Achieving Glycaemic Targets in Type 2 Diabetes: the Role of the Basal Insulin Analogue Insulin Glargine and How to Use it in Clinical Practice: Moving from Evidence to Practice

This Article

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Article Information:


Group: 2008
Subgroup: Volume 6, Issue 1, Winter
Date: January 2008
Type: Review Article
Start Page: 38
End Page: 49

Authors:

  • MJ Davies
  • Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
  • J Jarvis
  • Diabetes Research,University Hospital of Leicester, Leicester, UK
  • K Khunti
  • Department of Cardiovascular Sciences, University of Leicester, Leicester, UK

      Correspondence:

      Affiliation: Diabetes Research,University Hospital of Leicester
      City, Province: Leicester,
      Country: UK
      Tel:
      Fax:
      E-mail: janet.jarvis@uhl-tr.nhs.ukja

Abstract:


This review examines the role of the basal insu-lin analogue, insulin glargine in the treatment of type 2 diabetes, focusing on how research evi-dence can inform its use in clinical practice. The importance of achieving optimal glycaemic con-trol has been emphasised by bodies such as the IDF who have set strict targets for HbA1c levels. We know that FPG plays an important role in helping to achieve optimal glycaemic control and basal insulin therapy can play a role in this area. Insulin glargine is a once-daily, peakless basal insulin which has been shown to achieve the same degree of glycaemic control as NPH insulin but with significantly reduced rates of hypogly-caemia. This allows patients to improve self management of their diabetes by optimising treatment without the risk of hypoglycaemia. Research has shown that patients can safely op-timise therapy with a patient-led titration algo-rithm based on an insulin dose adjustment of 2 units every 3 days. Initiation of insulin glargine has been shown to be effective within a group as well as individually, allowing health care pro-fessionals to manage their time more effectively between the growing numbers of people requir-ing insulin therapy. Conclusions: This basal insulin analogue is a welcome addition to the plethora of treatments available to treat type 2 diabetes and efficacy data can now be converted into practical meth-ods of optimising insulin therapy for the type of patients healthcare professionals routinely en-counter in their practice.

Keywords: Glycaemic control;Insulin ana-logues;Basal insulin;Insulin glargine

Manuscript Body:


Introduction

The 2005 Annual Meeting of the European Association for the Study of Diabetes (EASD) reignited the debate regarding what constitutes good glycaemic control. While the American Diabetes Association (ADA) recommend that people with diabetes aim for a HbA1c level <7.0%1, a global guideline for Type 2 diabetes compiled by the International Diabetes Federation (IDF), recommends a target level of <6.5%.2 This move mirrors the recommendations of the UK-based National Institute of Clinical Excellence (NICE), which set an HbA1c target for those with Type 2 diabetes of between 6.5% and 7.5%. The lower target is recommended for people at high risk of macrovascular complications, while the higher target should be set in cases where there is a risk of hypoglycaemia.3

Importance of tight glycaemic control

Data from the United Kingdom Prospective Diabetes Study (UKPDS) highlighted the importance of tight glycaemic control in reducing the risk of diabetes complications.4 This landmark study randomised 3,867 patients with Type 2 diabetes to receive intensive anti-hyperglycaemic therapy using sulphonylureas or insulin, or ‘conventional’ therapy (diet alone plus pharmacological therapy in the presence of hyperglycaemic symptoms, or fasting plasma glucose [FPG] >15mmol/l). Over 10 years, the mean HbA1c was 7.0% in the intensive group compared with 7.9% in the group receiving ‘conventional’ therapy. This improvement was associated with a 25% (p=0.0099) decrease in the risk of microvascular endpoints. Furthermore, the risk of myocardial infarction (MI) was reduced by 16%, although this observation was of borderline significance (p=0.052). A further report from the UKPDS demonstrated that each 1% reduction in HbA1c was associated with a 37% (p<0.0001) reduction in the risk of microvascular complications, and a 21% (p<0.0001) reduction in the risk of death related to diabetes.5 Subsequent reports from the UKPDS have found that the HbA1C was higher in those with fatal versus non-fatal MI (odds ratio 1.17 per 1% HbA1c, p=0.014) and in those with fatal versus non-fatal stroke (odds ratio 1.37 per 1% HbA1c; p=0.007).6

