg per deciliter [2.9 mmol per liter], P=0.01) and 25 percent (83 mg per deciliter [4.6 mmol per liter], P<0.001). Endogenous glucose production decreased during metformin therapy by a mean of 19 percent (P=0.001), whereas it was unchanged by troglitazone therapy (P=0.04 for the comparison between groups). The mean rate of glucose disposal increased by 54 percent during troglitazone therapy (P=0.006) and 13 percent during metformin therapy (P= 0.03 for the comparison within the group and between groups). In combination, metformin and troglitazone further lowered fasting and postprandial plasma glucose concentrations by 18 percent (41 mg per deciliter [2.3 mmol per liter], P=0.001) and 21 percent (54 mg per deciliter [3.0 mmol per liter], P<0.001), respectively, and the mean glycosylated hemoglobin value decreased 1.2 percentage points. Metformin and troglitazone have equal and additive beneficial effects on glycemic control in patients with type 2 diabetes. Metformin acts primarily by decreasing endogenous glucose production, and troglitazone by increasing the rate of peripheral glucose disposal.
Article
Forty-eight diabetic subjects with diet-failed Type 2 mellitus, aged 40-69 years, were randomised to metformin (24 patients) or glipizide (24 patients) therapy, and followed prospectively for 12 months. Most subjects were obese. Metformin gave better fasting plasma glucose control compared to glipizide at 24 (p < 0.01), 36 (p < 0.05) and 52 weeks (p < 0.05) with a lower HbA1 concentration at 52 weeks (p < 0.05). Metformin treated patients lost weight whereas glipizide treated subjects gained weight. The weight change between the treatment groups reached significance at 4 weeks (p < 0.05) and was highly significant (p < 0.001) at 8, 12, 24, 36 and 52 weeks. There were no significant changes in either fasting plasma lipid or blood lactate levels in either the metformin or glipizide treated groups. Both drugs caused a similar reduction in albumin excretion rates. In conclusion, metformin gave better glycaemic control than glipizide, with weight loss rather than weight gain in obese Type 2 patients.
Article
To compare the different therapeutic principles of alpha-glucosidase inhibitors and sulphonylureas as first-line treatment in non-insulin-dependent diabetes mellitus (NIDDM) patients with dietary failure. Ninety-six NIDDM patients (35-70 years of age, body mass index [BMI] < or = 35), insufficiently treated with diet alone (HbA1c 7-9%) were randomized into three groups and treated for 24 weeks with acarbose, glibenclamide, or placebo. Efficacy, based on fasting blood glucose (BG), BG 1 h after ingestion of standard breakfast (postprandial), serum insulin, postprandial insulin increase, and HbA1c; and tolerability, based on subjective symptoms and laboratory values, were investigated every 6 weeks. Efficacy evaluation was valid for 85 patients. The test drugs were dosed as follows: 100 mg acarbose (A) three times a day, 1 placebo tablet three times a day, 3.5 mg glibenclamide tablets dosed 1-0-0 or 1-0-1, mean dose 4.3 mg/day. Compared with the placebo, both drugs showed the same mean efficacy on fasting BG (-1.4 mM with acarbose, -1.6 mM with glibenclamide), 1-h postprandial BG (-2.2 mM with acarbose, -1.9 mM with glibenclamide), and HbA1c (-1.1% with acarbose, -0.9% with glibenclamide); but they showed a marked difference in 1-h postprandial insulin values (-80.7 pM with acarbose, 96.7 pM with glibenclamide). The mean relative insulin increase (1-h postprandial) was 1.5 in the placebo group, 1.1 in the acarbose group, and 2.5 in the glibenclamide group. No changes in body weight could be observed. No adverse events were seen under placebo. Acarbose led to mild or moderate intestinal symptoms in 38% of patients. Glibenclamide led to hypoglycemia, which could be solved by dose reduction, in 6% of patients. No dropouts occurred in any of the treatment groups. Acarbose and glibenclamide are effective drugs for the monotherapy of NIDDM patients when diet alone fails. Because postprandial insulin increase has been shown to be associated with increased risk for cardiovascular disease, acarbose, which lowers pp increase, may be superior to glibenclamide, which elevates postprandial insulin increase.
Article
Alpha-glucosidase inhibitors are antihyperglycemic agents that lower blood glucose by delaying the digestion and absorption of complex carbohydrates. They are competitive inhibitors of the enzymes in the brush border of enterocytes that cleave eligosaccharides to monosaccharides. Their major action is to reduce the rise of postprandial plasma glucose. In non-insulin-dependent diabetes mellitus patients, these inhibitors decrease postprandial plasma glucose by 40 to 50 mg/dL and hemoglobin A1C by 0.5% to 1.0%.
