Current Status of Diabetes Treatment. (Featured CME Topic: Diabetes Mellitus).

SCREENING FOR DIABETES

To treat diabetes, we must first make the diagnosis. Based on the presence of diabetic retinopathy, it is estimated that in the United States the newly diagnosed type 2 diabetic patient has had diabetes for an average of 8 years. It is now recommended that everyone over age 45 have the fasting glucose level assessed every 3 years, with those at high risk (African American, Native American, or Mexican American; family history of diabetes; presence of obesity, hypertension, or dyslipidemia; or history of gestational diabetes) being assessed earlier and more frequently. (1) At least 10% of diabetes diagnosed in people under the age of 18 in the United States is in fact type 2 diabetes; this frequency is much greater in high-risk ethnic groups (African Americans, Hispanic Americans, and Native Americans) (2)

DIAGNOSING DIABETES

The diagnosis of diabetes is now based on a fasting serum glucose level of more than 126 mg/dL on two occasions. If the fasting glucose level is tinder 110 mg/dL, the patient is nondiabetic. If the fasting glucose level is between 110 mg/dL and 126 mg/dL, however, the patient should be given 75 g of glucose orally in the fasting state and a 2-hour serum glucose level should be drawn. A 2-hour serum glucose level of less than 140 mg/dL is normal, more than 200 mg/dL is diagnostic of diabetes, and between 140 mg/dL and 200 mg/dL is classified as glucose intolerance. (1)

DIETARY THERAPY

A medication that would result in a maintained, significant weight loss would be the ideal therapy for 90% of patients with type 2 diabetes. Such a medication does not exist, however, and bariatric surgery is the only method that can result in a prolonged significant weight loss. (3) In our institution, we use a Roux-en-Y gastrectomy with gastric stapling, which usually results in a weight loss of 70 lb or more over a 6-month period in morbidly obese patients, followed by plateauing or a slight increase in weight. In most cases, the weight loss is accompanied by a marked improvement or even cure of the diabetes, hypertension, and dyslipidemia.

Ideal body weight (IBW) should be known in prescribing a diabetic diet. This is easily calculated by adding five pounds for every inch over five feet to 100 pounds in a woman and adding six pounds for every inch over five feet in a man. Ten percent should be added or subtracted for a large or small frame, respectively. To calculate basal caloric needs, multiply the IBW by 10, then add 20% to 40% to this figure, depending upon the usual level of physical activity. A deficit of 3,600 calories is needed to lose one pound of fat; therefore, to lose one pound of fat per week, 500 calories should be subtracted from the calculated daily caloric needs. (4) A diet designed to lose one to two pounds per week should be instituted in most type 2 diabetic patients and a eucaloric diet in most type 1 diabetic patients. As little as a 5% loss of body weight results in a significant and disproportionate decrease in insulin resistance and improved glycemic control. Every patient will benefit from dietary counseling, not only when diabetes is diagnosed, but also at regular intervals after diagnosis.

EXERCISE THERAPY

Exercise is a powerful, underutilized, non-pharmacologic tool that lowers insulin resistance and improves glycemic control. Walking for as little as 150 minutes per week is enough to lower insulin resistance. (5) For every five miles per week, a nondiabetic subject walks, there is a 6% reduction in the incidence of diabetes, with a much greater reduction in those who are at higher risk, eg, the obese and those with a family history of diabetes. We should include an exercise prescription in the therapy of almost all diabetic patients, therefore, remembering that those in the lowest quartile for physical fitness have the highest incidence of diabetes and those diabetic patients in the lowest quintile for physical fitness have the highest mortality rate. (6)

ORAL AGENTS

Traditionally, when diet and exercise failed, we added a sulfonylurea, and when the sulfonylurea lost its effectiveness, we added or substituted insulin. Now we have six different classes of oral antidiabetic agents, and choosing between these classes of agents and their combinations is difficult.

Sulfonylureas, the benzoic acid derivative repaglinide (Prandin), and the phenylalanine derivative nateglenide (Starlix) all work in the same way, at different points and for varying durations, on the sulfonylurea receptor. They all close the energy-sensitive potassium channels in the wall of the pancreatic beta cell, which leads to an influx of calcium, depolarization of the beta cell, and an increased release (but not production) of insulin. (7)

Metformin works mainly on the liver to decrease hepatic glucose production, but it also reduces insulin resistance in the myocyte and adipocyte by stimulating the mobilization of glucose transporters to the surface of the cell where they facilitate the entry of glucose. Metformin also lowers insulin resistance through its anorectic effect on weight loss. (8)

