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Insulin therapy: optimizing control in type 1 and type 2 diabetes
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Insulin Therapy: Optimizing Control in Type 1 and Type 2 Diabetes Julio Rosenstock, University
MD
Clinical Professor of Medicine of Texas Southwestern Medical Center Dallas Diabetes and Endocrine Center Dallas,Texas
at Dallas
Insulin has been available for therapeutic use for more than 75 years and remains a powerful pharmacologic tool with nearly unlimited potential to lower plasma glucose levels in patients with diabetes. Required essentially by all patients with type 1 diabetes and many patients with type 2 diabetes, insulin is capable of restoring near-normoglycemiathe primary treatment goal to forestall the onset and progression of long-term complications. Attainment and maintenance of near-normal glycemic control can be achieved with the use of insulin replacement strategies designed to simulate the physiologic, nondiabetic patterns of insulin secretion in response to 24-hour postabsorptive and postprandial glucose profiles. This article reviews the physiologic basis and current therapeutic agents for optimal insulin replacement and provides practical clinical guidelines and strategies to achieve near-normal glycemic control in patients with either type 1 or type 2 diabetes.
PHYSIOLOGY OF INSULIN SECRETION Normal insulin secretion consists of 2 major components: a basal secretion and a meal-related secretion. The role of continuous low-level basal insulin secretion into the portal circulation is to modulate the rate of overnight hepatic glucose production and glucose output during prolonged periods between meals. In this way basal glucose levels are maintained constant and within a narrow concentration range. Meal-related insulin secretion controls the postprandial elevations of blood glucose levels (Figure 1).
betes) in a physiologically sound manner, mimicking normal insulin secretion patterns. Ideal insulin replacement therapy should be modeled with a combination of preparations capable of reproducing both the basal postabsorptive and the prandial/postprandial normal secretion profile, thereby reflecting the dynamics of daylong glycemic control. Conceptually this strategy is known as the basal/bolus regimen because it combines both the basal and
Ideal Insulin Replacement Therapy The primary objective of insulin therapy is to replace the prevailing lack of insulin (type 1 diabetes) or progressive deficit of insulin (type 2 dia-
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On subcutaneous administration, regular human insulin is slowly absorbed into the systemic circulation with a consequent slow onset of action (Table II). The time it takes to reach peak concentrations requires that regular insulin be administered 20 to 40 minutes prior to a meal to avoid or minimize the potential mismatch with the hyperglycemic peak that follows meal ingestion. This conventional recommendation for regular insulin administration is inconvenient and unrealistic and poses a risk of premeal hypoglycemia if the meal is inadvertently delayed. Furthermore, the duration of action of regular insulin, especially when large doses are used, is much longer than the physiologic insulin peak in response to a meal, thereby increasing the risk of late postprandial hypoglycemia. The intermediate-acting insulins neutral protamine Hagedorn (NPH) and Lente@, which are used to approximate basal secretion in regimens of 1 or 2 daily doses, have a gradual onset of action with a pronounced peak effect between 4 and 8 hours after injection. Both preparations exhibit significant interpatient and intrapatient action variability. As
Homoeostasis
0.08 -
n
.’
Figure 1. 24-hour plasma glucose and insulin projiles in healthy individuals (n = 12). Mean values with 9.5% CI. Modified and reprinted with permission from Owens DR, Zinman B, Bolli GB. Insulins today and beyond. Lancet. 2001;358:739-746.
meal-induced components of normal insulin secretion. Basal insulin replacement, which meets -half of the patient’s daily insulin requirements, modulates the rate of hepatic glucose production to match the uptake by glucose-dependent tissues during the night and between meals. Bolus insulin limits postprandial hyperglycemia, regulating meal-related glycemic peaks (TableI). Unfortunately no combination of available insulin preparations possesses the characteristics necessary to simulate normal insulin secretion. However, recent advances in protein engineering through recombinant DNA technology have resulted in insulin analogs with properties that may significantly improve insulin replacement therapy.
PHARMACOKINETICS OF AVAILABLE INSULINS Human Insulin Preparations
with regular insulin, these preparations carry the disadvantage of requiring a rigid time schedule for meal intake to match the effect of the insulin dose administered several hours earlier. Moreover, their prolonged effects may induce late postprandial hypoglycemia and their pronounced peak effects may overlap with the short-acting insulin peaks, thereby contributing to the increased risk of nocturnal hypoglycemia when administered at dinnertime. Intended for basal insulin replacement, Ultralente@ has a somewhat longer action than NPH and Lente but falls short of the ideal 24-hour effect
Despite major improvements (eg, purity, use of absorption-retarding agents) in human insulin preparations over the years, pharmacokinetic profiles still significantly limit metabolic outcomes. The onset of action, peak, and duration of effect (the most clinically relevant pharmacologic parameters) denote to some extent the highly variable and inconsistent absorption rates of standard human insulins, which are reflected in erratic and unpredictable blood glucose-lowering effects.
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Applying
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the BasallBolus
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Insulin
Concept
l
Basal insulin - Nearly constant day-long insulin level - Suppress hepatic glucose production between meals and overnight - Cover 50% of daily needs
l
Bolus insulin (mealtime) - Immediate rise and sharp peak at 1 hour - Limit postmeal hyperglycemia - Cover 10% to 20% of total daily insulin requirement
l
at each meal
Ideally, each component should come from a different insulin, with a specific profile
duration. It has demonstrated substantial day-today variability with modest but broad and erratic peaks that may cause unpredictable hypoglycemia. Indeed, the lack of reproducibility in glucose-lowering effects of all the standard insulin preparations used for prandial and basal replacement has been a major limitation for most insulin regimens.
tered immediately before meals (Table II). From a patient’s perspective, these characteristics allow more flexibility in the timing of administration relative to meal consumption, making the use of these analogs more convenient and effective. In studies comparing lispro or aspart pharmacokinetics with those of regular insulin, the overall properties of the fast-acting analogs demonstrated profiles that provide more closely physiologic insulin coverage in response to meals, with peak action at -60 minutes following administration. However, these rapidacting insulin analogs have an overall shorter (4 to 5 hours) duration of activity, uncovering the need for a basal insulin replacement. Designing an insulin analog that overcomes the limitations of intermediate-acting (NPH and Lente) and long-acting (Ultralente) preparations commonly used for basal replacement has been, until recently, a more elusive goal. Insulin glargine (Lantus@), recently approved by the US Food and Drug Administration, is the first insulin analog with a flat prolonged duration of action (Table II). Changes in the amino acid sequence of human insulin produce a shift in the isoelectric point of the molecule, which results in an acidic insulin analog soluble only at pH 4 (clear solution in the prescription vial). The reduced solubility of the analog at physiologic pH leads it to precipitate after subcutaneous injection, which stabilizes the hexameric form of insulin and delays dissociation into dimers and monomers and subsequent absorption into the systemic circulation. Consistent with its slow absorption
Insulin Analogs Under physiologic conditions, insulin molecules exhibit a tendency to self-associate into dimers and hexamers following subcutaneous administration. A major obstacle affecting absorption into the systemic circulation, and thus the time-action profile of standard insulin preparations, is the dissociation time of hexamers to dimeric and monomeric insulin units. Amino acid substitutions on the primary structure of the insulin molecule have resulted in analogs characterized by modified absorption profiles, a more favorable insulin replacement pattern, and lower variability of effect. Two fast-acting insulin analogs, lispro (Humalog@) and aspart (Novolog@) have absorption profiles that allow for more physiologic replacement of mealtime insulin secretion. Their fast absorption pattern, resulting from substitutions or minimal alterations in amino acid sequence relative to human insulin, reduces their tendency to selfassociate into dimers or hexamers, thus increasing the absorption rate of insulin monomers after injection. Because of their rapid onset of action, unlike regular insulin, lispro and aspart may be adminis-
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Onset of Action
(h)
Peak (h)
1
Duration
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of Action (h)
Human insulin 0.5-l
2-4
6-10
NPH
l-3
5-7
lo-20
Lente@
l-3
4-S
lo-20
Ultralente@
26,
Unpredictable
16-20
Regular
Analogs Lispro (Humalog@)
5 min-15
min
1
4-5
Aspart (NovologB)
5 min-15
min
1
4-5
Flat
-24
Glargine (Lantus@)
l-2
The time course of action of any insulin may vary between individuals, or at different times in the same individual. Consequently, table data should be considered only as general guidelines.
Twice Daily Split-Mixed
rate, insulin glargine has a prolonged biologic effect that spans 24 hours following administration without a peak effect and with less variability than NPH and Ultralente (Figure 2). Insulin glargine appears to have the major pharmacokinetic properties that characterize the ideal basal insulin replacement for regulating blood glucose levels during the night and between meals.
INSULIN FORTHE OFTYPE
Regimens
These regimens consist of a morning and evening mix of NPH and short-acting insulin. The prandial insulin (regular, lispro, or insulin aspart) of the morning dose has major effects between breakfast and lunch, whereas the glucose-lowering effects of the intermediate-acting insulin NPH extend until dinnertime. Administered in the evening, the second “split-mixed” dose provides insulin coverage between the dinner and bedtime interval via the prandial component and overnight coverage through the intermediate-acting insulin component of the mixed dose. The dose proportions of each type of insulin during the morning and evening administrations depend on the patient’s needs. In some cases, a 70/30 premixed NPH/regular insulin or 75/25 premixed NPWlispro may be used, but these preparations are clearly not recommended for patients with type 1 diabetes because they lack flexibility for specific insulin adjustments based on self blood-glucose monitoring. Patients with type 1 diabetes using these regimens rarely achieve reasonable control by present standards of glycemic targets because these strategies do not provide sufficient insulin supplementation.
