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day-long glycemia had improved to within normal range and remained at this level through 6 month of therapy. The Aic, which was 7.7% ± 0.3% at baseline, decreased to 5.1% ± 0.2% at 6 months. This study underscores the importance of early insulin therapy, when the baseline A1c is only mildly elevated just above 7%, and insulin is aggressively titrated.

However, these results are hardly ever achieved when the split-mixed regimen, which fails to mimic the basal/bolus needs, is used in general practice and insufficient insulin is administered. Often, premixed 70/30 insulin is used but the insulin profiles do not come close to matching the normal endogenous secretory pattern to control fasting and postprandial hyperglycemia. In addition, the rigid premixed preparations have the significant limitation of having no flexibility for insulin adjustments according to the patient's blood glucose profile.

Multiple daily doses of short acting insulin can be added when patients do not attain adequate control. Lindstrom and colleagues showed that this strategy may be effective in normalizing HbA1c but was best accomplished with four injection of regular per day (137). They performed a randomized crossover study of 8 weeks of oral hypoglycemic agents followed by 8 weeks of 2- or 4-dose insulin regimens. Mean blood glucose and free-insulin profiles show that patients taking the oral agents had higher blood glucose and lower postprandial insulin concentrations than those receiving insulin. When patients received the daily 4-dose regimen of preprandial regular insulin and intermediate-acting NPH insulin at 10:00 PM, glycemic control improved. The mean HbA1c was 8.8% during treatment with oral therapy compared with 5.6% on the intensive 4-dose insulin regimen.

Perhaps the best evidence that near-normoglycemia is beneficial and feasible with multiple daily insulin injections in type 2 diabetes is the Kumamoto Study. The 8 year analysis of the Kumamoto Study showed a sustained lowering of A1cs and of microvascular complications in the 99 patients treated with either conventional (once or twice daily intermediate insulin) or multiple injection therapy (short and intermediate-acting insulin with a goal of FBG< 140 mg/dL, 2-h postprandial < 200 mg/dL, an A1c < 7% and a mean amplitude of glycemic excursion < 100mg/dL).138 They found no worsening of retinopathy or nephropathy in patients whose A1c , FBG and 2-h postprandial blood glucose concentration were below 6.5%, 110 mg/dL, and 180 mg/dL, respectively. The longest study includes 15 patients that have been followed for 110 months while taking insulin after sulfonylurea failure (139). While there was little difference in insulin dosage between the first weeks of insulin treatment and the 27-month examination, the dosage was increased at the 110-month examination from 51.3 ± 5.2 to 79.5 ± 10.8 U. The glycemic control was improved with reduction of HbA1c from 8.9 ± 0.2% during treatment with oral hypoglycemic agents to 7.3 ± 0.3% (p < 0.001 vs. baseline) at the 110-month examination. Body weight increased rapidly during the first 4-5 months, but after 12 months there was no significant change.

Adding Oral Agents to Insulin Therapy

Most of the studies reported on the combination insulin plus oral sensitizers have been based on the addition of an oral agent such as metformin or a glitazone to patients already treated with conventional insulin therapy, which is fundamentally a different issue than starting and intensifying insulin replacement strategies to achieve target glycemic control as was discussed extensively above. Nevertheless, the option of adding an insulin sensitizer or even a secretagogue to patients who are already on insulin therapy should be considered if the A1c target is not achieved despite aggressive insulin replacement therapy.

Metformin Plus Insulin

There are several studies that have used metformin as "add-on" therapy to insulin with significant improvements in HbA1c. The addition of metformin to pre-existing insulin therapy was first shown to have efficacy beyond that of continuing insulin alone in a study by Giugliano et al in 1993 (148). Subsequently, several studies have addressed this strategy with decreases in HbAic between 1 to 2.5% (149-151).

The largest A1c reduction was obtained with maximized intensive insulin therapy in 43 patients with type 2 DM who were randomize to added placebo or metformin (149) (Fig. 9). The goal of this study was to maximally decrease HbAic with intensive insulin adjustments

*

FIGURE 9 Metformin plus insulin. The change in Hemoglobin A1c from baseline to 24 weeks after the addition of metformin to insulin in patients with poorly controlled type 2 diabetes. Source: From Ref. 149.

