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Diabetes Care. 2009 Nov; 32(Suppl 2): S253–S259.
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PMID: 19875560

Sanne G. Swinnen

From the Department of Internal Medicine, Academic Medical Center, Amsterdam, the Netherlands.

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Joost B. Hoekstra

From the Department of Internal Medicine, Academic Medical Center, Amsterdam, the Netherlands.

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J. Hans DeVries

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From the Department of Internal Medicine, Academic Medical Center, Amsterdam, the Netherlands.
Corresponding author: Sanne G. Swinnen, [email protected].
Copyright © 2009 by the American Diabetes Association.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
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reverses diabetes type 2 song (⭐️ symptoms) | reverses diabetes type 2 teenshow to reverses diabetes type 2 for A number of landmark randomized clinical trials established that insulin therapy reduces microvascular complications (1,2). In addition, recent follow-up data from the U.K. Prospective Diabetes Study (UKPDS) suggest that early insulin treatment also lowers macrovascular risk in type 2 diabetes (3). Whereas there is consensus on the need for insulin, controversy exists on how to initiate and intensify insulin therapy. The options for the practical implementation of insulin therapy are many. In this for 1 last update 29 May 2020 presentation, we will give an overview of the evidence on the various insulin regimens commonly used to treat type 2 diabetes.A number of landmark randomized clinical trials established that insulin therapy reduces microvascular complications (1,2). In addition, recent follow-up data from the U.K. Prospective Diabetes Study (UKPDS) suggest that early insulin treatment also lowers macrovascular risk in type 2 diabetes (3). Whereas there is consensus on the need for insulin, controversy exists on how to initiate and intensify insulin therapy. The options for the practical implementation of insulin therapy are many. In this presentation, we will give an overview of the evidence on the various insulin regimens commonly used to treat type 2 diabetes.

Secondary analyses of the aforementioned landmark trials endeavored to establish a glycemic threshold value below which no complications would occur. The UKPDS found no evidence for such a threshold for A1C, but instead showed that better glycemic control was associated with reduced risks of complications over the whole glycemic range (“the lower the better”) (4). For the management of type 2 diabetes, this resulted in the recommendation to “maintain glycemic levels as close to the nondiabetic range as possible” (5). However, in contrast to the UKPDS, the Kumamoto study observed a threshold, with no exacerbation of microvascular complications in patients with type 2 diabetes whose A1C was <6.5%, suggesting no additional benefit in lowering A1C below this level (2). Moreover, the intensive glycemia treatment arm of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, targeting A1C <6.0%, was discontinued because of higher mortality in this group compared with the standard therapy group targeting A1C from 7.0 to 7.9% (6). Therefore, the American Diabetes Association (ADA) recommendation of an A1C target <7.0% seems the most balanced compromise at present (7).

Another important conclusion of the UKPDS was that the risk reductions in long-term complications were related to the levels of glycemic control achieved, rather than to a specific glucose-lowering agent (1). This has left health care providers and patients with the difficult task of choosing from the wide variety of glucose-lowering interventions currently available. When considering the effectiveness, tolerability, and cost of the various diabetes treatments, insulin is not only the most potent, but also the most cost-effective intervention (8). Although insulin has no upper dose limit and numerous trials established that glycemic goals could be attained by using adequate insulin doses (5,8), in clinical practice, many patients have elevated A1C levels and experience years of uncontrolled hyperglycemia (9). Moreover, the Steno-2 Study demonstrated that only a minority of patients reached the intensive A1C target of <6.5%, compared with a far greater percentage of patients who reached the respective intensive treatment goals for blood pressure and serum lipid levels (10). Apparently, the initiation and intensification of insulin therapy is not as straightforward and simple as we had hoped. In accordance with the ADA and the European Association for the Study of Diabetes (EASD) (5,7), we advocate an algorithmic approach for the start and adjustment of insulin treatment, with modifications for individual patients as needed. This review contains an overview of the currently available insulin preparations and an outline of the merits and disadvantages of the various regimens commonly used for the initiation and intensification of insulin therapy in patients with type 2 diabetes. Our aim is to assist clinicians in designing individualized management plans for insulin therapy in type 2 diabetic patients.

