Medications for the Treatment of Type 2 Diabetes

Diabetes is a major health problem in the United States and its incidence is rising. The term echogenic disease, a disease with environmental and genetic factors, certainly describes type 2 diabetes mellitus. The alarming increase of type 2 diabetes is certainly linked to the environmental factors of a sedentary lifestyle and increasing rates of obesity, as well as family history and genetics.

Prior to 1994, the treatments for type 2 diabetes were limited to the sulfonylurea (SU) class of oral hypoglycemic agents, injectable insulin, and diet and exercise. Four new classes and at least 8 new oral agents have become available for the treatment of type 2 diabetes since 1994. In addition, several new types of insulin have become available, including 2 short-acting agents and 1 basal/long-acting agent. Clearly, the clinical choices today are more confusing and complicated than they were only a few years ago.


Sulfonylureas
The SU class of oral hypoglycemic agents (insulin secretagogues) has been in existence since tolbutamide was introduced in 1956. In 1970, the University Group Diabetes Program study (UGDP) incorrectly linked the use of SUs with adverse cardiac events. However, until 1994, SUs were the only oral medication available for patients with type 2 diabetes in the United States and were the mainstay of noninsulin pharmacologic treatment.
The mechanisms of action for all of the SUs are the same. They are potassium channel blockers whose effect on the pancreatic beta-islet cells is to allow an influx of calcium into the cell, which causes an increase in the release of insulin. The SUs have other effects, including a decrease in glucagon and hepatic gluconeogenesis, and an increase in somatostatin and insulin binding to target receptors. Clinically, one can expect an average 1% to 2% drop in hemoglobin A1c (HbA1c).

The older first-generation SUs are acetohexamide (Dymelor), chlorpropamide (Diabinese), tolazamide (Tolinase), and tolbutamide (Orinase). The second-generation SUs are glimepiride (Amaryl), glipizide (Glucotrol and Glucotrol XL [extended release]), and glyburide (Diabeta, Glynase, Micronase). The major adverse effects of these first- and second-generation drugs are hypoglycemia, hypoglycemic coma, and secondary failure.

One of the main differences between first- and second-generation agents is cost. All are equally effective in lowering HbA1c. The second-generation SUs also show a lower incidence of hyponatremia, disulfiram-like reaction, and severe/persistent hypoglycemia. Glimepiride appears to cause less weight gain than all the others, which is most likely due to its insulin-sparing effect. Contraindications for the use of glimepiride include sulfa allergy, pregnancy, type 1 diabetes, ketoacidosis, renal failure, hepatic failure, and major surgery.

Although some consider SUs to be dated compared with the newer oral hypoglycemic drugs, there remains a large number of patients that will continue to benefit from them.


Biguanides
Experience with metformin (Glucophage) goes back to 1957 when it was introduced in Europe with phenformin (both are biguanides). Only phenformin was released in the United States, but it was removed from the market in 1976 because of an unacceptably high incidence of fatal lactic acidosis. Metformin was finally introduced in the United States in 1994. Metformin has many characteristics that are ideal for treating type 2 diabetes, including weight loss, insulin sensitization, positive lipid effect, mild hypotensive effect, and low or no incidence of hypoglycemia. Many experts believe that because metformin addresses so many of the key effects of type 2 diabetes, it should be considered the first-line medication.

Adverse Effects
The adverse effects of metformin include gastrointestinal (GI) complaints (eg, diarrhea, bloating), metallic taste, and effect on vitamin B12 levels. The GI adverse effects are self-limited and can be managed by starting with a low dose and increasing in an every 2- to 4-week regimen, rather than implementing the manufacturer's recommended weekly increase. The major complication of metformin is a low, but significant, risk for fatal lactic acidosis. In comparison, the incidence of fatal lactic acidosis with metformin is significantly less common than SU-induced hypoglycemic coma.
Because the kidneys excrete metformin, any agent that affects renal function increases the risk of lactic acidosis. Patients receiving metformin should have their serum creatinine monitored periodically. Patients with serum creatinine above 1.4 (women) and 1.5 (men) should be taken off the medication.