STRATEGIES MANAGEMENT 1 DIABETES
The shortcomings of standard insulin preparations, with significant risk of hypoglycemia, have limited the success of insulin replacement therapy. Despite improvement in the kinetic properties of new insulin analogs, the regimen of mixing insulins with different action profiles to achieve metabolic control is still necessary and remains a barrier to patients’ acceptance and compliance.
Multiple
Daily Injections (MDI) Regimens
This strategy is widely used in the treatment of type 1 diabetes. Traditionally, it has consisted of 2 daily injections of NPH plus 2 or 3 injections of
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NpH
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24
Ultralente Continuous Glargine
subcutaneous
1
infusion
,.,“,.~, ,;.._,
l6-
8-----,,*-___ oTime
I 0
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Figure 2. Time-action characteristics of the protracted-acting insulins NPH, Ultralente@, and glargine and continuous subcutaneous infusion with insulin lispro. Reprinted with permission from Owens DR, Zinman B, Bolli GB. Insulins today and beyond. Lancet. 2001;358:739-746.
regular insulin with meals. The second injection of NPH is given at bedtime rather than at dinner in an attempt to decrease the risk of nocturnal hypoglycemia while providing enough insulin to control overnight basal glucose levels. An additional approach consists of 2 or 3 premeal injections of insulin lispro or aspart rather than regular insulin at mealtime. The peaks of lispro or aspart most closely match normal prandial insulin patterns. However, when administered in conjunction with morning and bedtime NPH, the 4to 5-hour effect duration of the short-acting insulin analogs leaves late-afternoon intervals poorly covered. A different dose/injection regimen that combines NPH at bedtime and 3 lispro or aspart injections with meals also fails to provide adequate basal insulin coverage during the late afternoon or evening hours. The recent advent of insulin glargine provides a potentially better alternative to the use of intermediate- and long-acting standard insulin preparations as basal components of MD1 regimens. The constant 24-hour flat insulin levels obtained with glargine therapy more closely simulate basal insulin secretion than does traditionally used NPH. Coverage of early morning requirements with bedtime NPH is often inadequate, with frequent fasting hyperglycemia because of limited duration of effect. Increments in the bedtime NPH dose to
improve fasting hyperglycemia result in pronounced nocturnal insulin peaks that often lead to nocturnal hypoglycemia. Recent studies suggest that an MD1 regimen using premeal short-acting insulins can be optimized with once-daily bedtime insulin glargine, which can provide more predictable basal control compared with regimens using once-daily (bedtime) or twice-daily (before breakfast and bedtime) NPH. The evidence suggests greater basal glucose-lowering effects, better coverage of early-morning insulin requirements (lower fasting hyperglycemia), and fewer episodes of nocturnal hypoglycemia with insulin glargine compared with regimens in which NPH was used as the basal component.
Insulin Pump Therapy Continuous subcutaneous insulin infusion via small programmable pump devices stands as a viable alternative to MD1 strategies. Infusion pumps can deliver short-acting insulin continuously at specific rates according to glucose patterns (basal component). Preprandial insulin doses at mealtime are promptly delivered by the patient at the touch of a button according to blood glucose monitoring results, carbohydrate and caloric content of the upcoming meal, physical activity, and other factors (bolus dose or prandial component). This form of insulin replacement closely approximates the basal/bolus
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physiologic pattern of secretion because of a more consistent insulin delivery. Compared with MD1 regimens, continuous subcutaneous infusions of buffered regular insulin have shown more flexibility but similar glycemic outcomes. Insulin lispro and aspart have proved compatible with infusion pumps and have shown a more optimal bolus dose action than regular insulin because of their more rapid subcutaneous absorption. The use of this strategy is clearly not suitable for all patients-it is expensive and requires a significant amount of patient education, motivation, and involvement to consistently monitor glycemic status throughout the day to optimally manage insulin requirements.
INSULIN OFTYPE
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secretion, thus potentially sparing beta cells from further overstimulation and possibly preserving beta cell reserve and function, and can also overcome insulin resistance at sufficient doses. Its use, however, has been traditionally postponed for years and reserved as a last resort when the traditional stepwise approach of diet, exercise, and oral antidiabetic agents has failed to produce or maintain adequate glycemic control. For patients with significant initial hyperglycemia at the time of diagnosis, temporary insulin therapy may reestablish glycemic control. Nevertheless, because of the progressive worsening of underlying beta cell abnormalities, most patients will eventually require insulin therapy ideally much earlier in the course of the disease if optimal glycemic targets are to be achieved.
IN THE MANAGEMENT 2 DIABETES
In contrast to patients with type 1 diabetes, patients with type 2 diabetes have residual insulin secretory capacity. However, the dynamics of insulin secretion are compromised, and insulin levels are insufficient to compensate for insulin resistance, the other major pathogenic defect of type 2 diabetes. Pharmacologic management of the resultant hyperglycemic state requires intervention targeting the dual pathology of this disease. Early insulin replacement is an evolving strategy for optimal metabolic control of patients with type 2 diabetes. The ultimate goal of management, substantiated by results of the UK Prospective Diabetes Study (UKPDS), is the same as for type 1 diabetes-to prevent acute and long-term complications by improving glycemic control. Progressive in nature, the course of type 2 diabetes is reflective of the relentless decline in pancreatic beta cell function, which is presumed to start years before diagnosis (Figure 3). Furthermore, based on glycemic levels at the time of diagnosis and the progressive nature of this disorder, it is conceivable that long-term complications, which normally take years to develop, may already be present when diabetes is first diagnosed. Patients with type 2 diabetes are not dependent on insulin to prevent ketoacidosis and preserve life; however, insulin does play a major role in controlling glycemic levels. Insulin replacement therapy can compensate for insufficient endogenous
Barriers to Insulin Therapy The major barriers that discourage some physicians from using insulin in the treatment of type 2 diabetes are excessive concerns with weight gain, the potential risk of hypoglycemia, and, most notably, the misconception that insulin therapy may increase the risk of cardiovascular (CV) disease. (Table III). Insulin resistance and the consequent hyperinsulinemia are strongly associated with central obesity, hypertension, and dyslipidemia, all factors that contribute substantially to CV risk. Consequently, the possibility of overinsulinization during replacement therapy has raised concerns about the potential for acceleration of atherosclerosis. To date, there is no evidence linking exogenous insulin therapy and atherosclerosis, nor is there any evidence indicating that insulin therapy worsens CV risk, as clearly demonstrated by the UKPDS. Moreover, the 5-year Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) trial, which evaluated the
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the impact of weight gain. The combination of metformin and insulin therapy has been shown to minimize weight gain. Importantly, intensive insulin therapy has been demonstrated to improve rather than worsen insulin sensitivity in peripheral tissues by virtue of
effects of intensive insulin therapy in patients with type 2 diabetes who enrolled at the time of myocardial infarction (MI), reported some revealing results. Compared with the control group (treated according to physician’s judgment), patients receiving insulin infusion therapy during acute MI followed by intensive MD1 therapy exhibited a relative mortality risk reduction of 28% after 5 years of insulin treatment. These results suggest that insulin may very well be the most appropriate treatment for patients with type 2 diabetes with high CV risk, particularly at the time of MI. Of note, studies of obese patients with type 2 diabetes treated with insulin therapy have shown that despite weight gain, CV risk factors such as blood pressure remained unchanged, and lipid patterns (triglycerides, lipoproteins) were generally improved. These findings challenge the notion that insulin therapy negatively affects blood pressure and lipid profiles. Although modest weight gain during insulin therapy is a well-recognized phenomenon, the benefits of improved glycemic control clearly surpass
improving glycemic control, thus reducing and to some degree reversing the toxic effects of hyperglycemia (glucotoxicity).
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Insulin resistance
Improves insulin sensitivity by reducing glucotoxicity
Cardiovascular
No evidence of atherosclerotic May reduce CV risk
(CV) risk
Weight gain
Modest
Hypoglycemia
Rarely causes severe events
effects
underlying insulin deficiency typically progresses, most patients will eventually need both basal and mealtime insulin if optimal glycemic control is to be achieved and maintained. The basal/bolus strategy of insulin replacement stands as the most closely physiologic approach to treat type 2 diabetes as well as type 1 diabetes (Table I). The success of diabetes management often depends on the patient’s level of education regarding the disease process and the understanding that insulin is indeed an expected therapy at earlier stages once oral agents are insufficient to reach or maintain hemoglobin A,, (HbAi,) targets of ~7%.
The risk of mild to severe hypoglycemia, generally increased with intensive insulin therapy, depends on a number of factors, including age, weight, degree of insulin resistance, duration of disease, duration of insulin therapy, targeted degree of glycemic control, and history of hypoglycemic episodes. The UKPDS found that over a IO-year period, the incidence of hypoglycemia in patients randomized to intensive insulin therapy was, as expected, greater than that of patients assigned to treatment with sulfonylurea or metformin. However, most episodes of hypoglycemia were mild to moderate in intensity, and the 1Zmonth average incidence of severe episodes was 2% to 3%, significantly lower than that for patients with type 1 diabetes. Ample data like those presented above address concerns that have hindered the use of insulin therapy in the management of patients with type 2 diabetes. Increased understanding of the natural history and progressive nature of type 2 diabetes, coupled with a growing awareness of the need for more effective treatment strategies and significant improvements in insulin therapy, merit reassessment of the role of insulin in treating type 2 diabetes.