Article
To compare the therapeutic potential of acarbose, metformin, or placebo as first line treatment in patients with non-insulin-dependent diabetes mellitus (NIDDM). Ninety-six patients with NIDDM (35-70 years of age, body mass index (BMI) < or = 35 kg/m2, insufficiently treated with diet alone, glycated hemoglobin (HbA1c; 7% to 11%) were randomized into 3 groups and treated for 24 weeks with acarbose, 3 x 100 mg/day, or metformin, 2 x 850 mg/day, or placebo. Efficacy, based on HbA1c (primary efficacy criterion), fasting blood glucose (BG) and insulin, 1 hour postprandial BG and insulin (after standard meal test), postprandial insulin increase, plasma lipid profile, and tolerability, based on subjective symptoms and laboratory values were determined every 6 weeks. Analysis of covariance was performed for endvalues with adjustment on baseline values. Ninety-four patients were valid for efficacy evaluation. Both active drugs showed the same improvement of efficacy criteria compared with placebo. Baseline adjusted means at endpoint were as follows: BG, fasting and 1 hour postprandial, 9.2 mM and 10.9 mM with placebo, 7.6 mM and 8.7 mM with acarbose, and 7.8 mM and 9.0 mM with metformin; HbA1c was 9.8% with placebo, 8.5% with acarbose, and 8.7% with metformin. Comparisons: acarbose versus placebo and metformin versus placebo were statistically significant, but not acarbose versus metformin. No effect on fasting insulin could be observed. Relative postprandial insulin increase was 1.90 with placebo, 1.09 with acarbose, and 1.03 with metformin. Comparisons: acarbose versus placebo and metformin versus placebo were statistically significant, but not acarbose versus metformin. With respect to lipid profile, acarbose was superior to metformin. Low-density lipoprotein (LDL)/high-density lipoprotein (HDL) cholesterol ratio increased by 14.4% with placebo, was unchanged with metformin, but decreased by 26.7% with acarbose. Comparisons: acarbose versus placebo and acarbose versus metformin were statistically significant, but not metformin versus placebo. Slight body weight changes were observed with acarbose (-0.8 kg) and metformin (-0.5 kg), but not with placebo. Acarbose led to mild or moderate intestinal symptoms in 50% of the patients within the first 4 weeks, but in only 13.8% of the patients within the last 4 weeks. Acarbose and metformin are effective drugs for the first line monotherapy of patients with NIDDM. With respect to plasma lipid profile, especially HDL cholesterol, LDL cholesterol and LDL/HDL cholesterol ratio acarbose may be superior to metformin.
Article
To determine if the combination of troglitazone (a peroxisome proliferator-activated receptor-gamma activator) and sulfonylurea will provide efficacy not attainable by either medication alone. There were 552 patients inadequately controlled on maximum doses of sulfonylurea who participated in a 52-week randomized active-controlled multicenter study. Patients were randomized to micronized glyburide 12 mg q.d. (G12); troglitazone monotherapy 200, 400, or 600 mg q.d. (T200, T400, T600); or combined troglitazone and glyburide q.d. (T200/G12, T400/G12, T600/G12). Efficacy measures included HbA1c, fasting serum glucose (FSG), insulin, and C-peptide. Effects on lipids and safety were also assessed. Patients on T600/G12 had significantly lower mean (+/- SEM) FSG (9.3 +/- 0.4 mmol/l; 167.4 +/- 6.6 mg/dl) compared with control subjects (13.7 +/- 0.4 mmol/l; 246.5 +/- 6.8 mg/dl; P < 0.0001) and significantly lower mean HbA1c (7.79 +/- 0.2 vs. 10.58 +/- 0.18%, P < 0.0001). Significant dose-related decreases were also seen with T200/G12 and T400/G12. Among patients on T600/G12, 60% achieved HbA1c < or =8%, 42% achieved HbA1c < or =7%, and 40% achieved FSG < or =7.8 mmol/l (140 mg/dl). Fasting insulin and C-peptide decreased with all treatments. Overall, triglycerides and free fatty acids decreased, whereas HDL cholesterol increased. LDL cholesterol increased slightly, with no change in apolipoprotein B. Adverse events were similar across treatments. Hypoglycemia occurred in 3% of T600/G 12 patients compared with <1% on G12 or troglitazone monotherapy Patients with type 2 diabetes inadequately controlled on sulfonylurea can be effectively managed with a combination of troglitazone and sulfonylurea that is safe, well tolerated, and represents a new approach to achieving the glycemic targets recommended by the American Diabetes Association.
Article
Care of patients with type 2 diabetes has been revolutionized throughout the past several years-first, by the realization of the importance of tight glycemic control in forestalling complications, and second, by the availability of several unique classes of oral antidiabetic agents. Deciphering which agent to use in certain clinical situations is a new dilemma facing the primary care physician. To systematically review available data from the literature regarding the efficacy of oral antidiabetic agents, both as monotherapy and in combination. A MEDLINE search was performed to identify all English-language reports of unique, randomized controlled clinical trials involving recently available oral agents for type 2 diabetes. Bibliographies were also reviewed to find additional reports not otherwise identified. Studies (63) were included in the analysis if they had a study period of at least 3 months; if each group contained at least 10 subjects at the study's conclusion; and if hemoglobin A(1c) was reported. When multiple dosages of a drug were tested, the results of the highest approved dosage were used. In placebo-controlled trials, hemoglobin A(1c) data are presented as the difference between the change in treated vs placebo subjects. Five distinct oral drug classes are now available for the treatment of type 2 diabetes. Compared with placebo treatment, most of these agents lower hemoglobin A(1c) levels approximately 1% to 2%. Equivalent efficacy is usually demonstrated when different agents are compared with one another in the same study population. When they are used in combination, there are additional glycemic benefits. Long-term vascular risk reduction has been demonstrated only with sulfonylureas and metformin. With few exceptions, the available oral antidiabetic agents are equally effective at lowering glucose concentrations. Their mechanisms of action are different, however, and as a result they appear to have distinct metabolic effects. These are reflected in their adverse effect profiles and their effect on cardiovascular risk, which may influence drug choice.