It has been argued that because serum creatinine is a poor predictor of renal function, creatinine clearance (based on a 24-hour urine test) could be used to monitor patients whose serum creatinine is borderline. The recommended creatinine clearance has been 60. In addition to renal function, patients with congestive heart failure and severe chronic obstructive pulmonary disease should not receive metformin. These conditions increase the patient's acidic state as well as the risk of lactic acidosis despite normal serum creatinine. Metformin may be combined with all of the other classes of oral hypoglycemic agents and insulin. Because of its insulin sensitizing and weight loss effects, metformin is clearly the first choice in managing type 2 diabetes.


Dosing
The manufacturer recommends a starting dose of 500 mg twice daily, which is increased each week up to 850 mg 3 times daily. Based on clinical experience, the lectures during this session recommended starting metformin at 500 mg once daily and advancing at a slower rate than once a week. The advantages of starting at a lower dose and increasing at a slower rate were better compliance and a decrease in the GI adverse effects. A recent clinical trial (see the article by Garber and colleagues in the suggested reading list) noted that the minimum effective dose was 500 mg once daily and that the most effective dose was 1000 mg twice daily rather than the higher dose of 850 mg 3 times a day.

Update
In August, Bristol-Myers Squibb introduced a metformin/glyburide combination agent called Glucovance. Initial reports appear promising, the cost is modest, and the reported adverse effect profile is very good. There are few data published on the combination pill. Over the next few months more information should be available.

Thiazolidinediones
The thiazolidinedione (TZD) class of oral hypoglycemics was developed in 1997 and offers a new mechanism for treatment of type 2 diabetes. The first, troglitazone (Rezulin), was taken off the market in 1999 because of its association with hepatic toxicity. Rosiglitazone (Avandia) and pioglitazone (Actos) have been available since 1999.
The primary effect of TZDs is peripheral, with increasing insulin sensitivity and increased glucose uptake. The TZDs have some effect on hepatic glucose uptake and sensitivity to a lesser degree. Interestingly, the TZDs' peripheral/hepatic (75%/25%) effect is complementary to that for metformin (25% peripheral and 75% hepatic). The mechanism of action is upregulation of insulin-responsive genes and increasing the GLUT-1 and GLUT-4 glucose transport proteins.


Advantages
The TZDs are equally potent when combined with most of the other classes of oral diabetic medication, with an average drop in HbA1c of 1% to 2%. They increase insulin sensitivity and do not stimulate the pancreas to produce more insulin. TZDs are hepatically metabolized and thus can be used safely in patients with renal dysfunction. They can be dosed once daily, although rosiglitazone works better with twice-daily dosing.
Unlike troglitazone, statistically both pioglitazone and rosiglitazone do not have hepatic toxic effects. Only 2 cases of hepatic toxicity have been reported with rosiglitazone use during the past 2 years, and 1 of the 2 cases had many other risk factors. To date, pioglitazone has had no reported cases of hepatic toxicity. Both pioglitazone and rosiglitazone are approved for monotherapy and in combination with metformin, SUs, and insulin.


Disadvantages
Pioglitazone and rosiglitazone are both associated with significant weight gain. Notably, the patients with the greatest weight gain also appear to have the greatest drop in HgA1c. Both drugs are metabolized by the cytochrome P450 enzyme pathway and have many potential drug interactions. The only known interactions are with pioglitazone -- a potential decrease in the effectiveness of oral contraceptives and delayed metabolism with ketoconazole. Another disadvantage is cost; both pioglitazone and rosiglitazone are higher-priced oral diabetic medications.
Pioglitazone and rosiglitazone both appear to cause fluid retention, which can make the effects of congestive heart failure or other fluid overload diseases worse. Both drugs also have notable effects on lipids. The current data show that pioglitazone has a minimal effect on low-density lipoprotein (LDL) cholesterol levels and a favorable effect on high-density lipoprotein (HDL) cholesterol and triglyceride levels. Rosiglitazone has a favorable effect on HDL cholesterol levels but a negative effect on LDL cholesterol levels. Unfortunately, there are no published head-to-head trials, and given the differences in the clinical trials, no meaningful comparison can be made between the 2 medications concerning lipids.