The [alpha]-glucosidase inhibitors slow the breakdown of complex carbohydrates into simple carbohydrates by acting on the [alpha]-glucosidase enzymes at the brush border of the small intestine, and are thus most effective in lowering postprandial glucose levels. (9) Finally, the thiazolidinediones improve glycemic control by lowering insulin resistance and hepatic glucose output, and perhaps also by rejuvenating the beta cells. (10)

With the insulin sensitizers metformin and the thiazolidinediones, there are additional cardiovascular benefits. Metformin lowers the number of low-density lipoprotein (LDL) particles and triglyceride levels, as well as decreasing platelet aggregation, fibrinogen levels, plasminogen-activator inhibitor-1 (PAI-l) levels, and coagulation factors." In addition, metformin is also the only antidiabetic agent that is associated with weight loss, or at least weight stabilization. (12) Thiazolidinediones increase the LDL particle size (which is associated with less atherogenicity), raise high-density lipoprotein (HDL) cholesterol levels by as much as 19%, and lower triglyceride levels. (13) Both metformin and the thiazolidinediones, furthermore, have been shown to decrease the highly sensitive Creactive protein levels, which should be associated with plaque stabilization and improved endothelial function." Interestingly, animal studies have shown that thiazolidinediones decrease the migration and proliferation of the vascular smooth muscle cells, which in humans should result in decreased formation of atheromatous plaque and coronary artery restenosis after angioplasty. (15)

Studies in humans have shown a decrease in intimal-medial thickening in the carotid arteries and a decrease in restenosis after stent placement in coronary arteries, presumably due to a decrease in proliferation of vascular smooth muscle cells. (16,17)

SIDE EFFECTS OF ORAL ANTIDIABETIC AGENTS

All oral antidiabetic agents have side effects. Sulfonylureas are associated with weight gain and hypoglycemia. The shorter-acting insulin secretagogues repaglinide and nateglinide, and the sulfonylurea glimepiride do not, at least in theory, stimulate insulin secretion in the presence of normoglycemia or when there is no food intake. (18)

Glucophage is associated with a low frequency of lactic acidosis, and in fact this incidence may be no higher than that which occurred in diabetic patients in the United States before metformin became available. Lactic acidosis due to metformin should not occur if metformin is avoided in patients with a creatinine level of 1.5 or above, hepatic decompensation, congestive heart failure, a history of alcohol abuse, or in those patients age 80 or older. Metformin's major side effects are seen in the gastrointestinal tract, with nausea, cramps, and diarrhea. These side effects occur in 30% of patients but are usually transient and can be ameliorated or avoided by prescribing metformin to be taken after meals and starting with a low dose that is built up slowly. Only 3% of patients have to discontinue metformin because of gastrointestinal problems, and many in this group, in my experience, are also lactose intolerant. Vitamin [B.sub.12] deficiency occurs after 1 year in approximately 7% of patients using metformin and can be prevented with oral calcium supplements. (11) Many side effects of metformin can be ameliorated if it is taken in the slow-release form.

The major side effect of [alpha]-glucosidase inhibitors is flatulence. This occurs when undigested carbohydrate enters the large bowel, where it is digested by colonic bacteria resulting in gas formation. At high doses or in the presence of renal decompensation, hepatic necrosis may occur due to high serum [alpha]-glucosidase levels. In addition, because of suppressed [alpha]-glucosidase activity, sucrose is unlikely to correct hypoglycemia in those patients who take insulin or sulfonylureas in addition to taking an [alpha]-glucosidase inhibitor; in these patients, glucose tablets should be given to correct hypoglycemia. (9)

The thiazolidinediones pioglitazone and rosiglitazone, unlike their predecessor, troglitazone, have not been associated with significant hepatic problems, though because of the history of hepatic problems with trogliazone, we are still required to monitor liver function tests on a regular basis. At this time, the major problems with the thiazolidinediones are those of fluid retention, weight gain, and a normochromic, normocytic, dilutional anemia. The dilutional anemia may even be beneficial, since the oxygen carrying capacity of the blood is maintained, and with the increased plasma volume there is a decrease in blood viscosity and improved blood flow. The weight gain that occurs with the thiazolidinediones is in excess of that which would be associated with better glycemic control; it is mostly due to formation of new adipocytes in the subcutaneous fat, where it is not associated with an increase in insulin resistance. The weight gain that occurs with the thiazolidinediones may also be associated with fluid retention, however. Fluid retention is most likely to occur with higher doses of thiazolidinediones and in the more obese patient, but especially occurs when thiazolidinediones are used in combination with insulin. The mechanisms proposed for the fluid retention are excess production of the cytokine vascular endothelial growth factor (VEGF), which causes increased permeability in the microcirculation, closure of calcium channels, and excess stimulation of the peroxisome proliferator-activated receptor (PPAR) gamma receptors. (10) The usual edema associated with thiazolidinediones does not respond to loop diuretics, thiazide diuretics, or spironolactone, and only responds to reduction or discontinuance of the drug. In this respect, it resembles the edema seen with the dihydropyridine calcium channel blockers. Should the edema respond to diuretics, then it is most likely due to an underlying condition associated with high aldosterone levels (congestive heart failure, hepatic dysfunction, or renal dysfunction) being worsened by the addition of a thiazolidinedione. (19)

WHICH DRUG TO USE INITIALLY?