Metformin group Placebo group instead of the traditional goal of reducing insulin doses to demonstrate the sensitizer effect. Hemoglobin A1c levels decreased by 2.5% in the metformin group, a significantly greater change than the decrease of 1.6% in the placebo group. Average final HbA1c levels were 6.5% in the metformin group and 7.6% in the placebo group. For patients who received placebo, the insulin dose increased 22.8 units which are 29% more than did the dose for patients who received metformin whose insulin dose decreased slightly. The strategy of adding metformin to insulin can result in significant improvements in HbA1c, especially when insulin dose is not decreased.

Thiazolidinedione Plus Insulin

The clinical availability of the thiazolidinediones introduced the possibility of improvements of insulin sensitivity in muscle, liver and adipose tissue potentiating the effects and reducing the doses of exogenous insulin. The first study to demonstrate the efficacy of this combination was utilizing troglitazone (152) which is no longer available in the United States due to idiosyncratic hepatotoxicity. Subsequently, the addition of either pioglitazone or rosiglitazone to insulin in patients with poorly controlled type 2 diabetes (A1c > 9%) showed a dose related decrease in A1c s of 1.2 to 1.3% despite mild reductions of insulin dosages (153,154). The addition of pioglitazone (15 or 30 mg daily) to pre-existing conventional insulin therapy for 16 weeks showed statistically significant decreases in A1c in 566 patients who were poorly controlled on conventional insulin alone (154). Low dose pioglitazone (15 mg) decreased A1c from 9.75% to 8.76% while medium dose (30 mg) decreased A1cs from 9.84% to 8.58% while the insulin doses remain constant. Similarly, the addition of rosiglitazone (4 or 8 mg daily) to preexisting insulin therapy for 26 weeks showed statistically significant decreases in A1c in 209 patients who were poorly controlled (146). Medium dose rosiglitazone (4 mg) decreased A1c from 9.1 — 1.3 to 8.5 -1.4% while high dose (8 mg) decreased A1cs from 9.0 -1.3 to 7.9 —1.4%. Body weight increased by 2.3 to 3.7 kg during 16 weeks treatment with pioglitazone or 4.0 to 5.3 kg during the 26 weeks of treatments with rosiglitazone. The incidence of edema was comparable 15.3% with pioglitazone and 14.7% with rosiglitazone. Safety issues remain a major concern especially fluid retention and the potential risk of developing or worsening congestive heart failure especially in high risk patients with coronary disease with or without preexisting CHF. However, the warning for its use in patients stresses extreme caution in patients with edema, coronary disease and mild forms of CHF (not recommended in NYHA Class III and IV but in our opinion better not to use it in any form of CHF at all). Further studies are ongoing to determine the long term safety effects of the glitazones on fluid retention and especially frequency and severity of CHF. When initiating these agents in any patients it is prudent to carefully evaluate their cardiovascular status and start at a very low dose and increase the dose very slowly (i.e. at 3 to 6 month intervals).

Combination Oral Agents Plus Once-Daily Insulin

The FINFAT study, conducted in four centers in Finland, randomly assigned 96 patients with type 2 diabetes who were inadequately controlled with sulfonylurea therapy alone to receive four different regimens in addition to bedtime NPH insulin: glyburide, metformin, glyburide + metformin, or a second injection of NPH insulin in the morning (155). The patients were instructed to self-adjust the evening insulin dose if their FPG level was elevated. After 12 months of therapy, this study suggested that self-adjustment of the insulin dose and the addition of metformin produced slightly better overall glucose control, less weight gain, and the lowest frequency of hypoglycemic episodes. However, the group receiving metformin alone in addition to the insulin had the highest dropout rate, with 21% of patients not completing the trial. The investigators of this study attributed the improved glycemic control seen across treatment groups to successful patient education regarding adjustment of insulin doses. Although it was expected that patients receiving only one oral drug in addition to bedtime insulin would require greater increases in the insulin doses than those receiving both oral drugs, this was not the case. Patients who received metformin had greater insulin requirements than those who received the sulfonylurea, who had a higher frequency of symptomatic, mild hypoglycemic episodes (Fig. 10).