Meglitinides
Repaglinide (Prandin), from the meglitinide drug class, was approved by the Food and Drug Administration (FDA) in late 1997 for the treatment of type 2 diabetes.. Repaglinide acts like an extremely short-acting SU (an insulin secretagogue) and is potentially useful as a SU replacement. The effect of repaglinide on the pancreas is very similar to that of the SUs. Repaglinide, like the SUs, blocks the potassium channels on the pancreatic islet beta-cells, which causes an influx of calcium into the cell and increasing the secretion of insulin. There appears to be 2 similar potassium channels on islet beta-cells, one of which is predominantly affected by repaglinide and the other is predominantly affected by SUs. The repaglinide-affected potassium channel appears to be glucose dependent, which may partially explain why repaglinide is associated with a much lower incidence of hypoglycemia.
What makes repaglinide clinically different from the SUs is its ultra-short half-life (1 hour). Repaglinide is taken just before or with meals, and the stimulation of the pancreas is limited only to a brief time around meals. Because of the short duration, the patient does not have continuous high levels of insulin and the resulting adverse effects.


Advantages
Repaglinide has been shown to be as effective as glyburide in clinical trials. Unlike the continuous stimulation of the pancreas by SUs, repaglinide only stimulates when taken around meals, more closely reproducing the natural response to a meal. The total insulin increase is substantially less than with the SUs and consequently patients gain less weight and have lower incidences of hypoglycemia. Because repaglinide is partially dependent on the presence of glucose, its effect is blunted when glucose levels are not elevated. Its biggest advantage over the other oral hypoglycemic medications is that it allows for flexible timing and missed meals.

Disadvantages
The most common adverse effect of repaglinide is hypoglycemia, although at a lower incidence than that of the SUs. Other adverse effects that occasionally occur include headaches, upper respiratory infection symptoms, arthralgia, and back and chest pain. Repaglinide's great disadvantage is that it is metabolized by the liver through the cytochrome P450 3A4 enzyme pathway because there are many potential interactions with other medications through this pathway. However, no specific drugs have demonstrated consistent interactions with repaglinide. Other disadvantages include compliance with 3-times-daily dosing and high cost.

Dosing
Repaglinide is dosed 15 to 30 minutes before eating, and the starting dose depends on HbA1C. In patients with HbA1C levels of 8% or less, it is recommended to start with 0.5 mg. For patients with HgbA1C levels over 8%, one can start with a 1-2 mg dose. The maximum dose is 4 mg if needed, with a maximum 24-hour dose of 16 mg. Repaglinide has been approved for use with metformin, and the combination appears to be a very effective. There are no clinical trials of repaglinide with the alpha-glucosidase inhibitors, and of the TZD class, only 1 clinical trial with troglitazone has been reported. There are theoretical interactions between repaglinide and the TZDs through their common metabolism in the P450 pathway, so more clinical trials are clearly needed.
Patient selection is key in choosing repaglinide therapy. Given its metabolism by the liver and theoretical drug interactions, the patients who are most likely to do well on repaglinide are younger, active patients, particularly those who need flexibility in their meal times. Certainly, its limited stimulation of the pancreas and decreased weight gain associated with the drug make it an attractive choice.


Update
Novartis is currently conducting clinical trials for a new meglitinide-type drug, nateglinide. Current reports and publications describe nateglinide's performance as being similar to that of repaglinide -- it is a non-SU, D-phenylalanine derivative similar to repaglinide and the SUs.

Alpha-Glucosidase Inhibitors
The alpha-glucosidase inhibitors (AGIs) are unique nonsystemic oral agents that can help manage type 2 diabetes. The AGIs target the alpha-glucosidase enzyme of the proximal small intestine brush border. Physiologically, the alpha-glucosidase enzyme is used to breakdown disaccharide-polysaccharides (starch) and sucrose (glucose + fructose [table sugar]).
Note that the AGIs do not prevent the absorption of carbohydrates and complex sugars, but they do delay their absorption. The initial blocking of the proximal small intestine alpha-glucosidase enzymes results in unabsorbed carbohydrate passing into the large intestines where it often causes an osmotic fluid retraction, fermentation, and resultant bloating, flatulence, and diarrhea. After 4 to 6 weeks of exposure to the carbohydrates, the distal small intestine develops new, locally active carbohydrate metabolizing enzymes that usually cause the GI adverse effects to subside. Starting with a very low dose and slowly increasing over 6 weeks can limit or significantly reduce the GI adverse effects. Having the absorption of the dietary carbohydrates delayed until reaching the distal small intestines is the mechanism by which the AGIs control postprandial hyperglycemia and lower HbA1c.