In my own practice, I measure a fasting C-peptide level, and if the C-peptide level is high-normal or high, I use insulin sensitizers. On the other hand, if the C-peptide is low-normal or low, I use an insulin secretagogue. (20) Which of the insulin sensitizers is best for initial therapy? Clearly metformin is a candidate because of its unique ability to induce weight loss, or at least inhibit the weight gain associated with improved glycemic control, in addition to its cardioprotective properties. The thiazolidinediones, however, in addition to their effects on decreasing insulin resistance and decreasing cardiac events, will also rejuvenate pancreatic beta cells. (21) At this time, my preference is to start with a combination of metformin and a thiazolidinedione. In addition to their combined effects on lowering insulin resistance and cardiac events, neither drug is associated with severe hypoglycemia, so that low [HbA.sub.lc] levels, which are associated with a lower incidence of cardiac events, can be obt ained. (22,23) In addition, the effect of metformin on stabilizing or lowering body weight may offset the tendency of the thiazolidinedione to cause weight gain.

COMBINATION ORAL THERAPY

If combination therapy is not used early in the course of diabetes, its use will be necessary at a later time. The advantages of combination therapy are that (1) better glycemic control can be obtained with a combination of two drugs that work at different sites, (2) there are fewer side effects with lower doses of two drugs than there would be from a large dose of one drug, and (3) if these drugs are combined in the same pill or capsule there will not only be better compliance, but also the cost will be lower. (24)

When metformin first became available more than 6 years ago, I wondered how many patients who had not had the opportunity for the addition of metformin when they had failure of sulfonylurea monotherapy, but had instead been initiated on insulin therapy, could be transferred back to oral combination therapy with metformin and a sulfonylurea. If the random C-peptide level was normal or elevated, I reduced the insulin by a third and initiated metformin therapy at 500 mg twice daily. Two weeks later, if the random blood glucose level obtained in the clinic was under 200 mg/dL, I would reduce the insulin by another third of the original dose and add a sulfonylurea (initially glyburide but later glimepiride). If all was well after an additional 2 weeks, I would stop the insulin and readjust the oral agents. I would again readjust the oral agents 2 weeks later. The whole process took 6 weeks. Initially, I was able to discontinue insulin in 80% of patients. Those in whom I was unsuccessful were more obese, needed hig her insulin doses, and had a longer duration of diabetes. (25) The most amazing finding was that the successfully converted patients were better controlled on a combination of a sulfonylurea and metformin than they were on insulin alone. (26) This is probably because fasting glucose levels in the type 2 diabetic patient are controlled as well with NPH and regular insulin as with oral agents, but postprandial glucose levels are better controlled with oral agents. To be sure that the improved glycemic control in these patients was due to the effects of the combined oral agents and not because of increased compliance due to biweekly clinic visits, I reassessed the outcome when the first 100 patients had been successfully taken off insulin. To obtain 100 successfully converted subjects, I had to enroll 130 patients (a 77% success rate). In those patients who were able to stay off insulin, improvement in glycemic control was maintained after 6 months. In addition, those patients who had to return to insulin therap y had one injection of premixed insulin added at dinnertime, and still had better glycemic control on this regimen than they had on insulin alone. Those patients who needed two injections of premixed insulin per day and were maintained on metformin only also had improved glycemic control when compared with when they were on insulin alone. On the other hand, those who went back on insulin alone had no improvement in glycemic control. (26) Thus, even when two injections of mixed insulin are needed in the type 2 diabetic patient, better glycemic control can be achieved on a combination of insulin and an insulin sensitizer than on insulin alone.

