SYMPOSIUM ON DIABETES

PREVIEW
In this second of two articles on treatment of type 2 diabetes, the authors discuss the addition of injection therapy to the failing existing oral regimen. A new option is exenatide, first in a new class of drugs called incretin mimetics. The use of once-daily and multiple injection insulin choices is also described.

When oral therapy is failing in patients with type 2 diabetes, injection therapy should be initiated. Injection therapy is an addition to, rather than a replacement for, the existing oral regimen. Traditionally, insulin injection is the usual choice, but recently an alternative therapy has become available.

Incretin mimetics

The incretin-mimetic exendin-4 is a recently available alternative to insulin injection. Endogenous insulin release is greater with oral glucose administration than with intravenous glucose administration. The reason is that oral glucose stimulates the release of incretins, which are gastrointestinal hormones.

The most significant incretin is glucagon-like peptide 1 (GLP-1), which is deficient in patients with type 2 diabetes. GLP-l slows gastric emptying, suppresses glucagon production, causes physiologic release of insulin, and, at least in animal studies, has been shown to increase beta cell mass by stimulating the production of new beta cells from stem cells in the pancreatic duct.1 Evidence that an increased beta cell mass may also be true in humans has come from studies of morbidly obese subjects with type 2 diabetes who have had gastric bypass surgery. Following such surgery, diabetes is cured in as much as 80% of diabetic subjects. This is not a result of weight loss, because “cure� occurs within a few weeks of the surgery and before significant weight loss occurs. By bypassing the foregut, production of the hormone grehlin (an irresistible appetite stimulant) is suppressed and a large volume of chyme is presented to the hindgut. This rapid presentation of chyme to the hindgut results in excess release of GLP-1.

As a result, cases of postgastric bypass hypoglycemia due to neisidioblastosis (excess formation of new beta cells from the pancreatic duct stem cells) and one case of insulinoma have been reported.2 Thus it would appear that in humans, as well as in animals, incretins result in new beta cell formation. Therefore, in the future, an ideal combination may be an incretin and a thiazolidinedione (TZD), with the former inducing new beta cell formation and the latter prolonging the life span of the beta cells by suppressing apoptosis (programmed cell death).

The problem with GLP-1 is that it has a short half-life following its release from the gastrointestinal tract. Therefore, it is effective when administered by continuous intravenous infusion. It is less effective when delivered subcutaneously by an insulin pump and is totally ineffective when delivered by intermittent subcutaneous injection.

To prolong the life span of GLP, an injection where it is bound to albumin and slowly released has been developed. Several oral agents that have an effect on DPP-4, the enzyme that breaks down GLP-1, are being evaluated in clinical trials.

At present, the only available incretin therapy is exenatide injection (synthetic exendin-4), a polypeptide obtained from the saliva of the Gila monster, a lizard whose meals are several months apart. Exenatide attaches to a receptor for GLP-1 and therefore is a mimetic for GLP-1. Over the next few years, as oral therapy that suppresses DPP-4 activity becomes available, the use of incretin mimetics may increase and become ideal initial therapy for type 2 diabetes in combination with TZDs.

Therefore, at this time, an alternative to insulin therapy is to add exenatide injection to the existing oral therapy regimen (figure 1). This should result in lowering of the HbA1c by as much as 1% and, in contrast to insulin therapy, where weight gain is inevitable, could result in decreases in both body weight and insulin resistance.

Insulin therapy

If more than a 1% decrease in the HbA1c is needed, advancement to insulin therapy bypassing the use of exenatide injection is indicated. The goal of insulin therapy is to prevent the rise in fasting glucose above a level of 100 mg/dL, so that a physiologic serum glucose level is present at the beginning of the day and the existing oral agents have the opportunity to maintain glycemic control through the remainder of the day.

To lower the fasting glucose level, one injection of insulin should be given before supper or at bedtime, starting at a dose of 0.2 U/kg (typically 14 to 20 U). The patient can slowly increase the dose once a week until a fasting glucose level of 100 mg/dL or below is achieved or until insulin-induced hypoglycemia leads to amelioration of this goal.