HUMAN INSULIN AND ITS ANALOGS

Insulin therapy with the conventional mealtime and basal insulin preparations has many shortcomings. First, the absorption of regular human insulin from the subcutaneous tissue is slow, and the metabolic action takes effect only 30–60 min after injection and peaks after 2–3 h. Consequently, treatment with regular insulin is associated with postmeal hyperglycemia and an increased risk of late-postprandial hypoglycemia. Second, the conventional basal NPH insulin has a distinct peak glucose-lowering effect, has a duration of action considerably shorter than 24 h, and is absorbed from the subcutaneous tissue at variable rates. These pharmacodynamic limitations predispose users to elevated glucose levels before breakfast and nocturnal hypoglycemia (11,12). To overcome these difficulties, insulin analogs with a modified amino acid sequence from the human insulin molecule were developed. The three rapid-acting analogs (aspart, glulisine, lispro) are absorbed more quickly than regular insulin because of reduced self-association. Their onset of action is within 15 min after subcutaneous injection, and they have a faster and greater peak action. Insulin glargine, the first long-acting insulin analog to reach the market, was initially proclaimed to have the ideal “peakless,” nearly 24-h duration of action (13). However, these initial pharmacodynamic studies raised some criticism, and it should be concluded that there is no such thing as a “peakless” insulin preparation (12,14,15). Nevertheless, both long-acting insulin analogs (detemir and glargine) have a limited peak effect and a longer mean duration of action compared with NPH insulin (with glargine having a slightly longer action than detemir [13,16,17]).

It was expected that the rapid-acting and long-acting analogs, which more closely approximate physiological insulin secretion, would confer important clinical benefits (11). With respect to type 2 diabetes, the topic of this review, it is important to note that most patients with type 2 diabetes have residual endogenous insulin secretion in the context of insulin resistance. Therefore, the rationale for imitating the insulin secretion pattern of human physiology is less convincing than in type 1 diabetes. Indeed, in patients with type 2 diabetes, the rapid-acting analogs were not found to be superior to regular insulin in reducing A1C levels or rates of overall hypoglycemia (18). The clinical benefits of the long-acting insulin analogs compared with NPH insulin are limited to a reduction in (nocturnal) hypoglycemia (19).

WHEN SHOULD INSULIN THERAPY BE INITIATED?

Type 2 diabetes is a progressive disease, and thus, ultimately this question will arise for many of our patients. Unfortunately, there is no unequivocal answer, which was nicely illustrated by a recent interactive case vignette. The polling results demonstrated once again that the management of patients with type 2 diabetes uncontrolled by two oral glucose-lowering agents is controversial. Furthermore, the preferred treatment option was found to be related to the respondents''s findings need to be confirmed, and also for reasons of practicality and patients'' acceptance, three injections per day is the least attractive option for initiation of insulin therapy.

Although many are accustomed to initiation with biphasic insulin, we generally recommend the addition of once-daily basal insulin to oral therapy for several reasons. First, the lower A1C levels reached with biphasic insulin comes at the expense of increased risks of hypoglycemia and weight gain (32,42,43). Second, and as aforementioned, trials with systematic dose titration demonstrated that once-daily basal insulin achieves the currently recommended glycemic levels in many patients with type 2 diabetes (27,29). In this respect, it has frequently been argued that in patients with badly controlled hyperglycemia (e.g., A1C >8.5% at the start of insulin therapy), treatment with once-daily basal insulin alone would not attain glycemic goals (11,32,33). However, the LANMET study proved otherwise. In this clinical trial, A1C levels decreased from 9.1% at baseline to 7.1% with combination therapy of bedtime insulin glargine or NPH insulin and metformin (36). Finally, it seems likely that insulin initiation by means of one (basal) injection may also facilitate patients'' diurnal blood glucose profiles. When considering the profiles obtained with NPH insulin or long-acting insulin analog once daily, the effect appears to wane during the day, even in patients starting insulin therapy, i.e., with remaining endogenous insulin secretion (33,37,48). These patients could benefit from adding a second injection of basal insulin (48). However, in the context of declining endogenous insulin secretion, daytime hyperglycemia is usually related to elevated postprandial glucose levels, favoring the initiation of prandial or biphasic insulin.