As would be expected, the number of patients maintained on combination oral therapy after being transferred from insulin alone decreased slowly over time. After 3 years, however, 40% of patients were still well controlled on combination of metformin and a sulfonylurea. We were able to calculate from these data that when monotherapy with a sulfonylurea fails, adequate glycemic control with metformin and a sulfonylurea can be maintained for an average of 7.8 years. (27) In response to these data, Kaiser Permanente's data for the 3 years after the availability of metformin were examined. The number of patients taking combination oral therapy doubled, the number taking insulin declined by a third, and the number of patients with an [HbA.sub.1c] level below 8% increased by 25%. (28)

When patients were transferred from insulin therapy, there was a significant weight loss (15 lb over 1 year), and it was 22 months before these patients started to regain weight. (12) This was undoubtedly due to anorectic properties of metformin, which have been confirmed in a double-blind study. Metformin's anorectic effect is due to early satiety, and even in combination with insulin metformin has the ability to minimize weight gain.

We have also shown that when a combination of metformin and a sulfonylurea is failing, the addition of a thiazolidinedione will result in a return of the [HbA.sub.1c] level to within the therapeutic range. (29) We have also shown that this effect is prolonged, and believe that it is due to the rejuvenating effect of the thiazolidinediones on the pancreatic beta cells rather than the insulin-sensitizing effect of the thiazolidinediones. (30)

INSULIN THERAPY

When insulin is required, one injection per day is added to the existing oral regimen. This can either be glargine, NPH, or lente insulin at bedtime, or premixed insulin (70/30 or 75/25) at dinnertime. I prefer to use glargine insulin at bedtime, since this has the advantage of lowering the fasting glucose level with a lower incidence of nocturnal hypoglycemia. (31) In most situations, lowering the fasting glucose level to below 110 mg/dL will result in the oral agents maintaining control during the day. When the ability to maintain control with oral agents during the day is lost, control can be achieved with two injections of mixed insulin in the morning and at dinnertime; or injection of a short-acting insulin before each meal with the basal insulin provided by glargine. (32,33) In these situations, better control will be achieved with one or two insulin sensitizers being used with the insulin. (26,34)

In the type 1 diabetic patient, we currently use the long-acting insulin glargine at bedtime and short-acting insulin (lispro or aspart insulin) shortly before or with meals. The glargine insulin is adjusted every 2 or 3 days until a fasting glucose level of 110 mg/dL or under is obtained without nocturnal hypoglycemia occurring; the glargine dose is then fixed. (35) The short-acting insulins, however, are adjusted at or after each meal based on the preprandial serum glucose level, the amount of food eaten, and the intended exercise (or lack of exercise) to be undertaken after eating. (36,37) Many patients now count carbohydrates and base their insulin dose on the calculated grams of carbohydrate eaten or to be eaten. The addition of a preset sliding scale based on preprandial glucose levels is used to further adjust preprandial shortacting insulin doses.

When a multiple-insulin-injection regimen fails to maintain the [HbA.sub.lc] level in the desired range, usually because of severe and perhaps unrecognized hypoglycemia, insulin pump therapy should be initiated in patients with type 1 diabetes. An insulin pump maintains a preprogrammed basal insulin level by injecting a small amount of short-acting insulin sub-cutaneously every 2 to 3 minutes; at each meal a bolus of short-acting insulin is also administered through the insulin pump, the amount of which is based on the preprandial glucose level, the amount of food eaten, and the postprandial activity. (38) In this way, the desired [HbA.sub.lc]. level of 7% or below can be reached in most patients with type 1 diabetes. (39)

In the past 5 years, the treatment of both type 1 and type 2 diabetes has been revolutionized due to the availability of insulin sensitizers, better and more physiologic insulin secretagogues, and more physiologic short-acting and long-acting insulins. We should now be able to reach our goals of [HbA.sub.lc] levels of 7% or below in type 1 patients and 6.5% or below in type 2 patients. This will dramatically reduce the incidence and prevalence of both the microvascular (retinopathy, nephropathy and neuropathy) and macrovascular (ischemic heart disease, peripheral vascular disease, and carotid artery disease) complications of diabetes.

References

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(2.) American Diabetes Association: Screening for Type 2 Diabetes ADA clinical Practice Recommendations. Diabetes Care 1998; 21(suppl):520-522

(3.) Sjostrom CD, Lissner L, weedel H, et al: Reduction in incidence of diabetes, hypertension and lipid disturbances after intentional weight loss induced by bariatric surgery: the SOS interevention study. Obes Res 1999; 5:477-484

(4.) Bell DSH, Ovalle F: Advances in therapy for type 2 diabetes. Patient Care 1999; 33:189-200

(5.) Horton ES: Role and management of exercise in diabetes mellitus. Diabetes Core 1988; 11:201-211

(6.) Helmrich SP, Ragland DR, Leung RW, et al: Physical activity and reduced occurrence of non-insulin-dependent diabetes mellitus. N Engl J Med 1991; 325:147-152