Once-daily insulin choices

The choices for once-daily insulin therapy in combination with existing oral antidiabetic therapy are NPH insulin, insulin glargine or detemir, and premixed fixed-dose insulin (see figure 1). Each of these insulins has its own advantages and disadvantages, and all can be used in an attempt to achieve the goal of a fasting glucose level of 100 mg/dL or below.

NPH insulin given at bedtime has the advantage of peaking in the early morning, when insulin resistance is at its highest, due to a delayed response to nocturnal surges of growth hormone.3 The potential disadvantage of NPH insulin is that it may peak in the earlier morning hours, when insulin resistance is at its lowest, and cause recognized or unrecognized nocturnal hypoglycemia. However, the peak of NPH insulin's action is flatter and more prolonged in patients with type 2 diabetes than in patients with type 1 diabetes, on account of a slower, steadier, and more prolonged absorption from the more abundant subcutaneous fat found in most patients with type 2 diabetes.4

The advantage of insulin glargine is its stable level, without peaks or troughs, that is sustained over a 24-hour period in most patients with type 2 diabetes. Because of this stable level, insulin glargine has the ability to achieve the desired goal of a fasting serum glucose level below 100 mg/dL, with a lower frequency of nocturnal hypoglycemia than occurs when NPH is given before supper or at bedtime.

A disadvantage of insulin glargine is the absence of insulin peaks, which are needed to lower postprandial glucose levels, and this is why a secretagogue (ie, sulfonylureas and metaglitinides) should not be removed from the oral regimen when insulin glargine therapy is initiated. Another disadvantage is the lack of a “dawn peak� in basal insulin levels to handle early morning insulin resistance and hyperglycemia.5

Premixed fixed-dose insulin (70/30, 75/25, or 50/50), preferably containing a rapid-acting insulin (aspart or lispro) rather than short-acting insulin (regular), given before or with the evening meal has the advantage of increasing serum insulin levels to coincide with the glucose peak that follows the evening meal, which in the United States is almost invariably the largest meal of the day.6 The disadvantage of premixed fixed-dose insulin is the possibility of an early morning peak, causing both nocturnal hypoglycemia and prebreakfast hyperglycemia due to inadequate serum insulin levels during the prebreakfast period, when insulin resistance is at its zenith.7

Therefore, each of the three once-daily insulins added to failing oral therapy has advantages and disadvantages, and pending “head-to-head� studies, no single insulin can be preferred in every patient. Furthermore, insulin detemir, a long-acting insulin that has a remarkably low coefficient of variation and thus more predictable effects, is now available. Insulin detemir taken at bedtime therefore provides another option for once-daily insulin in combination with oral diabetic agents in patients with type 2 diabetes.

Multiple-injection insulin therapy

If the desired HbA1c level is not attained with oral therapy and a single evening or bedtime insulin injection, at least one other insulin injection needs to be added to the regimen. At this time, the best option is twice-daily fixed-dose mixed intermediate and rapid-acting insulin (see figure 1).

If an evening premixed fixed-dose insulin is already being used, then a morning injection of the same insulin is added at a dose of 0.2 U/kg. This dose is gradually increased once a week by the patient on the basis of the predinner home glucose monitoring readings to a level that results in prelunch and predinner serum glucose levels of below 100 mg/dL. If NPH insulin is being used at bedtime, it should be replaced with premixed fixed-dose insulin at the same total daily dose or at a total dose of 0.4 U/kg, whichever is higher, divided into half at breakfast and half at supper, with appropriate adjustments being made according to serum glucose readings and the presence or absence of hypoglycemia.

If insulin glargine or detemir is being used, a change to the above regimen of premixed fixed-dose insulin can be made, using a total daily dose of NPH that is equivalent to the current glargine dose, or a fast-acting insulin (aspart or lispro) can be added before each meal. This basal-bolus regimen, which is widely used in type 1 diabetes but rarely used in type 2 diabetes, should have to be used only when endogenous insulin production is so low that a patient with type 2 diabetes behaves like a patient with type 1 diabetes. In some cases with glargine, if the secretagogue is continued, fast-acting insulin may only have to be given before one or two meals.8 An unresearched but clinically used alternative may be premixed fixed-dose insulin given three times daily with meals.