Starting Basal Insulin Therapy in Type 2 Diabetes For physicians managing patients with type 2 diabetes, practical guidelines for pharmacologic interventions are particularly important in view of the major changes over the past 5 years in managing type 2 diabetes and the growing movement toward starting aggressive pharmacotherapy earlier in the course of the disease. There has also been a paradigm shift that involves the increased use of flexible combination therapy with lower doses of any of the insulin secretagogues plus an insulin sensitizer (metformin or glitazone) almost from the initiation of pharmacotherapy. This strategy is embraced by the community of diabetes experts who also view early insulin therapy to supplement oral treatment as an effective tactic to reach a patient’s glycemic target (Table IV). A practical approach to overcome the complexity of MD1 regimens-and perhaps the best and most acceptable way to initiate insulin therapy-is to start with evening basal insulin replacement in patients who are no longer responding to oral agents.
Insulin Strategies: Overcoming Practical Barriers In addition to the concerns addressed above, barriers causing patients to resist the use of insulin include the need to mix and inject preparations, the complexity of conventional and intensive insulin regimens, and the practical kinetic limitations of standard insulin preparations. Because both fasting and postprandial glucose levels are abnormal in type 2 diabetes and the
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Average patient - Early combination of insulin secretagogue and insulin sensitizer - Most simple and cost-effective - Start low-dose, once-daily sulfonylurea with increasing doses of metformin - Full-dose sulfonylurea in combination with maximally tolerated metformin For marked insulin - Combination
resistance of metformin
+ glitazone
Zf target HbAIC ~7% not achieved - Try triple oral therapy or - Add evening basal insulin while continuing
oral therapy
An alternative way to initiate insulin therapy is to use mealtime insulin supplementation to improve postprandial hyperglycemic peaks while continuing sulfonylureas with or without sensitizing agents such as metformin or a glitazone. Treatment with 3 injections of mealtime lispro insulin added to a sulfonylurea has been shown to provide slightly lower HbAtC levels but greater weight gain than sulfonylureas in combination with bedtime NPH or with metformin. However, for patients starting insulin therapy, the need for multiple premeal injections makes the mealtime insulin supplementation strategy considerably more complex and less attractive than the once-daily evening dose of basal insulin. Perhaps in the future, when inhaled insulin becomes available, noninjectable premeal insulin replacement
Starting basal insulin replacement while maintaining the use of oral agents has considerable advantages: (a) only 1 daily injection may be required without the need of mixing different insulin preparations; (b) titration can be accomplished in a slow, safe, and simple fashion; and (c) a lower total dose of insulin will eventually be required because of the synergy of effects from the oral combination therapy. The synergistic effects of insulin secretagogues, such as sulfonylureas plus basal insulin, have been demonstrated in a number of studies adding once-daily Ultralente to sulfonylureas, bedtime NPH to glipizide, dinnertime 70/30 mix to glimepiride, or bedtime NPH to various oral agents (other than sulfonylureas), including metformin (Table V).
l
Continue oral agent(s) at same dosage (eventually
l
Add single, evening insulin dose (around 10 units) - Glargine (bedtime or anytime?) - NPH (bedtime)
reduce)
0 Adjust dose according to fasting blood glucose (FBG) monitoring l
Increase insulin - Increase by 2 - Increase by 4 - Increase by 6
dose units units units
weekly if FBG if FBG if FBG
as needed >120 mg/dL >140 mg/dL >180 mg/dL
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Indicated when FBG acceptable but - HbAtc >7% and/or - SBGM before dinner >160-180
mg/dL
0 Insulin options - To glargine, add mealtime lispro or aspart - To bedtime NPH, add morning NPH and mealtime lispro or aspart l
Oral agent options - Continue sulfonylurea
for endogenous secretion?
- Continue metformin for weight control? - Continue glitazone for glycemic stability?
to reach glycemic targets. Glycemic control can be further improved if patients follow simple algorithms, based on self-monitoring of blood glucose levels to adjust and deliver sufficient premeal insulin doses, using insulin aspart or lispro independently with no mixing to supplement the evening basal insulin regimen. This approach provides more flexibility and allows additional doses of supplemental insulin as needed to control postprandial hyperglycemia. MD1 regimens are progressively introduced as a further step toward intensifying insulin therapy (Table VI). Recently, a study comparing once- or twicedaily NPH with once-daily bedtime insulin glargine with or without preprandial regular insulin in patients with type 2 diabetes who had been previously treated with insulin-only therapy seemed to indicate a significantly lower risk of nocturnal hypoglycemia and lower weight gain with insulin glargine therapy. It is conceivable that similar strategies will benefit patients who have progressively intensified oral combination therapy by adding evening basal insulin glargine and eventually will require premeal lispro, aspart insulin, or inhaled insulin (when available) to control postprandial glycemic peaks. The use of effective and less troublesome injection devices, such as insulin pens, may facilitate the implementation of the new advances in insulin replacement therapy.
may turn into first-line intervention followed by basal insulin supplementation as required. An ongoing study comparing basal replacement therapy with bedtime insulin glargine or NPH added to oral combination therapy in insulin-naive patients will reveal the relative efficacy of these insulins administered in a forced titration manner to achieve fasting plasma glucose (FPG) levels of 400 mg/dL and reach HbA,, levels of ~7%. Preliminary results have shown remarkable glycemic improvement in the overall study population with rare incidence of severe hypoglycemia, no patterns of serious adverse events, and only a modest increase in body weight. HbAlc values decreased from 8.6% at baseline to 6.9% with highly significant differences in FPG between baseline and endpoint. Comparative data on the efficacy of the 2 basal regimens are awaited.
Advancing Toward Basal/Bolus Insulin Therapy Over time, the need to intensify insulin regimens arises in response to disease progression. The traditional way of supplying insulin with a twice daily, split-mixed insulin regimen has been usually considered when it becomes necessary to intensify the once-daily basal insulin in combination with oral agents. However, the use of “premixed” insulin preparations, such as 70/30 or 75125, do not provide enough flexibility and are seldom effective
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SUMMARY New strategies involving insulin analogs with improved pharmacokinetic properties, the new armamentarium of oral agents for type 2 diabetes, and future development in routes of insulin administration will expand treatment options and combination regimens to facilitate the attainment of specific targeted glycemic levels in a safe and more effective manner. To prevent and retard the progression of microvascular and macrovascular complications are the ultimate objectives in the management of patients with either type 1 or type 2 diabetes.
izing glycosylated hemoglobin in type 2 diabetes: application, benefits, and risks. Diabetes Rev. 1995; 3:308-334. Galloway JA. New directions in drug development: mixtures, analogues, and modeling. Diabetes Care. 1993;16(Suppl 3):16-23. Heinemann L, Klappoth W, Rave K, et al. Intraindividual variability of the metabolic effect of inhaled insulin together with an absorption enhancer. Diabetes Care. 2000;23: 1343-1347. Janssen MM, Snoek FJ, Masurel N, et al. optimized basal-bolus therapy using a fixed mixture of 75% lispro and 25% NPH insulin in type 1 diabetes patients: no favorable effects on glycemic control, physiological responses to hypoglycemia, well-being, or treatment satisfaction. Diabetes Care. 2000;23:629-633.
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Mudaliar SR, Lindberg FA, Joyce M, et al. Insulin aspart (B28 asp-insulin): a fast-acting analog of human insulin: absorption kinetics and action profile compared with regular human insulin in healthy nondiabetic subjects. Diabetes Care. 1999;22: 1501-1506.
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with type 2 diabetes on oral agents. Diabetes. 2001;5O(Suppl2):A520. Rosenstock J, Schwartz SL, Clark CM, Donley DW. Efficacy and safety of HOE 901 (insulin glargine) in subjects with type 2 DM: a 28-week randomized, NPH insulin-controlled trial. Diabetes. 1999;48(Suppl 1):AlOO.
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Scholtz HE, van Niekerk N, Meyer BH. An assessment of the variability in the pharmacodynamics (glucose-lowering effect) of HOE901 compared to NPH and Ultralente human insulins using the euglycaemic clamp technique. Diabetologia. 1999; 42(Suppl l):A235.
Ratner RE, Hirsch IB, Neifing JL, et al. Less hypoglycemia with insulin glargine in intensive insulin therapy for type 1 diabetes. U.S. Study Group of Insulin Glargine in Type 1 Diabetes. Diabetes Care.
Skyler JS, Cefalu WT, Kourides IA, et al. Efficacy of inhaled human insulin in type 1 diabetes mellitus: a randomised proof-of-concept study. Lancet.
2000;23:639-643.
Riddle MC. Evening insulin strategy. Diabetes Care. 1990;13:676-686.
2001;357:331-335.
Skyler JS. Insulin therapy in type 2 diabetes mellitus. In: DeFronzo RA, ed. Current Therapy of Diabetes Mellitus. St. Louis, MO: Mosby; 1998: 108-l 16.
Riddle MC, Schneider J. Beginning insulin treatment of obese patients with evening 70/30 insulin plus glimepiride versus insulin alone. Glimepiride Combination Group. Diabetes Care. 1998;21:
Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. JAMA. 1999;281:2005-2012.
1052-1057.
Rosenfalck AM, Thorsby P, Kjems L, et al. Improved postprandial glycaemic control with insulin aspart in type 2 diabetic patients treated with insulin. Acta Diabetol. 2000;37:4146. 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-l 142.
UK Prospective Diabetes Study Group. UK Prospective Diabetes Study 16. Overview of 6 years’ therapy of type II diabetes: a progressive disease. Diabetes. 1995;44:1249-1258. Weiss SR, Berger S, Cheng S, et al, for the Phase II Insulin Study Group. Adjunctive therapy with inhaled human insulin type 2 diabetic patients failing oral agents: a multi-center phase II trial. Diabetes. 1999;48(Suppl l):A12.