Delaying the absorption of carbohydrates is a unique mechanism among oral diabetic medications for lowering HgbA1c levels. The effectiveness of this mechanism is one of the physiologic characteristics of type 2 diabetes. Patients with type 2 diabetes demonstrate a delayed or sluggish insulin response from the pancreas to a glucose (a meal) load. By delaying the absorption of glucose, the insulin response is more matched to the serum glucose, resulting in less postprandial hyperglycemia and a lowering of the HbA1c. The AGIs also demonstrate a lowering of total insulin output of the pancreas, increased insulin sensitivity, a variable but mild decrease in triglycerides, with no effect on patient weight. Compared with the other oral agents, the AGIs appear to be about half as potent, with an average lowering of HbA1c of 0.5% to 1%.

There are currently 3 AGIs: miglitol (Glyset), acarbose (Precose), and voglibose (not available in the United States). Miglitol and acarbose appear to be equally effective, but miglitol clearly is the preferred choice. Acarbose has occasionally been associated with liver toxicity and requires liver monitoring, whereas miglitol does not. Neither appears to have any significant drug interactions. Miglitol has been clinically tested and found effective as a single agent and in combination with SUs, metformin, and insulin. There have been no trials comparing AGIs with TZDs or repaglinide; however, there are no obvious reasons that the AGIs could not be used with the TZDs, but there are some theoretical concerns in using them with repaglinide. Some disadvantages associated with the AGIs are that they are dosed 3 times daily and are relatively expensive.


Insulin
Insulin has historically been the backbone of diabetic treatment. During the past 6 years, clinician experience and comfort with insulin has decreased with the development of many new oral agents and with the incorrect assertion that insulin was atherosclerogenic. In addition, there have been a number of new types of insulin, new combinations of insulin, and new injection devices released on the market during the past several years.
It is generally felt that persistently high serum glucose levels not only damage peripheral tissues but also can permanently affect the pancreas' ability to produce adequate amounts of insulin. Advantages offered by the newer insulins are better control with fewer adverse effects. The new ultra-short-acting insulins (aspart and lispro) are much better at reproducing the natural insulin response to meals. Regular insulin, the traditional short-acting insulin, generally lasts too long, causing hypoglycemia or necessitating multiple snacks throughout the day, making weight control much harder. The new ultra-short-acting insulin should supplant most use of regular insulin. The major disadvantage is that patients will need to use the ultra-short-acting insulin with each meal.

One of the problems with current insulin therapy is that there has not been an acceptable very-long-acting or basal insulin. Isophane NPH and lente are generally too short acting, and ultra lente is too unpredictable. A new type of insulin, glargine, is about to be released by Aventis and appears to be predictable, with full 24-hour coverage. Glargine should provide clinicians and patients with an appropriate basal insulin.

Finally, the new insulin pens (2 disposable, 5 durable reusable) have made dosing insulin more comfortable (smaller needles), more accurate, and more convenient. Clinicians need to be familiar with the new insulins and devices. As our diabetic patients age, more and more of them will fail to achieve American Diabetes Association goals and will need insulin to maintain HbA1c levels and prevent secondary complications of diabetes.

David M. Quillen, MD
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Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions.

Herbal medicinals are being used by an increasing number of patients who typically do not advise their clinicians of concomitant use. Known or potential drug-herb interactions exist and should be screened for. If used beyond 8 weeks, Echinacea could cause hepatotoxicity and therefore should not be used with other known hepatoxic drugs, such as anabolic steroids, amiodarone, methotrexate, and ketoconazole.

However, Echinacea lacks the 1,2 saturated necrine ring associated with hepatoxicity of pyrrolizidine alkaloids. Nonsteroidal anti-inflammatory drugs may negate the usefulness of feverfew in the treatment of migraine headaches. Feverfew, garlic, Ginkgo, ginger, and ginseng may alter bleeding time and should not be used concomitantly with warfarin sodium. Additionally, ginseng may cause headache, tremulousness, and manic episodes in patients treated with phenelzine sulfate. Ginseng should also not be used with estrogens or corticosteroids because of possible additive effects. Since the mechanism of action of St John wort is uncertain, concomitant use with monoamine oxidase inhibitors and selective serotonin reuptake inhibitors is ill advised. Valerian should not be used concomitantly with barbiturates because excessive sedation may occur. Kyushin, licorice, plantain, uzara root, hawthorn, and ginseng may interfere with either digoxin pharmacodynamically or with digoxin monitoring. Evening primrose oil and borage should not be used with anticonvulsants because they may lower the seizure threshold. Shankapulshpi, an Ayurvedic preparation, may decrease phenytoin levels as well as diminish drug efficacy. Kava when used with alprazolam has resulted in coma. Immunostimulants (eg, Echinacea and zinc) should not be given with immunosuppressants (eg, corticosteroids and cyclosporine). Tannic acids present in some herbs (eg, St John wort and saw palmetto) may inhibit the absorption of iron. Kelp as a source of iodine may interfere with thyroid replacement therapies. Licorice can offset the pharmacological effect of spironolactone. Numerous herbs (eg, karela and ginseng) may affect blood glucose levels and should not be used in patients with diabetes mellitus.
Miller LG
Department of Pharmacy Practice, Texas Tech University Health Sciences Center, Amarillo 79121, USA.