A current and increasingly used strategy would be to add to the oral agents the peakless long acting analogue, either insulin glargine or insulin detemir, at bedtime. The Treat to Target Study, is a 24-week U.S. multicenter, randomised, parallel-group comparing basal replacement therapy with bedtime insulin glargine (Lantus®) or NPH added to oral combination therapy (70% of patients were on sulfonylurea + metformin and the rest on different combinations of two agents such as sulfonylurea + glitazone or metformin + glitazone with only 10% on monotherapy) in 756 insulin-naive patients. This study confirmed the efficacy of these insulin when administered in a forced titration manner to achieve fasting plasma glucose (FPG) levels of < 100 mg/dL and reach HbA1c levels of < 7% (100,101). This was the first study to demonstrate that starting insulin therapy with a low dose of 10 units at bedtime followed by a very simple algorithm based on FPGs was successful in achieving remarkable glycemic improvements 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. HbAic values decreased from 8.6% at baseline to 6.9% by the end of the study, with highly significant differences in FPG between baseline and endpoint. Significantly more patients treated with insulin glargine attained an Aic < 7% without documented hypoglycemia. Most notably 58% of the patients in both groups achieved the target A1c of < 7 % but patients on the insulin glargine group had a 44 to 48% risk reduction in confirmed nocturnal hypoglycemia which is an advantage for the basal insulin, insulin glargine, especially as this strategy has the potential to be applied to large populations of patients with type 2 diabetes managed by general physicians.

Combination Oral Agents Plus Once, Twice or Thrice Daily Premixed Insulin

The strategy of starting insulin therapy with a low dose of 10 to 12 units daily, whether once or twice daily or at bedtime, followed by a very simple titration algorithm based on FPGs has now

FIGURE 10 Starting with Bedtime Insulin: FINFAT Study. Changes in HgbA1c, insulin dose and weight and percent dropout of the patients with type 2 diabetes who were inadequately controlled with sulfonylurea therapy that received four different regimens in addition to bedtime NPH insulin: glyburide, metformin, glyburide + metformin, or a second injection of NPH insulin in the morning. Source: From Ref. 155.

FIGURE 10 Starting with Bedtime Insulin: FINFAT Study. Changes in HgbA1c, insulin dose and weight and percent dropout of the patients with type 2 diabetes who were inadequately controlled with sulfonylurea therapy that received four different regimens in addition to bedtime NPH insulin: glyburide, metformin, glyburide + metformin, or a second injection of NPH insulin in the morning. Source: From Ref. 155.

been tested in several studies employing different strategies using basal or premixed insulin analogs. The first study, described above, was the Treat-to-Target Study which compared the addition at bedtime of NPH versus Glargine (5). Subsequently, the INITIATE Trial showed that starting 5 to 6 units twice daily of premixed biphasic insulin aspart 70/30 (BIAsp 70/30) was superior to using 10 to 12 units of insulin glargine at bedtime when patients self-titrated the dose to target blood glucose (80-110 mg/dL) by algorithm-directed titration (6). The patient controlled strategy was taken one step further in the 1-2-3 Study which started with a low dose of BIAsp 70/30 prior to the evening meal and every the dose titrated 3 to 4 days to achieve fasting blood glucose of 80 to 110 mg/dL (7). If the A1c was not <6.5% at 16 weeks then the insulin was increased to twice daily. If the A1c was not < 6.5% at 32 weeks then the insulin was further increased to three times daily. Addition of once-daily BIAsp 70/30 before dinner enabled 41% to achieve an A1c < 7% and 21% of the patients attained an A1c < 6.5%. With two daily injections of BIAsp 70/30, these glycemic goals were achieved by 70 and 52% of the subjects. With three daily BIAsp 70/30 injections, 77% achieved an Aic < 7.0% and 60% achieved an A1c <6.5%. Further studies have shown the value of patient controlled titration. The important points are that the insulin can be started at low doses and increased by the patient, based on home blood glucose monitoring, safely with few side effects.

Practical Guidelines for Insulin Replacement Therapy

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 10 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 (whether sulfonylurea, incretin mimetic or DPP-4 inhibitor) plus metformin and a 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.

A practical approach to overcome the complexity of MDI 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. 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.