Rosenstock J, Riddle MC, Dailey G, et al. Treatment to target study: feasibility of achieving control with the addition of basal bedtime insulin glargine (Lantus) or NPH insulin in insulin-naive patients
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tion therapy in type 2 diabetes. HOE 901/3002 Study Group. Diabetes Care. 2000;23: 1130-1136.
Yki-Jarvinen H, Dressler A, Ziemen M. Less nocturnal hypoglycemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combina-
ADVISORY
BOARD
ADVISORY
Has it been definitively shown that starting insulin therapy earlier in type 2 diabetes may prevent or delay beta cell exhaustion?
ROSENSTOCK There are absolutely no data to support this; thus, at this point the answer is no. Some overweight type I diabetics may have insulin resistance, but you really don’t want to prescribe a glitazone in the adolescent type 1 because of long-term safety concerns. Moreover, it really doesn’t matter how much insulin you give as long as it’s safe. Insulin by itself isn’t a problem in type 1 diabetics provided they don’t have hypoglycemia.
ROSENSTOCK No, it has not. We do know, however, that by reversing glucotoxicity and reducing insulin resistance, intensive insulin therapy appears to recharge the beta cell by allowing it to rest and regranulate. It stands to reason that avoiding glucotoxicity from the beginning should serve to preserve beta cell function. ADVISORY
BOARD
Is there a role in type 1 diabetics for insulin sensitizers to reduce overall insulin levels?
BOARD
For the patient who has failed on triple therapy and you choose to start insulin, do you routinely discontinue the sulfonylurea first since the beta cells are likely exhausted?
ADVISORY
BOARD
In light of its 24-hour half-life and its flat course of action, isn’t it acceptable for a patient to use insulin glargine at suppertime as opposed to bedtime?
ROSENSTOCK I would not necessarily drop the secretagogue first. It’s really not that simple. Instead, you should go through a thought process and decide which of the oral agents is the most appropriate one to stop. For example, if the patient has gained 20 or 25 pounds due to fluid retention, I would stop the thiazolidinedione instead. If you have a patient whose serum creatinine is hovering around 1.4 to 1.5 mg/dL and is taking metformin, I might drop metformin first. With regard to stopping the sulfonylurea, remember that as you improve hyperglycemia with insulin therapy and reduce glucotoxicity, beta cell function should improve and the activity of a sulfonylurea should be enhanced.
ROSENSTOCK Yes. The reason the package insert specifies bedtime is because the studies on which FDA approval was based all compared insulin glargine with NPH insulin and to give the 2 at suppertime would have put NPH insulin at a disadvantage. In terms of practicality, there would be no problem giving insulin glargine at suppertime. ADVISORY
BOARD
What is the metric you use for adjusting the dose of insulin glargine? ROSENSTOCK The parameter that should be followed is the fast-
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ing blood sugar with the major limiting factor obviously being the development of hypoglycemia. So long as you have no hypoglycemia and the blood sugar is >120 mg/dL, you can keep titrating the dose upward. ADVISORY
ADVISORY
.
DIABETES
. Vol.4 No.2
BOARD
How does insulin glargine compare with other insulins in terms of cost? ROSENSTOCK It is very similar in cost to lispro and insulin aspart. It is more expensive than NPH insulin but less expensive than the 75/25 premixed. The 70/30 premixed is probably cheaper but may be more expensive if used in pens.
BOARD
Do you use the mixed insulins, 70/30 or 75125, in your practice? ROSENSTOCK I’ve used them in the past. I used the 70/30 because I found it a good way to introduce insulin therapy in type 2 diabetics. I typically began by giving 70130 at suppertime in combination with oral agents, adjusting the dose on the basis of the fasting and nocturnal blood sugars. If the blood sugars continued to run high in the afternoon, I would add a second injection. It was a great concept when we didn’t have anything better. The 75125 mix conceptually may make a lot of sense but it is twice as expensive, and there are very few studies comparing it to 70/30. The major problem with both of these premixed insulins is that their fixed combination dosage tends to really tie your hands. My experience is that the lack of flexibility inherent in them resulted in very few people reaching their target goal. Why? Because when you found it necessary to push the insulin dose higher, hypoglycemia became a problem, making it difficult to make the needed adjustments. At the present time, I favor starting insulin therapy with insulin glargine in the evening with frequent adjustments to get the fasting glucose to goal. For patients in whom postprandial glucoses remain above goal and the glycosylated hemoglobin above 7%, I prescribe little pens with lispro or insulin aspart and have the patients give themselves an injection before meals. This approach seems to me much more rational and flexible.
ADVISORY
BOARD
When would you opt for regular insulin instead of prescribing an insulin analog such as lispro? ROSENSTOCK The use of short-acting insulin analogs can be problematic for a type 1 diabetic patient who eats lunch at noon and does not eat dinner until 7 or 8 hours later. What can happen is that because of the short 4- or 5-hour duration of action, hyperglycemia can develop by late afternoon. If the dose of morning NPH insulin is increased, you run the risk of causing hypoglycemia to occur before noon. With such patients I would use regular insulin at lunchtime because its 6 to S-hour duration of action will provide better coverage until dinner. Another possible indication is the elderly patient for whom you feel uncomfortable using a really quick-acting insulin and would prefer taking it a bit slower with regular insulin, which does not have such a rapid onset of action. ADVISORY
BOARD
Is the use of insulin glargine compatible in terms of mixing it in the same syringe with other insulin preparations? ROSENSTOCK No, you can’t mix insulin glargine with other insulins. I view this as an advantage because
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DIABETES
.
Vol.4 No.2
there are studies that show mixing different insulins introduces tremendous variability in their action and a real potential for error. The new insulin pens have 30-gauge needles, and patients really don’t seem to mind giving themselves multiple injections with them. ADVISORY
increasing the risk for hypoglycemia. Third, the fact that it is cloudy is an issue since it introduces the variable that you have to shake it and suspend it properly, otherwise the absorpton is very unpredictable. Finally, studies suggest that its rate of absorption varies more than insulin glargine depending on where you inject it (ie, abdomen, thigh, arm) and the depth of the injection.
BOARD
Is insulin glargiue associated with a low risk for causing hypoglycemia and, if so, why?
ADVISORY
BOARD
What do you use in an insulin pump? ROSENSTOCK Yes, a reduced risk of hypoglycemia has been a fairly consistent finding in most of the studies, especially a reduced risk of nocturnal hypoglycemia. A big reason is that you don’t have to deal with overlapping activity spikes. For example, NPH insulin has a spike and regular insulin, lispro, and aspart each have a spike, and the overlap of these spikes in patients using them increases the risk of hypoglycemia. This is not an issue with insulin glargine since it has no spike. ADVISORY
ROSENSTOCK I’m using lispro. Insulin aspart does not have it as an indication yet, but there are papers that show it is as good as lispro and it is likely that it will soon get the indication. ADVISORY
BOARD
Where are we with inhaled insulin? ROSENSTOCK Phase 3 studies have been completed, and I think we are looking at 2 years before patients will be able to simply take a puff before each meal to reduce the postprandial hyperglycemia. If the hemoglobin AtC is below 7% using just inhaled insulin-great. However, for the patient who continues to run high blood sugars throughout the night and morning, an agent like insulin glargine would have to be added at night; thus, the patient may end up with 1 injection and 3 puffs.
BOARD
How does NPH insulin compare with insulin glargine? ROSENSTOCK Although NPH insulin is less expensive and in many patients works quite well, it does have limitations. First, it has a typical duration of action of 12 to 14 hours and thus is not as long acting. Second, it is associated with spikes of activity,
64
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Vol.4 No.2
Insulin Therapy: Optimizing Control in Type 1 and Type 2 Diabetes Julio Rosenstock, University
MD
Clinical Professor of Medicine of Texas Southwestern Medical Center Dallas Diabetes and Endocrine Center Dallas,Texas
at Dallas
Insulin has been available for therapeutic use for more than 75 years and remains a powerful pharmacologic tool with nearly unlimited potential to lower plasma glucose levels in patients with diabetes. Required essentially by all patients with type 1 diabetes and many patients with type 2 diabetes, insulin is capable of restoring near-normoglycemiathe primary treatment goal to forestall the onset and progression of long-term complications. Attainment and maintenance of near-normal glycemic control can be achieved with the use of insulin replacement strategies designed to simulate the physiologic, nondiabetic patterns of insulin secretion in response to 24-hour postabsorptive and postprandial glucose profiles. This article reviews the physiologic basis and current therapeutic agents for optimal insulin replacement and provides practical clinical guidelines and strategies to achieve near-normal glycemic control in patients with either type 1 or type 2 diabetes.
PHYSIOLOGY OF INSULIN SECRETION Normal insulin secretion consists of 2 major components: a basal secretion and a meal-related secretion. The role of continuous low-level basal insulin secretion into the portal circulation is to modulate the rate of overnight hepatic glucose production and glucose output during prolonged periods between meals. In this way basal glucose levels are maintained constant and within a narrow concentration range. Meal-related insulin secretion controls the postprandial elevations of blood glucose levels (Figure 1).
betes) in a physiologically sound manner, mimicking normal insulin secretion patterns. Ideal insulin replacement therapy should be modeled with a combination of preparations capable of reproducing both the basal postabsorptive and the prandial/postprandial normal secretion profile, thereby reflecting the dynamics of daylong glycemic control. Conceptually this strategy is known as the basal/bolus regimen because it combines both the basal and
Ideal Insulin Replacement Therapy The primary objective of insulin therapy is to replace the prevailing lack of insulin (type 1 diabetes) or progressive deficit of insulin (type 2 dia-
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Glucose
t
2 2 g2
0.04
144
i-
108 72 36
%I s a, 8
18
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t
08100
13100 Time
16:OO
19:OO
of Day (h) ‘,I’
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DIABETES
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On subcutaneous administration, regular human insulin is slowly absorbed into the systemic circulation with a consequent slow onset of action (Table II). The time it takes to reach peak concentrations requires that regular insulin be administered 20 to 40 minutes prior to a meal to avoid or minimize the potential mismatch with the hyperglycemic peak that follows meal ingestion. This conventional recommendation for regular insulin administration is inconvenient and unrealistic and poses a risk of premeal hypoglycemia if the meal is inadvertently delayed. Furthermore, the duration of action of regular insulin, especially when large doses are used, is much longer than the physiologic insulin peak in response to a meal, thereby increasing the risk of late postprandial hypoglycemia. The intermediate-acting insulins neutral protamine Hagedorn (NPH) and Lente@, which are used to approximate basal secretion in regimens of 1 or 2 daily doses, have a gradual onset of action with a pronounced peak effect between 4 and 8 hours after injection. Both preparations exhibit significant interpatient and intrapatient action variability. As
Homoeostasis
0.08 -
n
.’