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Benfotiamine Prevents Postprandial Symptoms in Diabetes

NEW YORK (Reuters Health) Sept 22 - Benfotiamine prevents the endothelial dysfunction and oxidative stress that follow a meal rich in advanced glycation end (AGE) products in type 2 diabetics, according to a report in the September issue of Diabetes Care.

"Benfotiamine was used for decades as a treatment of diabetic neuropathy, without any exact knowledge of the beneficial mechanism," Dr. Alin Stirban from Ruhr-University, Bochum, Germany told Reuters Health. "Our data bring benzoctamine from the relatively restricted field of diabetic neuropathy into the much larger field of vascular function and prove in humans effects previously postulated."

Dr. Stirban and colleagues investigated the effects of a real-life, cooked, AGE-rich meal on endothelial function and oxidative stress with or without benfotiamine pretreatment in 13 adults with type 2 diabetes.

The high-AGE meal significantly impaired endothelium-dependent vasodilatation, the authors report, but this impairment was completely prevented by benfotiamine.

The high-AGE meal, with or without benfotiamine pretreatment, did not affect endothelium-independent vasodilatation, the results indicate.

Benfotiamine pretreatment also prevented the decrease in reactive hyperemia and the increase in circulating markers of endothelial dysfunction, inflammation, and oxidative stress seen after a high-AGE meal, the researchers note. The beneficial effects of benfotiamine treatment were accompanied by lower serum levels of AGEs and dicarbonyls, the report indicates.

"Our study does not completely elucidate the mechanisms through which benfotiamine prevents postprandial vascular dysfunction but raises some hypotheses," the authors conclude. "Further studies are warranted to bring light into these subtle mechanisms."

"We intend to investigate in a placebo-controlled manner medium-term effects of benfotiamine on endothelial function," Dr. Stirban said. "But we will extend our observation also on other cell types of critical importance for people with diabetes, such as adipocytes."

Diabetes Care 2006;29:2064-2071.
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Effect of Diabecon on sugar-induced lens opacity in organ culture: mechanism of action.

Cataract is the leading cause of blindness worldwide. Apart from ageing, diabetes has been considered to be one of the major risk factors of cataract. The high sugar levels in diabetes may cause tissue disruption and intumescences by osmotic changes induced via aldose reductase (AR) mediated polyol pathway.

Therefore, agents that can inhibit AR and prevent sorbitol accumulation may be helpful to combat sugar-induced cataract. In the present study, AR inhibitory activity of Diabecon (an herbal drug used for diabetes) was studied together with its effect against sugar-induced lens opacity in organ culture. Diabecon aqueous extract (DAE) showed potential inhibitory activity with an IC50 value of 10 microg/ml against rat lens AR. Incubation of goat lens with supraphysiological concentrations of glucose (100 mM) led to the loss of lens transparency associated with increased AR activity, decreased soluble protein and increased protein carbonyls and glycation. Addition of DAE (0.3 mg/ml) to the medium preserved transparency and ameliorated the decrease in lens soluble protein due to hyperglycemia and also prevented the formation of glycated protein. Interestingly DAE inhibited aldose reductase activity in lens incubated with 100 mM glucose. DAE decreased protein carbonyls, prevented the loss of beta(L)-crystallin against 100 mM of glucose. We have also demonstrated here that most of these effects are mainly due to Gymnema sylvestre, one of the constituent herbs of Diabecon. These results suggest that Diabecon protect the lens against sugar-induced cataract by multiple mechanisms.
Moghaddam MS ; Kumar PA ; Reddy GB ; Ghole VS
Biochemistry Division, Department of Chemistry, University of Pune, Pune 411007, India

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