When insulin is added to combination oral agent in asymptomatic patients with type

2 diabetes, it can be initiated with a simple regimen with a low dose of 5 to 10 units of insulin daily (Table 5). The patient can then increase the dose weekly according to fasting self monitored blood glucose (SMBG) based on the average of 2 to 5 consecutive days, as long as

TABLE 5 Practical Guidelines: Starting insulin

Continue oral agent(s) at same dosage (eventually reduce the secretagogue) Add single, evening insulin dose (around 10 units) Glargine (morning, noon, evening or bedtime)

NPH (bedtime) Premixed insulin

Adjust dose according to an average of 2-5 fasting blood glucose monitoring increase insulin dose weekly as needed increase by 2 units if FBG 100-120 mg/dL increase by 4 units if FBG 121-140 mg/dL increase by 6 units if FBG 141-180 mg/dL increase by 8 units if FBG >180 mg/dL

Abbreviation: NPH, neutral protamine hagedorn.

there is no evidence of nocturnal hypoglycemia with any measurements < 72 mg/dL (Table 5). Insulin adjustments with appropriate reductions will be required in instances of SMBG < 56 mg/dL or with the occurrence of a severe hypoglycemic episode.

Whether the oral agents should be continued once the insulin regimen has been optimized, will depend on the individual patient response. If the secretagogue is stopped then it would need to be switched to prandial insulin. Metformin should be continued to provide weight control as long as there is no evidence of renal impairment or CHF. A glitazone should also be continued to reduce insulin resistance and potentially preserve beta-cell function. Ideally the glitazone would have been added prior to insulin initiation as adding high doses of glitazones to ongoing insulin therapy is associated with substantial weight gain and fluid retention. The use of a DPP-4 inhibitor with insulin has not yet been studied so cannot be addressed here. Similarly, incretin mimetics, such as exenatide, have not yet been studied in combination with insulin.

Over time, the need to intensify insulin regimens arises in response to disease progression. Clinical judgment should prevail to determine when to advance to a more intensive basal/bolus insulin regimen. Clearly, when the target fasting plasma glucose of 80 to 120 mg/dL has been achieved and the HbA1c remains >7% further increments of the evening basal insulin glargine may be attempted but this approach can result in increased risk of hypoglycemia. Therefore, at this point adding pre-prandial fast acting insulin analogues at their main meal or meals will result in subsequent improvements of the A1c levels. Postprandial hyperglycemia 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, glulisine, lispro or inhaled insulin independently. This approach provides more flexibility and allows additional doses of supplemental insulin as needed to control postprandial hyperglycemia. MDI regimens are progressively introduced as a further step toward intensifying insulin therapy (Table 6). The use of effective and less troublesome injection devices, such as insulin pens, can facilitate the implementation of the new advances in insulin replacement therapy.

It is conceivable that this practical and simple strategy may have translational implications and benefit large number of patients with type 2 DM when followed by general practitioners. This structured regimen can realistically reach A1c targets in patients who have progressively intensified oral combination therapy by adding evening basal insulin glargine and eventually premeal lispro, aspart or glulisine insulin, or inhaled insulin, to control fasting and postprandial glycemic levels.

Future Insulin Replacement Therapies

Traditionally, the approach to glucose lowering therapy has been that most patients with type 2 diabetes require insulin—but used as a "last resort after maximal combination therapy has failed—10 to 15 years after disease onset. However, our improved understanding of the natural history of type 2 diabetes suggests that insulin therapy should be started sooner rather

TABLE 6 Practical Guidelines: Advancing Basal/Bolus Insulin

Indicated when FBG is acceptable (80-120 mg/dL) but HbA1c >6.5% and/or

SBGM before dinner >140-180 mg/dL Insulin options

To glargine: add lispro, aspart, glulisine or inhaled insulin at main meal or all meals To bedtime NPH: add morning NPH and mealtime lispro, aspart, glulisine or inhaled insulin Oral agent options Continue secretagogue for endogenous insulin secretion? Continue metformin for weight control? Continue glitazone for glycemic stability?

Abbreviations: FBG, fasting blood glucose; HbA1c, hemoglobin A1c; NPH, neutral protamine hagedorn; SBGM, self blood-glucose monitoring.

than later and that insulin should be viewed as an essential therapeutic tool for achieving disease management goals, at an earlier stage in the natural progression of the disease, rather than a sign of failure on the part of the physician or patient. New strategies involving insulin analogues with improved pharmacokinetic properties, the new armamentarium of oral agents for type 2 diabetes, and new injectable agents will expand treatment options and combination regimens to facilitate the attainment of specific targeted glycemic levels in a safer and more effective manner.

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