Two recent studies established that in patients not achieving adequate glycemic control with once-daily basal insulin, basal-bolus therapy results in greater A1C reductions than biphasic insulin twice or thrice daily (49,50). However, when a more gradual intensification of insulin treatment is preferred, patients can be switched to biphasic insulin two, and subsequently three, times daily. The latter regimen has been shown to significantly improve A1C levels of patients previously treated with insulin glargine (50). Whether stepwise introduction of meal-time injections is as safe and effective as the rapid initiation of a full basal-bolus regimen is currently under investigation (51).

Finally, regarding the choice of prandial insulin, rapid-acting insulin analogs are not superior to regular insulin in reducing A1C levels or rates for overall and nocturnal hypoglycemia, despite improving postprandial control (18). In some studies, treatment with rapid-acting analogs was associated with fewer severe hypoglycemic episodes and improved treatment satisfaction (18), the latter probably being related to increased convenience because of injection immediately before meals. In conclusion, there is no compelling reason to overall favor rapid-acting insulin analogs over regular insulin in type 2 diabetes. Whereas in some countries the price of rapid-acting analogs has been lowered to the level of regular insulin, in others, it remains around twice as high (31).

Continuous subcutaneous insulin infusion

In patients with type 2 diabetes already using at least one daily insulin injection, the introduction of intensive insulin therapy with continuous subcutaneous insulin infusion resulted in comparable glycemic control, weight gain, and hypoglycemia risk as multiple daily injection therapy (52,53). Although continuous subcutaneous insulin infusion was associated with greater improvements in treatment satisfaction in one study (53), we recommend that its use be restricted to selected patients in experienced centers only.

DRAWBACKS OF INSULIN THERAPY

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Intensive glucose-lowering therapy inevitably results in an increased rate of hypoglycemia, which was once again confirmed in the recent ACCORD study with annualized rates of hypoglycemic episodes requiring medical assistance of 3.1 and 1.0% in the intensive and standard therapy groups, respectively (6). Iatrogenic hypoglycemia hampers tight glycemic control and is considered the limiting factor in diabetes management (54).

Opinions are divided on the extent of the problem, with cited event rates for severe hypoglycemia in insulin-treated type 2 diabetic patients ranging from between 1 and 3 (5) to between 10 and 73 per 100 patient-years (55). Of note, the relatively low rates were found in clinical trials (2,56), whereas the higher figures were reported in retrospective and population-based studies (5759). The difference is probably explained by varying durations of disease or insulin therapy in the cited studies. The risks of mild and severe hypoglycemia are low among type 2 diabetic patients just beginning insulin therapy (30) and appear to increase with increasing durations of diabetes and insulin treatment (5759).

To conclude, in type 2 diabetes, the frequency of hypoglycemia is generally lower than that in type 1 diabetes (54). This is presumably the result of relative protection of type 2 diabetic patients against hypoglycemia by residual endogenous (i.e., physiologically regulated) insulin and glucagon secretion, insulin resistance, and higher glycemic thresholds for counterregulatory and symptomatic responses to hypoglycemia (60,61). Therefore, when initiating insulin therapy, attempts to attain A1C goals should not be hampered too much by concerns about hypoglycemia. However, iatrogenic hypoglycemia appears to become a more frequent problem at the insulin-deficient stage of the disease, warranting more vigilance as the disease advances (54).