Figure 1. 24-hour plasma glucose and insulin projiles in healthy individuals (n = 12). Mean values with 9.5% CI. Modified and reprinted with permission from Owens DR, Zinman B, Bolli GB. Insulins today and beyond. Lancet. 2001;358:739-746.
meal-induced components of normal insulin secretion. Basal insulin replacement, which meets -half of the patient’s daily insulin requirements, modulates the rate of hepatic glucose production to match the uptake by glucose-dependent tissues during the night and between meals. Bolus insulin limits postprandial hyperglycemia, regulating meal-related glycemic peaks (TableI). Unfortunately no combination of available insulin preparations possesses the characteristics necessary to simulate normal insulin secretion. However, recent advances in protein engineering through recombinant DNA technology have resulted in insulin analogs with properties that may significantly improve insulin replacement therapy.
PHARMACOKINETICS OF AVAILABLE INSULINS Human Insulin Preparations
with regular insulin, these preparations carry the disadvantage of requiring a rigid time schedule for meal intake to match the effect of the insulin dose administered several hours earlier. Moreover, their prolonged effects may induce late postprandial hypoglycemia and their pronounced peak effects may overlap with the short-acting insulin peaks, thereby contributing to the increased risk of nocturnal hypoglycemia when administered at dinnertime. Intended for basal insulin replacement, Ultralente@ has a somewhat longer action than NPH and Lente but falls short of the ideal 24-hour effect
Despite major improvements (eg, purity, use of absorption-retarding agents) in human insulin preparations over the years, pharmacokinetic profiles still significantly limit metabolic outcomes. The onset of action, peak, and duration of effect (the most clinically relevant pharmacologic parameters) denote to some extent the highly variable and inconsistent absorption rates of standard human insulins, which are reflected in erratic and unpredictable blood glucose-lowering effects.
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Applying
1
DIABETES
the BasallBolus
1 Vol.4 No.2
Insulin
Concept
l
Basal insulin - Nearly constant day-long insulin level - Suppress hepatic glucose production between meals and overnight - Cover 50% of daily needs
l
Bolus insulin (mealtime) - Immediate rise and sharp peak at 1 hour - Limit postmeal hyperglycemia - Cover 10% to 20% of total daily insulin requirement
l
at each meal
Ideally, each component should come from a different insulin, with a specific profile
duration. It has demonstrated substantial day-today variability with modest but broad and erratic peaks that may cause unpredictable hypoglycemia. Indeed, the lack of reproducibility in glucose-lowering effects of all the standard insulin preparations used for prandial and basal replacement has been a major limitation for most insulin regimens.
tered immediately before meals (Table II). From a patient’s perspective, these characteristics allow more flexibility in the timing of administration relative to meal consumption, making the use of these analogs more convenient and effective. In studies comparing lispro or aspart pharmacokinetics with those of regular insulin, the overall properties of the fast-acting analogs demonstrated profiles that provide more closely physiologic insulin coverage in response to meals, with peak action at -60 minutes following administration. However, these rapidacting insulin analogs have an overall shorter (4 to 5 hours) duration of activity, uncovering the need for a basal insulin replacement. Designing an insulin analog that overcomes the limitations of intermediate-acting (NPH and Lente) and long-acting (Ultralente) preparations commonly used for basal replacement has been, until recently, a more elusive goal. Insulin glargine (Lantus@), recently approved by the US Food and Drug Administration, is the first insulin analog with a flat prolonged duration of action (Table II). Changes in the amino acid sequence of human insulin produce a shift in the isoelectric point of the molecule, which results in an acidic insulin analog soluble only at pH 4 (clear solution in the prescription vial). The reduced solubility of the analog at physiologic pH leads it to precipitate after subcutaneous injection, which stabilizes the hexameric form of insulin and delays dissociation into dimers and monomers and subsequent absorption into the systemic circulation. Consistent with its slow absorption
Insulin Analogs Under physiologic conditions, insulin molecules exhibit a tendency to self-associate into dimers and hexamers following subcutaneous administration. A major obstacle affecting absorption into the systemic circulation, and thus the time-action profile of standard insulin preparations, is the dissociation time of hexamers to dimeric and monomeric insulin units. Amino acid substitutions on the primary structure of the insulin molecule have resulted in analogs characterized by modified absorption profiles, a more favorable insulin replacement pattern, and lower variability of effect. Two fast-acting insulin analogs, lispro (Humalog@) and aspart (Novolog@) have absorption profiles that allow for more physiologic replacement of mealtime insulin secretion. Their fast absorption pattern, resulting from substitutions or minimal alterations in amino acid sequence relative to human insulin, reduces their tendency to selfassociate into dimers or hexamers, thus increasing the absorption rate of insulin monomers after injection. Because of their rapid onset of action, unlike regular insulin, lispro and aspart may be adminis-
52
clinical CORNERSTONE
Onset of Action
(h)
Peak (h)
1
Duration
DIABETES
m Vol.4 No.2
of Action (h)
Human insulin 0.5-l
2-4
6-10
NPH
l-3
5-7
lo-20
Lente@
l-3
4-S
lo-20
Ultralente@
26,
Unpredictable
16-20
Regular
Analogs Lispro (Humalog@)
5 min-15
min
1
4-5
Aspart (NovologB)
5 min-15
min
1
4-5
Flat
-24
Glargine (Lantus@)
l-2
The time course of action of any insulin may vary between individuals, or at different times in the same individual. Consequently, table data should be considered only as general guidelines.
Twice Daily Split-Mixed
rate, insulin glargine has a prolonged biologic effect that spans 24 hours following administration without a peak effect and with less variability than NPH and Ultralente (Figure 2). Insulin glargine appears to have the major pharmacokinetic properties that characterize the ideal basal insulin replacement for regulating blood glucose levels during the night and between meals.
INSULIN FORTHE OFTYPE
Regimens
These regimens consist of a morning and evening mix of NPH and short-acting insulin. The prandial insulin (regular, lispro, or insulin aspart) of the morning dose has major effects between breakfast and lunch, whereas the glucose-lowering effects of the intermediate-acting insulin NPH extend until dinnertime. Administered in the evening, the second “split-mixed” dose provides insulin coverage between the dinner and bedtime interval via the prandial component and overnight coverage through the intermediate-acting insulin component of the mixed dose. The dose proportions of each type of insulin during the morning and evening administrations depend on the patient’s needs. In some cases, a 70/30 premixed NPH/regular insulin or 75/25 premixed NPWlispro may be used, but these preparations are clearly not recommended for patients with type 1 diabetes because they lack flexibility for specific insulin adjustments based on self blood-glucose monitoring. Patients with type 1 diabetes using these regimens rarely achieve reasonable control by present standards of glycemic targets because these strategies do not provide sufficient insulin supplementation.
STRATEGIES MANAGEMENT 1 DIABETES
The shortcomings of standard insulin preparations, with significant risk of hypoglycemia, have limited the success of insulin replacement therapy. Despite improvement in the kinetic properties of new insulin analogs, the regimen of mixing insulins with different action profiles to achieve metabolic control is still necessary and remains a barrier to patients’ acceptance and compliance.
Multiple
Daily Injections (MDI) Regimens
This strategy is widely used in the treatment of type 1 diabetes. Traditionally, it has consisted of 2 daily injections of NPH plus 2 or 3 injections of
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DIABETES
m Vol.4 No. 2
NpH
B ----
24
Ultralente Continuous Glargine
subcutaneous
1
infusion
,.,“,.~, ,;.._,
l6-
8-----,,*-___ oTime
I 0
I 8
16 Time
(h)
I 24
(h)
Figure 2. Time-action characteristics of the protracted-acting insulins NPH, Ultralente@, and glargine and continuous subcutaneous infusion with insulin lispro. Reprinted with permission from Owens DR, Zinman B, Bolli GB. Insulins today and beyond. Lancet. 2001;358:739-746.
regular insulin with meals. The second injection of NPH is given at bedtime rather than at dinner in an attempt to decrease the risk of nocturnal hypoglycemia while providing enough insulin to control overnight basal glucose levels. An additional approach consists of 2 or 3 premeal injections of insulin lispro or aspart rather than regular insulin at mealtime. The peaks of lispro or aspart most closely match normal prandial insulin patterns. However, when administered in conjunction with morning and bedtime NPH, the 4to 5-hour effect duration of the short-acting insulin analogs leaves late-afternoon intervals poorly covered. A different dose/injection regimen that combines NPH at bedtime and 3 lispro or aspart injections with meals also fails to provide adequate basal insulin coverage during the late afternoon or evening hours. The recent advent of insulin glargine provides a potentially better alternative to the use of intermediate- and long-acting standard insulin preparations as basal components of MD1 regimens. The constant 24-hour flat insulin levels obtained with glargine therapy more closely simulate basal insulin secretion than does traditionally used NPH. Coverage of early morning requirements with bedtime NPH is often inadequate, with frequent fasting hyperglycemia because of limited duration of effect. Increments in the bedtime NPH dose to
improve fasting hyperglycemia result in pronounced nocturnal insulin peaks that often lead to nocturnal hypoglycemia. Recent studies suggest that an MD1 regimen using premeal short-acting insulins can be optimized with once-daily bedtime insulin glargine, which can provide more predictable basal control compared with regimens using once-daily (bedtime) or twice-daily (before breakfast and bedtime) NPH. The evidence suggests greater basal glucose-lowering effects, better coverage of early-morning insulin requirements (lower fasting hyperglycemia), and fewer episodes of nocturnal hypoglycemia with insulin glargine compared with regimens in which NPH was used as the basal component.