When multiple insulin injections are being used in a patient with type 2 diabetes, secretagogue use becomes superfluous and is no longer needed (see figure 1). This is because the fast-acting insulin provides for the rise in postprandial serum insulin levels that is needed to avoid postprandial hyperglycemia. However, use of metformin or a TZD or both should be continued, because by lowering insulin resistance, these sensitizers have been shown, when used with insulin, to not only achieve better glycemic control, but to achieve this better glycemic control with lower doses of insulin.9 Furthermore, the weight gain that can be expected with an insulin-induced improvement in glycemic control does not occur when metformin is used in combination with insulin.9 Indeed, the significant weight gain that would be expected to occur with use of insulin and a TZD is neutralized when, prior to the addition of a TZD, metformin is being used with insulin.10

Therefore, because of the better glycemic control without significant weight gain that results when insulin therapy is being used in combination with one or two insulin sensitizers, in most situations insulin should not be used as monotherapy in patients with type 2 diabetes.

When is insulin therapy justified in new-onset diabetes?

From the time of diagnosis of type 1 diabetes, insulin should be used. Unfortunately, in middle-aged or older patients, the onset of type 1 diabetes may be indistinguishable from that of type 2 diabetes. In some situations, such as a symptomatic onset (polyuria, polydipsia, and weight loss) with or without the presence of urinary ketones or even ketoacidosis, type 1 rather than type 2 diabetes should be suspected. However, in older people, the onset of type 1 diabetes can be as insidious as the onset of type 2 diabetes. The most likely explanation for this is that the velocity of pancreatic beta cell loss is much less in older than in younger patients with type 1 diabetes, so that hyperglycemia occurs gradually rather than acutely, and that negative changes in well-being are not noted by the patient.

The definitive test for late-onset type 1 diabetes is the presence of serum anti-GAD (glutamic acid decarboxylase) antibodies.11 The presence of these antibodies, and therefore also the presence of late-onset type 1 diabetes, can be suspected with a symptomatic presentation, with a lack of evidence for the presence of the insulin resistance syndrome (hypertension, low levels of high-density lipoprotein cholesterol, high triglyceride levels), or with a normal or low C-peptide level at the time of diagnosis.12

With a diagnosis of latent autoimmune diabetes of adults, initiation of insulin therapy is essential because the activated immune system attacks and damages only insulin-producing beta cells.13 Therefore, with exogenous insulin therapy, the workload of the beta cell is decreased and the autoimmune “attack� on the beta cell is less intense. Alternatively, use of a secretagogue intensifies the autoimmune attack� and the damage to the beta cells is accelerated. Preservation of the beta cell mass should lead to improved glycemic control and fewer diabetic complications.14

Even when type 1 diabetes rather than type 2 diabetes is diagnosed, the combination of insulin and a TZD may help to preserve the beta cell mass, possibly because of the anti-inflammatory effects of these drugs.15 In addition, the insulin resistance syndrome can coexist with type 1 diabetes. Under these circumstances, a combination of a TZD and/or metformin with insulin therapy can result in not only better glycemic control but also decreases in cardiac risk factors.

Conclusion

Synthetic exendin-4 may be an alternative to insulin initiation in patients with type 2 diabetes who are mildly hyperglycemic and are failing oral therapy. Otherwise, insulin therapy should be initiated. When more than one injection of insulin is needed in patients with type 2 diabetes, for maximal efficacy, insulin should be used with metformin, a TZD, or both, and the secretagogue should be discontinued. To decelerate beta cell damage in patients with late-onset type 1 diabetes, insulin should be used from the time of diagnosis.