Weight gain

The ∼2- to 4-kg increase in body weight associated with insulin therapy has traditionally been explained by reductions of glucosuria and resting energy expenditure when glycemic control is improved (5,46). Other explanations are snacking to prevent, or in response to, hypoglycemia or restoration of the weight loss usually preceding insulin initiation to the weight before onset of diabetes. In contrast, a recent study found that the mean weight gain of 1.8 kg in 23 type 2 diabetic patients during the first 6 months of insulin therapy was not accompanied by a change in glucosuria, resting energy expenditure, or physical activity. The authors concluded that increased energy intake was the only plausible explanation for the observed weight increments (62). Although the mechanisms underlying insulin-associated weight gain are still not fully understood, it is thought to be proportional to the number of insulin injections, or the total daily insulin dose (32,45,46). Interestingly, when considering studies investigating basal insulin initiation in type 2 diabetes, we found no evidence for such a dose-response relationship (Fig. 1C).

Finally, when directly comparing the mean increases in body weight during insulin initiation with NPH insulin versus long-acting insulin analogs, insulin glargine is associated with similar weight gain (27,3537). Treatment with insulin detemir, on the other hand, appears to result in less weight gain than NPH insulin (28,33). However, considering the limited magnitude of the reported weight-sparing effect, we still recommend NPH insulin for the initiation of insulin therapy in patients with type 2 diabetes.

CONCLUSIONS

Although insulin has no upper dose limit and numerous trials established the 1 last update 29 May 2020 that glycemic goals can be attained by using adequate doses, in clinical practice, many patients experience years of uncontrolled hyperglycemia.Although insulin has no upper dose limit and numerous trials established that glycemic goals can be attained by using adequate doses, in clinical practice, many patients experience years of uncontrolled hyperglycemia.

Because most type 2 diabetic patients have residual endogenous insulin secretion, the rationale for imitating the physiological insulin secretion pattern is less convincing than in type 1 diabetes.

Glycemic treatment should be stepwise with swift introduction of successive interventions after treatment failure (i.e., A1C ≥7.0%). Insulin should be initiated when A1C is ≥7.0% after 2–3 months of dual oral therapy. The preferred regimen for insulin initiation in type 2 diabetes is once-daily basal insulin. In addition to timely initiation, rapid titration of the dose is indispensable for successful insulin therapy. Hypoglycemia risk is very low among type 2 diabetic patients just starting insulin therapy, making NPH insulin the most cost-effective drug.

When glycemic goals are not attained despite successful basal insulin dose titration (i.e., fasting plasma glucose ≤100 mg/dl), or when titration is limited by hypoglycemia, treatment should be intensified by addition of prandial or biphasic insulin.

Acknowledgments

S.G.S. is employed by the Department of Internal Medicine of the Academic Medical Center, partly through funding from Novo Nordisk and sanofi-aventis for the conduct of clinical trials. J.B.H. has received honoraria for consultancy work from Novartis the 1 last update 29 May 2020 and sanofi-aventis. J.H.D. has received honoraria for consultancy work as well as research funding from Novo Nordisk and sanofi-aventis.S.G.S. is employed by the Department of Internal Medicine of the Academic Medical Center, partly through funding from Novo Nordisk and sanofi-aventis for the conduct of clinical trials. J.B.H. has received honoraria for consultancy work from Novartis and sanofi-aventis. J.H.D. has received honoraria for consultancy work as well as research funding from Novo Nordisk and sanofi-aventis.

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Footnotes

The publication of this supplement was made possible in part by unrestricted educational grants from Eli Lilly, Ethicon Endo-Surgery, Generex Biotechnology, Hoffmann-La Roche, Johnson & Johnson, LifeScan, Medtronic, MSD, Novo Nordisk, Pfizer, sanofi-aventis, and WorldWIDE.

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