Insulin Pump Therapy Continuous subcutaneous insulin infusion via small programmable pump devices stands as a viable alternative to MD1 strategies. Infusion pumps can deliver short-acting insulin continuously at specific rates according to glucose patterns (basal component). Preprandial insulin doses at mealtime are promptly delivered by the patient at the touch of a button according to blood glucose monitoring results, carbohydrate and caloric content of the upcoming meal, physical activity, and other factors (bolus dose or prandial component). This form of insulin replacement closely approximates the basal/bolus
54
chid
physiologic pattern of secretion because of a more consistent insulin delivery. Compared with MD1 regimens, continuous subcutaneous infusions of buffered regular insulin have shown more flexibility but similar glycemic outcomes. Insulin lispro and aspart have proved compatible with infusion pumps and have shown a more optimal bolus dose action than regular insulin because of their more rapid subcutaneous absorption. The use of this strategy is clearly not suitable for all patients-it is expensive and requires a significant amount of patient education, motivation, and involvement to consistently monitor glycemic status throughout the day to optimally manage insulin requirements.
INSULIN OFTYPE
CORNERSTONE
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DIABETES
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Vol.4 No. 2
secretion, thus potentially sparing beta cells from further overstimulation and possibly preserving beta cell reserve and function, and can also overcome insulin resistance at sufficient doses. Its use, however, has been traditionally postponed for years and reserved as a last resort when the traditional stepwise approach of diet, exercise, and oral antidiabetic agents has failed to produce or maintain adequate glycemic control. For patients with significant initial hyperglycemia at the time of diagnosis, temporary insulin therapy may reestablish glycemic control. Nevertheless, because of the progressive worsening of underlying beta cell abnormalities, most patients will eventually require insulin therapy ideally much earlier in the course of the disease if optimal glycemic targets are to be achieved.
IN THE MANAGEMENT 2 DIABETES
In contrast to patients with type 1 diabetes, patients with type 2 diabetes have residual insulin secretory capacity. However, the dynamics of insulin secretion are compromised, and insulin levels are insufficient to compensate for insulin resistance, the other major pathogenic defect of type 2 diabetes. Pharmacologic management of the resultant hyperglycemic state requires intervention targeting the dual pathology of this disease. Early insulin replacement is an evolving strategy for optimal metabolic control of patients with type 2 diabetes. The ultimate goal of management, substantiated by results of the UK Prospective Diabetes Study (UKPDS), is the same as for type 1 diabetes-to prevent acute and long-term complications by improving glycemic control. Progressive in nature, the course of type 2 diabetes is reflective of the relentless decline in pancreatic beta cell function, which is presumed to start years before diagnosis (Figure 3). Furthermore, based on glycemic levels at the time of diagnosis and the progressive nature of this disorder, it is conceivable that long-term complications, which normally take years to develop, may already be present when diabetes is first diagnosed. Patients with type 2 diabetes are not dependent on insulin to prevent ketoacidosis and preserve life; however, insulin does play a major role in controlling glycemic levels. Insulin replacement therapy can compensate for insufficient endogenous
Barriers to Insulin Therapy The major barriers that discourage some physicians from using insulin in the treatment of type 2 diabetes are excessive concerns with weight gain, the potential risk of hypoglycemia, and, most notably, the misconception that insulin therapy may increase the risk of cardiovascular (CV) disease. (Table III). Insulin resistance and the consequent hyperinsulinemia are strongly associated with central obesity, hypertension, and dyslipidemia, all factors that contribute substantially to CV risk. Consequently, the possibility of overinsulinization during replacement therapy has raised concerns about the potential for acceleration of atherosclerosis. To date, there is no evidence linking exogenous insulin therapy and atherosclerosis, nor is there any evidence indicating that insulin therapy worsens CV risk, as clearly demonstrated by the UKPDS. Moreover, the 5-year Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) trial, which evaluated the
55
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1
-10
DIABETES
-9
1 Vol.4 No. 2
-8
-7
-6
-5
-4
-3
-2
-1
0
1
2
3
4
5
6
Years ,I,,
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,
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3. Progressive decline of beta cell function in patients with type 2 diabetes. Adapted with permission from UK Prospective Diabetes Study Group. UK Prospective Diabetes Study 16. Overview of6 years’ therapy of type II diabetes: a progressive disease. Diabetes. 199.5;44:1249-12.58. Figure
the impact of weight gain. The combination of metformin and insulin therapy has been shown to minimize weight gain. Importantly, intensive insulin therapy has been demonstrated to improve rather than worsen insulin sensitivity in peripheral tissues by virtue of
effects of intensive insulin therapy in patients with type 2 diabetes who enrolled at the time of myocardial infarction (MI), reported some revealing results. Compared with the control group (treated according to physician’s judgment), patients receiving insulin infusion therapy during acute MI followed by intensive MD1 therapy exhibited a relative mortality risk reduction of 28% after 5 years of insulin treatment. These results suggest that insulin may very well be the most appropriate treatment for patients with type 2 diabetes with high CV risk, particularly at the time of MI. Of note, studies of obese patients with type 2 diabetes treated with insulin therapy have shown that despite weight gain, CV risk factors such as blood pressure remained unchanged, and lipid patterns (triglycerides, lipoproteins) were generally improved. These findings challenge the notion that insulin therapy negatively affects blood pressure and lipid profiles. Although modest weight gain during insulin therapy is a well-recognized phenomenon, the benefits of improved glycemic control clearly surpass
improving glycemic control, thus reducing and to some degree reversing the toxic effects of hyperglycemia (glucotoxicity).
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Vol.4 No. 2
Insulin resistance
Improves insulin sensitivity by reducing glucotoxicity
Cardiovascular
No evidence of atherosclerotic May reduce CV risk
(CV) risk
Weight gain
Modest
Hypoglycemia
Rarely causes severe events
effects
underlying insulin deficiency typically progresses, most patients will eventually need both basal and mealtime insulin if optimal glycemic control is to be achieved and maintained. The basal/bolus strategy of insulin replacement stands as the most closely physiologic approach to treat type 2 diabetes as well as type 1 diabetes (Table I). The success of diabetes management often depends on the patient’s level of education regarding the disease process and the understanding that insulin is indeed an expected therapy at earlier stages once oral agents are insufficient to reach or maintain hemoglobin A,, (HbAi,) targets of ~7%.
The risk of mild to severe hypoglycemia, generally increased with intensive insulin therapy, depends on a number of factors, including age, weight, degree of insulin resistance, duration of disease, duration of insulin therapy, targeted degree of glycemic control, and history of hypoglycemic episodes. The UKPDS found that over a IO-year period, the incidence of hypoglycemia in patients randomized to intensive insulin therapy was, as expected, greater than that of patients assigned to treatment with sulfonylurea or metformin. However, most episodes of hypoglycemia were mild to moderate in intensity, and the 1Zmonth average incidence of severe episodes was 2% to 3%, significantly lower than that for patients with type 1 diabetes. Ample data like those presented above address concerns that have hindered the use of insulin therapy in the management of patients with type 2 diabetes. Increased understanding of the natural history and progressive nature of type 2 diabetes, coupled with a growing awareness of the need for more effective treatment strategies and significant improvements in insulin therapy, merit reassessment of the role of insulin in treating type 2 diabetes.
Starting Basal Insulin Therapy in Type 2 Diabetes For physicians managing patients with type 2 diabetes, practical guidelines for pharmacologic interventions are particularly important in view of the major changes over the past 5 years in managing type 2 diabetes and the growing movement toward starting aggressive pharmacotherapy earlier in the course of the disease. There has also been a paradigm shift that involves the increased use of flexible combination therapy with lower doses of any of the insulin secretagogues plus an insulin sensitizer (metformin or glitazone) almost from the initiation of pharmacotherapy. This strategy is embraced by the community of diabetes experts who also view early insulin therapy to supplement oral treatment as an effective tactic to reach a patient’s glycemic target (Table IV). A practical approach to overcome the complexity of MD1 regimens-and perhaps the best and most acceptable way to initiate insulin therapy-is to start with evening basal insulin replacement in patients who are no longer responding to oral agents.