Article
Treatment of type 2 diabetes has become more and more complex as the number of classes of oral antidiabetic agents has increased. Diet, exercise, and the attainment of ideal body weight are the central components of any therapeutic regimen, but most patients are unable to achieve glycemic goals with these measures alone. In this article, Drs Mayerson and Inzucchi review the five classes of available oral antidiabetic agents and discuss their relationship to the pathophysiologic variables that contribute to hyperglycemia in type 2 diabetes.
Article
Increasingly, type 2 diabetes takes a toll on public health and healthcare costs in the United States. Although the remedy for this growing problem is very complex, two critical components of its control are prevention and effective therapy. Progress in diabetes prevention is likely to take decades. But fortunately, growth in our understanding of what occurs in this chronic disease has led to advances in the pharmacologic options aimed at decreasing hyperglycemia, the main clinically measurable metabolic consequence of diabetes. In this article, Drs Ahmann and Riddle provide an overview of the oral agents now available for the treatment of diabetes and discuss the clinical factors that help determine when to use which medication and what outcome to expect.
Article
Nearly 16 million adults in the United States have diabetes mellitus, and the incidence of type 2 diabetes, the most prevalent form of diabetes, has steadily increased during the past decade. Patients with diabetes are at increased risk for microvascular and macrovascular complications and experience significant morbidity and mortality. Diabetes is the leading cause of blindness, end-stage renal disease, and nontraumatic amputations in adults. Because diabetes is a progressive disorder, the importance of early and appropriate treatment cannot be overemphasized. Present therapeutic strategies for the management of type 2 diabetes are adequate but are not maximally effective. Clearly, reappraisal of the pharmacologic approach to the optimal management of patients with type 2 diabetes is needed. A number of oral hypoglycemic agents, including thiazolidinediones, biguanides, sulfonylureas, and alpha-glucosidase inhibitors, may be used to normalize glucose levels in patients with type 2 diabetes. Because insulin resistance is an underlying pathologic defect in patients with type 2 diabetes, agents that increase insulin sensitivity should be used early in the course of therapy. By using a multifaceted approach to target insulin resistance, many patients with type 2 diabetes may achieve normoglycemia and improved long-term outcomes.
Article
An asymptomatic 45-year-old Hispanic man has a fasting plasma glucose level of 142 mg per deciliter (7.9 mmol per liter) on initial evaluation and 139 mg per deciliter (7.7 mmol per liter) on reevaluation. Other than a steady gain in weight since college and borderline hypertension, his medical history is unremarkable. He is 175 cm (5 ft 9 in.) tall and weighs 95 kg (209 lb; body-mass index, 31.2), and his blood pressure is 138/88 mm Hg. Physical examination is notable only for abdominal obesity and absent ankle reflexes. How should this patient be treated?
Article
The incidence of type 2 diabetes mellitus (DM) in the United States continues to grow rapidly, paralleling the overweight and obesity epidemic. For many years the only therapeutic options for type 2 DM were sulfonylureas and insulin. However, over the last 9 years there has been an explosion of new and exciting agents approved for the treatment of type 2 DM. Some of the treatments target insulin deficiency and others insulin resistance, the hallmarks of the disease. Other drugs delay the intestinal absorption of carbohydrate. Recently several combination agents have been released. With these new drugs has come an overwhelming mountain of information, making it difficult for the busy clinician to know how best to manage the ever-increasing portion of patients with type 2 DM. New questions have arisen: Which agent to start as first line? How much of this drug to use before adding something else? How long for this drug to reach full effect? Which agent to add second? Should a patient uncontrolled on dual therapy begin insulin or start a third oral agent? If insulin therapy is started, what should become of the patient's oral agents? How best to explain the patient's weight gain on therapy? These are not easy questions and no review can fully detail all the therapeutic combinations possible. Instead, the practical approach of reviewing the agents in terms of their mechanism of action and critically comparing their dosing, effect and cost, is undertaken herein. Also addressed is the possible niche some newer classes of agents and combination drugs may or may not hold in the management of type 2 DM. The decision of using insulin versus a third oral agent will be looked at from the standpoint of where the patient is on dual therapy in relation to the hemoglobin A1c goal. In this way it is hoped that some clarity will be brought to the dizzying array of information that both the physician and patient have to deal with in regard to the management of this prevalent and serious disease.