(7.) Gerich JE: Oral hypoglycemic agents. N Engl J Med 1989; 321:1231

(8.) Blonde L, Guthrie RD, Sandberg MI: Glucophage: an effective and safe agent for initial monotherapy in patients with non-insulin-dependent diabetes mellitus. Endocrinologist 1996; 6:431

(9.) Chaisson JC, Josse RG, Hunt JA, et al: The efficacy of acarbose in the treatment of patients with non-insulin-dependent diabetes mellitus. Ann Intern Med 1994; 121:928-935

(10.) Olefsky JM: Treatment of insulin resistance with peroxisome proliferator activated receptor gamma agonists. J Clin Invest 2000; 106:467-472

(11.) Bailie CJ: Biguanides and NIDDM: Diabetes Care 1992; 15:775-752

(12.) Bell DSH, Mayo MS: weight loss in patients treated with a metformin sulfonylurea combination in comparison with twice daily mixed insulin. Endocr Proc 1998; 4:360-364

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(17.) Takagi T, Akasaka T, Yamamuro A, et al: Troglitazone reduces neointimal tissue proliferation after coronary stent implantation in patients with non-insulin-dependent diabetes mellitus: a serial intravascular ultrasound study. J Am Call Cordial 2000; 36:1529-1535

(18.) Bell DSH: Prudent utilization of the present available treatment modalities for type 2 diabetes. Endocrinologist 1998; 83:332-341

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(21.) Bell DSH, Ovalle F: Tissue triglyceride levels in type 2 diabetes and the role of thiazolidinediones in reversing the effects of tissue hypertriglyceridemia: review of the evidence in animals and humans. Endocr Proc 2001; 7:135-137

(22.) Stratton IM, Adler Al, Neil HA, et al: Association of glycemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ2000; 321:405-412

(23.) Khaw K-T, wareham N, Luber R, et al: Glycated hemoglobin, diabetes and mortality in men in Norfolk cohort of European Prospective Investigation of cancer and Nutrition (EPIC-Norfolk). BMJ2001; 322:15-18

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(26.) Bell DSH, Mayo MS: Improved glycemic control with use of oral hypoglycemia therapy with or without insulin. Endocr Prac 1998: 4:82-85

(27.) Bell DSH, Ovalle F: How long can insulin be avoided in the patient with type 2 diabetes mellitus by use of a combination of metformin and a sulfonylurea? Endocr Prac 2000;6:293-295

(28.) Ziel F, Nakahiro R: Is avoiding insulin therapy an achievable and worthwhile goal? Endocr Prac 2000; 6:335-336

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(30.) Bell DSH, Ovalle F: Long-term efficacy of triple oral therapy for type 2 diabetes mellitus. Diabetes 2001; 50(suppl 2):A106

(31.) Jarvinen H, Dressier A, Ziemen M, for the HOE 901/3002 Study Group: Less nocturnal hypoglycemia and better postdinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes. Diabetes Care 2000; 23:1130-1136

(32.) Clements RS Jr, Bell DSH, Benbarka A, et al: Rapid insulin initiation in non-insulin-dependent diabetes mellitus. Am J Med 1987; 82:415-420

(33.) Rosenfalk AM, Thorsby P, Kjems I, et al: Improved post-prandial glycemic control with insulin aspart in type 2 diabetic patients treated with insulin. Acta Diabetol 2000; 37:41-46

(34.) Alvilez-Santa L, Sinding J, Raskin P: Effects of metformin in patients with poorly controlled insulin-treated type 2 diabetes mellitus. Ann Intern Med 1999; 131:182-188

(35.) Rosenstock J, Park G, Zimmerman J, for the US Insulin Glargine (HOE 901) type 1 Diabetes Investigator Group: Basal insulin glargine (HOE 901) versus NPH insulin in patients with type 1 diabetes on multiple daily insulin regimens. Diabetes Care 2000; 23:1137-1142

(36.) Lindholm A, McEwen J, Riss A: Improved postprandial glycemic control with insulin aspart: a randomized double-blind crossover trial in type 1 diabetes. Diabetes Care 1999; 22:801-805

(37.) Anderson J, Brunelle R, Kolvisto V, et al: Reduction of postprandial hyperglycemia in IDDM patients on insulin analog treatment. Multicenter Insulin Lispro Study Group. Diabetes 1997; 46:265-270

(38.) Bell DSH: Insulin pump therapy for the '90s. Endocrinologist 1994; 4:270-278

(39.) Bell DSH, Ovalle F: Improved glycemic control with use of continuous subcutaneous insulin infusion compared with multiple insulin injection therapy. Endocr Prac 2000; 6:357-360