Insulin Strategies: Overcoming Practical Barriers In addition to the concerns addressed above, barriers causing patients to resist the use of insulin include the need to mix and inject preparations, the complexity of conventional and intensive insulin regimens, and the practical kinetic limitations of standard insulin preparations. Because both fasting and postprandial glucose levels are abnormal in type 2 diabetes and the
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Average patient - Early combination of insulin secretagogue and insulin sensitizer - Most simple and cost-effective - Start low-dose, once-daily sulfonylurea with increasing doses of metformin - Full-dose sulfonylurea in combination with maximally tolerated metformin For marked insulin - Combination
resistance of metformin
+ glitazone
Zf target HbAIC ~7% not achieved - Try triple oral therapy or - Add evening basal insulin while continuing
oral therapy
An alternative way to initiate insulin therapy is to use mealtime insulin supplementation to improve postprandial hyperglycemic peaks while continuing sulfonylureas with or without sensitizing agents such as metformin or a glitazone. Treatment with 3 injections of mealtime lispro insulin added to a sulfonylurea has been shown to provide slightly lower HbAtC levels but greater weight gain than sulfonylureas in combination with bedtime NPH or with metformin. However, for patients starting insulin therapy, the need for multiple premeal injections makes the mealtime insulin supplementation strategy considerably more complex and less attractive than the once-daily evening dose of basal insulin. Perhaps in the future, when inhaled insulin becomes available, noninjectable premeal insulin replacement
Starting basal insulin replacement while maintaining the use of oral agents has considerable advantages: (a) only 1 daily injection may be required without the need of mixing different insulin preparations; (b) titration can be accomplished in a slow, safe, and simple fashion; and (c) a lower total dose of insulin will eventually be required because of the synergy of effects from the oral combination therapy. The synergistic effects of insulin secretagogues, such as sulfonylureas plus basal insulin, have been demonstrated in a number of studies adding once-daily Ultralente to sulfonylureas, bedtime NPH to glipizide, dinnertime 70/30 mix to glimepiride, or bedtime NPH to various oral agents (other than sulfonylureas), including metformin (Table V).
l
Continue oral agent(s) at same dosage (eventually
l
Add single, evening insulin dose (around 10 units) - Glargine (bedtime or anytime?) - NPH (bedtime)
reduce)
0 Adjust dose according to fasting blood glucose (FBG) monitoring l
Increase insulin - Increase by 2 - Increase by 4 - Increase by 6
dose units units units
weekly if FBG if FBG if FBG
as needed >120 mg/dL >140 mg/dL >180 mg/dL
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Indicated when FBG acceptable but - HbAtc >7% and/or - SBGM before dinner >160-180
mg/dL
0 Insulin options - To glargine, add mealtime lispro or aspart - To bedtime NPH, add morning NPH and mealtime lispro or aspart l
Oral agent options - Continue sulfonylurea
for endogenous secretion?
- Continue metformin for weight control? - Continue glitazone for glycemic stability?
to reach glycemic targets. Glycemic control can be further improved if patients follow simple algorithms, based on self-monitoring of blood glucose levels to adjust and deliver sufficient premeal insulin doses, using insulin aspart or lispro independently with no mixing to supplement the evening basal insulin regimen. This approach provides more flexibility and allows additional doses of supplemental insulin as needed to control postprandial hyperglycemia. MD1 regimens are progressively introduced as a further step toward intensifying insulin therapy (Table VI). Recently, a study comparing once- or twicedaily NPH with once-daily bedtime insulin glargine with or without preprandial regular insulin in patients with type 2 diabetes who had been previously treated with insulin-only therapy seemed to indicate a significantly lower risk of nocturnal hypoglycemia and lower weight gain with insulin glargine therapy. It is conceivable that similar strategies will benefit patients who have progressively intensified oral combination therapy by adding evening basal insulin glargine and eventually will require premeal lispro, aspart insulin, or inhaled insulin (when available) to control postprandial glycemic peaks. The use of effective and less troublesome injection devices, such as insulin pens, may facilitate the implementation of the new advances in insulin replacement therapy.
may turn into first-line intervention followed by basal insulin supplementation as required. An ongoing study comparing basal replacement therapy with bedtime insulin glargine or NPH added to oral combination therapy in insulin-naive patients will reveal the relative efficacy of these insulins administered in a forced titration manner to achieve fasting plasma glucose (FPG) levels of 400 mg/dL and reach HbA,, levels of ~7%. Preliminary results have shown remarkable glycemic improvement in the overall study population with rare incidence of severe hypoglycemia, no patterns of serious adverse events, and only a modest increase in body weight. HbAlc values decreased from 8.6% at baseline to 6.9% with highly significant differences in FPG between baseline and endpoint. Comparative data on the efficacy of the 2 basal regimens are awaited.
Advancing Toward Basal/Bolus Insulin Therapy Over time, the need to intensify insulin regimens arises in response to disease progression. The traditional way of supplying insulin with a twice daily, split-mixed insulin regimen has been usually considered when it becomes necessary to intensify the once-daily basal insulin in combination with oral agents. However, the use of “premixed” insulin preparations, such as 70/30 or 75125, do not provide enough flexibility and are seldom effective
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SUMMARY New strategies involving insulin analogs with improved pharmacokinetic properties, the new armamentarium of oral agents for type 2 diabetes, and future development in routes of insulin administration will expand treatment options and combination regimens to facilitate the attainment of specific targeted glycemic levels in a safe and more effective manner. To prevent and retard the progression of microvascular and macrovascular complications are the ultimate objectives in the management of patients with either type 1 or type 2 diabetes.
izing glycosylated hemoglobin in type 2 diabetes: application, benefits, and risks. Diabetes Rev. 1995; 3:308-334. Galloway JA. New directions in drug development: mixtures, analogues, and modeling. Diabetes Care. 1993;16(Suppl 3):16-23. Heinemann L, Klappoth W, Rave K, et al. Intraindividual variability of the metabolic effect of inhaled insulin together with an absorption enhancer. Diabetes Care. 2000;23: 1343-1347. Janssen MM, Snoek FJ, Masurel N, et al. optimized basal-bolus therapy using a fixed mixture of 75% lispro and 25% NPH insulin in type 1 diabetes patients: no favorable effects on glycemic control, physiological responses to hypoglycemia, well-being, or treatment satisfaction. Diabetes Care. 2000;23:629-633.
SUGGESTED READING American Diabetes Association Clinical Practice Recommendations 200 1. Diabetes Care. 200 1; 24(Suppl l):Sl-S133.
Kang S, Brange J, Burch A, et al. Subcutaneous insulin absorption explained by insulin’s physicochemical properties. Evidence from absorption studies of soluble human insulin and insulin analogues in humans. Diabetes Care. 1991;14:942-948.
Barnett AH, Owens DR. Insulin analogues. Lancet. 1997;349:47-5 1. Berger M, Jorgens V, Muhlhauser 1. Rationale for the use of insulin therapy alone as the pharmacological treatment of type 2 diabetes. Diabetes Care. 1999;22(Suppl3):C7 l-C75.
Kelley DB, ed. Medical management of type 2 diabetes, In: Medical Management of Type 2 Diabetes. Alexandria, Va: American Diabetes Association; 1998:56-72.
Bolli GB, Di Marchi RD, Park GD, et al. Insulin analogues and their potential in the management of diabetes mellitus. Diabetologia. 1999;42: 1151-1167.
Koivisto VA, Tuominen JA, Ebeling I? Lispro Mix25 insulin as premeal therapy in type 2 diabetic patients. Diabetes Care. 1999;22:459-462.
Brange J, Owens DR, Kang S, Volund A. Monomeric insulins and their experimental and clinical implications. Diabetes Care. 1990;13:923-954.
Lalli C, Ciofetta M, Del Sindaco P, et al. Long-term intensive treatment of type 1 diabetes with the shortacting insulin analog lispro in variable combination with NPH insulin at mealtime. Diabetes Care. 1999;22:4688477.
Brange J, Ribel U, Hansen JF, et al. Monomeric insulins obtained by protein engineering and their medical implications. Nature. 1988;333:679-682.
Lepore M, Kurzhals R, Pampanelli S, et al. Pharmacokinetics and dynamics of S.C.injection of the long-acting insulin glargine (HOEl) in TlDM. Diabetes. 1999;48(Suppl l):A97.
Campbell RK, Campbell LK, White JR. Insulin lispro: its role in the treatment of diabetes mellitus. Ann Pharmacother: 1996;30: 1263-l 27 1. Cefalu WT, Skyler JS, Kourides IA, et al. Inhaled human insulin treatment in patients with type 2 diabetes mellitus. Ann Intern Med. 200 1; 134:203-207.
Malmberg K. Prospective randomized study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. DIGAMI (Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group. Br Med .I. 1997;3 14: 1512-1515.
DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med. 1999; 13 1: 281-303. Edelman SV, Henry RR. Insulin therapy for normal-
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Mudaliar SR, Lindberg FA, Joyce M, et al. Insulin aspart (B28 asp-insulin): a fast-acting analog of human insulin: absorption kinetics and action profile compared with regular human insulin in healthy nondiabetic subjects. Diabetes Care. 1999;22: 1501-1506.
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with type 2 diabetes on oral agents. Diabetes. 2001;5O(Suppl2):A520. Rosenstock J, Schwartz SL, Clark CM, Donley DW. Efficacy and safety of HOE 901 (insulin glargine) in subjects with type 2 DM: a 28-week randomized, NPH insulin-controlled trial. Diabetes. 1999;48(Suppl 1):AlOO.
Owens DR, Zinman B, Bolli GB. Insulins today and beyond. Lancet. 2001;358:739-746.
Rosenstock J, Schwartz SL, Clark CM, Jr, et al. Basal insulin therapy in type 2 diabetes: 28-week comparison of insulin glargine (HOE 901) and NPH insulin. Diabetes Care. 2001;24:631-636.
Pieber TR, Eugene-Jolchine I, Derobert E, for the European Study Group of HOE 901 in Type 1 Diabetes. Efficacy and safety of HOE 901 versus NPH insulin in patients with type 1 diabetes. Diabetes Care. 2000;23:157-162.
Rosskamp RH, Park G. Long-acting insulin analogs. Diabetes Care. 1999;22(Suppl 2): B109-B113.