Dr Bell has served on the advisory boards for GlaxoSmithKline and on the speakers' bureau for GlaxoSmithKline, Bristol-Myers Squibb, AstraZeneca, and Novo Nordisk. Dr Bell is an adjunct clinical professor of medicine, University of Alabama at Birmingham School of Medicine. Dr Wyne is on the advisory board for GlaxoSmithKline, Novo Nordisk, and Sanofi-Aventis; is on the speakers' bureau for Abbott, Boehringer, Bristol-Myers Squibb, Novartis, Novo Nordisk, and Sanofi-Aventis; is a consultant for GlaxoSmithKline, Novo Nordisk, and Sanofi-Aventis; and has received research support from Novo Nordisk. Dr Wyne is associate professor of medicine, University of Texas Southwestern Medical School, Dallas.

References

1. Baggio LL, Drucker DJ . Harnessing the therapeutic potential of glucagon-like peptide-1: a critical review Treat Endocrinol 2002; 1( 2): 117-25
2. Service GJ, Thompson GB, Service FJ, et al. Hyperinsulinemic hypoglycemia with neisidioblastosis after gastric-bypass surgery N Engl J Med 2005; 353( 3): 249-54
3. DavidsonMB, HarrisMD, ZielFH, et al. Suppression of sleep-induced growth hormone secretion by anticholinergic agent abolishes dawn phenomenon Diabetes 1988; 37( 2): 166-71
4. Cusi K, Cunningham GR, Comstock JP . Safety and efficacy of normalizing fasting glucose with bedtime NPH insulin alone in NIDDM Diabetes Care 1995; 18( 6): 843-51
5. Fonseca V, Bell DS, Berger S, et al. A comparison of bedtime insulin glargine with bedtime neutral protamine hagedorn insulin in patients with type 2 diabetes: subgroup analysis of patients taking once-daily insulin in a multicenter, randomized, parallel group study Am J Med Sci 2004; 328( 5): 274-80
6. Hermansen K, Colombo M, Storgaard H, et al. Improved postprandial glycemic control with biphasic insulin aspart relative to biphasic insulin lispro and biphasic human insulin in patients with type 2 diabetes Diabetes Care 2002; 25( 5): 883-8
7. Bretzel RG, Arnold S, Medding J, et al. A direct efficacy and safety comparison of insulin aspart, human soluble insulin, and human premix insulin (70/30) in patients with type 2 diabetes Diabetes Care 2004; 27( 5): 1023-7
8. Fritsche A, Schweitzer MA, Haring HU; 4001 Study Group . Glimeperide combined with morning insulin glargine, bedtime neutral protamine hagedorn insulin, or bedtime insulin glargine in patients with type 2 diabetes. A randomized, controlled trial Ann Intern Med 2003; 138( 12): 952-9
9. Stowig SM, Aviles-Santa ML, Raskin P . Comparison of insulin monotherapy and combination therapy with insulin and metformin or insulin and troglitazone in type 2 diabetes Diabetes Care 2002; 25( 10): 1691-8
10. Strowig SM, Aviles-Santa ML, Raskin P . Improved glycemic control without weight gain using triple therapy in type 2 diabetes Diabetes Care 2004; 27( 7): 1577-83
11. BellD SH . Should anti-glutamic acid decarboxylase antibody levels be determined in new-onset diabetes? Endocrine Pract 2000; 6( 2): 214-6
12. Bell DS , Ovalle F. The role of C-peptide levels in screening for latent autoimmune diabetes in adults Am J Ther 2004; 11( 4): 308-11
13. Kretowski A, Myoeliwiec J, Szelachowska M, et al. Insulin increases in vitro production of Th2 profile cytokines in peripheral blood cultures in subjects at high risk of diabetes type 1 and patients with newly diagnosed IDDM Horm Metab Res 1999; 31: 289-92
14. Ovalle F , Bell DSH. Effect of rosiglitazone versus insulin on the pancreatic beta-cell function of subjects with type 2 diabetes Diabetes Care 2004; 27( 11): 2585-9
15. Zhou Z, Li X, Huang G, et al. Rosiglitazone combined with insulin preserves islet beta cell function in adult-onset latent autoimmune diabetes (LADA) Diabetes Metab Res Rev 2005; 21( 2): 203-8