Raskin P, Klaff L, Bergenstal R, et al. A 16-week comparison of the novel insulin analog insulin glargine (HOE 901) and NPH human insulin used with insulin lispro in patients with type 1 diabetes. Diabetes Care. 2000;23:1666-1671.
Scholtz HE, van Niekerk N, Meyer BH. An assessment of the variability in the pharmacodynamics (glucose-lowering effect) of HOE901 compared to NPH and Ultralente human insulins using the euglycaemic clamp technique. Diabetologia. 1999; 42(Suppl l):A235.
Ratner RE, Hirsch IB, Neifing JL, et al. Less hypoglycemia with insulin glargine in intensive insulin therapy for type 1 diabetes. U.S. Study Group of Insulin Glargine in Type 1 Diabetes. Diabetes Care.
Skyler JS, Cefalu WT, Kourides IA, et al. Efficacy of inhaled human insulin in type 1 diabetes mellitus: a randomised proof-of-concept study. Lancet.
2000;23:639-643.
Riddle MC. Evening insulin strategy. Diabetes Care. 1990;13:676-686.
2001;357:331-335.
Skyler JS. Insulin therapy in type 2 diabetes mellitus. In: DeFronzo RA, ed. Current Therapy of Diabetes Mellitus. St. Louis, MO: Mosby; 1998: 108-l 16.
Riddle MC, Schneider J. Beginning insulin treatment of obese patients with evening 70/30 insulin plus glimepiride versus insulin alone. Glimepiride Combination Group. Diabetes Care. 1998;21:
Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. JAMA. 1999;281:2005-2012.
1052-1057.
Rosenfalck AM, Thorsby P, Kjems L, et al. Improved postprandial glycaemic control with insulin aspart in type 2 diabetic patients treated with insulin. Acta Diabetol. 2000;37:4146. 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-l 142.
UK Prospective Diabetes Study Group. UK Prospective Diabetes Study 16. Overview of 6 years’ therapy of type II diabetes: a progressive disease. Diabetes. 1995;44:1249-1258. Weiss SR, Berger S, Cheng S, et al, for the Phase II Insulin Study Group. Adjunctive therapy with inhaled human insulin type 2 diabetic patients failing oral agents: a multi-center phase II trial. Diabetes. 1999;48(Suppl l):A12.
Rosenstock J, Riddle MC, Dailey G, et al. Treatment to target study: feasibility of achieving control with the addition of basal bedtime insulin glargine (Lantus) or NPH insulin in insulin-naive patients
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tion therapy in type 2 diabetes. HOE 901/3002 Study Group. Diabetes Care. 2000;23: 1130-1136.
Yki-Jarvinen H, Dressler A, Ziemen M. Less nocturnal hypoglycemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combina-
ADVISORY
BOARD
ADVISORY
Has it been definitively shown that starting insulin therapy earlier in type 2 diabetes may prevent or delay beta cell exhaustion?
ROSENSTOCK There are absolutely no data to support this; thus, at this point the answer is no. Some overweight type I diabetics may have insulin resistance, but you really don’t want to prescribe a glitazone in the adolescent type 1 because of long-term safety concerns. Moreover, it really doesn’t matter how much insulin you give as long as it’s safe. Insulin by itself isn’t a problem in type 1 diabetics provided they don’t have hypoglycemia.
ROSENSTOCK No, it has not. We do know, however, that by reversing glucotoxicity and reducing insulin resistance, intensive insulin therapy appears to recharge the beta cell by allowing it to rest and regranulate. It stands to reason that avoiding glucotoxicity from the beginning should serve to preserve beta cell function. ADVISORY
BOARD
Is there a role in type 1 diabetics for insulin sensitizers to reduce overall insulin levels?
BOARD
For the patient who has failed on triple therapy and you choose to start insulin, do you routinely discontinue the sulfonylurea first since the beta cells are likely exhausted?
ADVISORY
BOARD
In light of its 24-hour half-life and its flat course of action, isn’t it acceptable for a patient to use insulin glargine at suppertime as opposed to bedtime?
ROSENSTOCK I would not necessarily drop the secretagogue first. It’s really not that simple. Instead, you should go through a thought process and decide which of the oral agents is the most appropriate one to stop. For example, if the patient has gained 20 or 25 pounds due to fluid retention, I would stop the thiazolidinedione instead. If you have a patient whose serum creatinine is hovering around 1.4 to 1.5 mg/dL and is taking metformin, I might drop metformin first. With regard to stopping the sulfonylurea, remember that as you improve hyperglycemia with insulin therapy and reduce glucotoxicity, beta cell function should improve and the activity of a sulfonylurea should be enhanced.
ROSENSTOCK Yes. The reason the package insert specifies bedtime is because the studies on which FDA approval was based all compared insulin glargine with NPH insulin and to give the 2 at suppertime would have put NPH insulin at a disadvantage. In terms of practicality, there would be no problem giving insulin glargine at suppertime. ADVISORY
BOARD
What is the metric you use for adjusting the dose of insulin glargine? ROSENSTOCK The parameter that should be followed is the fast-
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ing blood sugar with the major limiting factor obviously being the development of hypoglycemia. So long as you have no hypoglycemia and the blood sugar is >120 mg/dL, you can keep titrating the dose upward. ADVISORY
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BOARD
How does insulin glargine compare with other insulins in terms of cost? ROSENSTOCK It is very similar in cost to lispro and insulin aspart. It is more expensive than NPH insulin but less expensive than the 75/25 premixed. The 70/30 premixed is probably cheaper but may be more expensive if used in pens.
BOARD
Do you use the mixed insulins, 70/30 or 75125, in your practice? ROSENSTOCK I’ve used them in the past. I used the 70/30 because I found it a good way to introduce insulin therapy in type 2 diabetics. I typically began by giving 70130 at suppertime in combination with oral agents, adjusting the dose on the basis of the fasting and nocturnal blood sugars. If the blood sugars continued to run high in the afternoon, I would add a second injection. It was a great concept when we didn’t have anything better. The 75125 mix conceptually may make a lot of sense but it is twice as expensive, and there are very few studies comparing it to 70/30. The major problem with both of these premixed insulins is that their fixed combination dosage tends to really tie your hands. My experience is that the lack of flexibility inherent in them resulted in very few people reaching their target goal. Why? Because when you found it necessary to push the insulin dose higher, hypoglycemia became a problem, making it difficult to make the needed adjustments. At the present time, I favor starting insulin therapy with insulin glargine in the evening with frequent adjustments to get the fasting glucose to goal. For patients in whom postprandial glucoses remain above goal and the glycosylated hemoglobin above 7%, I prescribe little pens with lispro or insulin aspart and have the patients give themselves an injection before meals. This approach seems to me much more rational and flexible.
ADVISORY
BOARD
When would you opt for regular insulin instead of prescribing an insulin analog such as lispro? ROSENSTOCK The use of short-acting insulin analogs can be problematic for a type 1 diabetic patient who eats lunch at noon and does not eat dinner until 7 or 8 hours later. What can happen is that because of the short 4- or 5-hour duration of action, hyperglycemia can develop by late afternoon. If the dose of morning NPH insulin is increased, you run the risk of causing hypoglycemia to occur before noon. With such patients I would use regular insulin at lunchtime because its 6 to S-hour duration of action will provide better coverage until dinner. Another possible indication is the elderly patient for whom you feel uncomfortable using a really quick-acting insulin and would prefer taking it a bit slower with regular insulin, which does not have such a rapid onset of action. ADVISORY
BOARD
Is the use of insulin glargine compatible in terms of mixing it in the same syringe with other insulin preparations? ROSENSTOCK No, you can’t mix insulin glargine with other insulins. I view this as an advantage because
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there are studies that show mixing different insulins introduces tremendous variability in their action and a real potential for error. The new insulin pens have 30-gauge needles, and patients really don’t seem to mind giving themselves multiple injections with them. ADVISORY
increasing the risk for hypoglycemia. Third, the fact that it is cloudy is an issue since it introduces the variable that you have to shake it and suspend it properly, otherwise the absorpton is very unpredictable. Finally, studies suggest that its rate of absorption varies more than insulin glargine depending on where you inject it (ie, abdomen, thigh, arm) and the depth of the injection.
BOARD
Is insulin glargiue associated with a low risk for causing hypoglycemia and, if so, why?
ADVISORY
BOARD
What do you use in an insulin pump? ROSENSTOCK Yes, a reduced risk of hypoglycemia has been a fairly consistent finding in most of the studies, especially a reduced risk of nocturnal hypoglycemia. A big reason is that you don’t have to deal with overlapping activity spikes. For example, NPH insulin has a spike and regular insulin, lispro, and aspart each have a spike, and the overlap of these spikes in patients using them increases the risk of hypoglycemia. This is not an issue with insulin glargine since it has no spike. ADVISORY
ROSENSTOCK I’m using lispro. Insulin aspart does not have it as an indication yet, but there are papers that show it is as good as lispro and it is likely that it will soon get the indication. ADVISORY
BOARD
Where are we with inhaled insulin? ROSENSTOCK Phase 3 studies have been completed, and I think we are looking at 2 years before patients will be able to simply take a puff before each meal to reduce the postprandial hyperglycemia. If the hemoglobin AtC is below 7% using just inhaled insulin-great. However, for the patient who continues to run high blood sugars throughout the night and morning, an agent like insulin glargine would have to be added at night; thus, the patient may end up with 1 injection and 3 puffs.
BOARD
How does NPH insulin compare with insulin glargine? ROSENSTOCK Although NPH insulin is less expensive and in many patients works quite well, it does have limitations. First, it has a typical duration of action of 12 to 14 hours and thus is not as long acting. Second, it is associated with spikes of activity,
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