Current strategies fail to reach glycaemic goals

Despite this overwhelming evidence of benefit for tight glycaemic control, most patients with Type 2 diabetes fail to reach appropriate levels of HbA1c. The General Medical Services (GMS) contract for England and Wales includes a Quality and Outcome Framework (QOF) target for HbA1c of 7.4% or less.7 UK data from the National Diabetes Audit for 2004-2005 shows that only 58% of people with diabetes were meeting this standard8 which was little improvement from data in 2003/2004 which showed just 56% of those with diabetes had a HbA1c lower than 7.5%, while just 23% were achieving a HbA1c lower than 6.5%.9 Liebel et al reported that just 31% of 7,000 patients from eight European countries who were involved in the Cost of Diabetes in Europe - Type 2 (CODE-2) study had a HbA1c level ≤6.5%, and 42% had a HbA1c level above 7.5%.10These figures for Europe are mirrored in results from the US-based National Health and Nutrition Examination Survey (NHANES). The survey defined glycaemic control rates as the proportion of patients with Type 2 diabetes who achieve a HbA1c level <7.0%. During the period 1988–1994 this proportion was 44.5%, but this dropped to 35.8% for the period 1999–2000.11Data from a UK community care database suggested that a decline in glycaemic control was manifest even when there was a tangible improvement in other aspects of diabetes care, such as control of hypertension and dyslipidaemia.12 Approximately 500,000 patients, including 10,000 with Type 2 diabetes, were registered in each year of the study, between 1994 and 2001 and not surprisingly, the prevalence of Type 2 diabetes increased during the study (from 19 to 27/1,000 patients). Surprisingly, while the percentage of patients attaining appropriate cholesterol targets significantly increased (approximately 20% reaching <5.0 mmol/l in 1994, versus 46.2% in 2001; p<0.001), the percentage of those attaining good glycaemic control decreased (28.9% patients with a HbA1c <6.5 in 1997 versus 22.5% in 2001; p<0.001).
Interestingly, the NHANES data found that the use of insulin declined along with deteriorating glycaemic control.11 Indeed, many experts believe that a reluctance to use insulin, by both physician and patient, may contribute to poor levels of glycaemic control and that insulin should no longer be considered the anti-hyperglycaemic therapy of last resort, but should be considered in timely manner to ensure tight glycaemic control is maintained in the long term.13-16 This assertion was emphasised by the results of the UKPDS, which found that Type 2 diabetes was a progressive disease and that glycaemic control deteriorated over time regardless of the intensity of treatment.17, 18 The UKPDS showed that Type 2 diabetes required progressive therapy with agents that have complementary mechanisms of action and that many patients will require insulin treatment to maintain tight glycaemic control.

Despite a high level of endorsement, patients and practitioners are unwilling to intensify or initiate insulin therapy and often have misconceptions about the therapy. A report from the large, multi-national Diabetes Attitudes, Wishes and Needs (DAWN) survey, which included 2,061 patients with Type 2 diabetes and 3,790 diabetes care providers, found that patients generally rate the clinical efficacy of insulin as low and often attached much self-blame for having to initiate insulin therapy. Furthermore, 50-55% of diabetes care providers indicated that they delayed insulin therapy until absolutely necessary.19

In addition to the reluctance to use insulin, it is acknowledged that much remains to be learned about how to maximise the efficacy of insulin regimens. This was emphasised by a recent US Department of Veteran’s Affairs registry study of 6,222 adults with Type 2 diabetes. Although those patients prescribed insulin used 77% of their dose (indicating a high willingness to adhere to therapy), the mean HbA1c level was only 7.98±1.66%. The authors concluded that the rate of insulin use, the prescribed regimen, or both, may be inadequate to achieve good glycaemic control in patients with long-term insulin use.20

A further issue that may limit the wider use of insulin is the perceived need for hospital based healthcare professionals to guide the initiation of insulin therapy.21 This is despite the fact that most of the routine management of Type 2 diabetes now occurs in the community setting,22 a burden which can only increase as the prevalence of Type 2 diabetes continues to rise.

There is clearly a need to refine the way insulin is used in the management of Type 2 diabetes and this review examines the potential of the first available basal insulin analogue, insulin glargine, to address some of these issues and increase the probability of achieving the elusive glycaemic control targets. Insulin glargine has now been available for 5 years. Over this time much evidence has accumulated of its role, particularly in the management of Type 2 diabetes.

Role of insulin versus oral antidiabetes therapy

Perceived patient barriers, such as needle phobia or, as discussed above, the sense of self-blame, have led researchers to look for alternatives to the initiation of insulin. One of these alternatives is use of a combination of three oral agents (metformin plus sulphonylurea plus glitazone). Schwartz et al reported that a combination of insulin 70/30 mix plus metformin was as effective as, and better tolerated than, triple oral therapy.23 Furthermore, a study by Rosenstock et al compared the addition of rosiglitazone or insulin glargine in patients inadequately controlled on a combination of sulphonylurea and metformin.24 This randomised trial, which included 217 patients, found that HbA1c levels were lowered by similar amounts in both groups (-1.7±0.1% vs -1.5±0.1 for insulin glargine and rosiglitazone, respectively). However, insulin glargine was associated with a greater reduction in FPG (-3.6±0.2 mmol/l vs 2.5±0.2 mmol/l; p0.001) and a much lower drop-out rate (8% vs 19%; p=0.005) compared with rosiglitazone. Additionally, rosiglitazone was associated with a less favourable lipid profile, more adverse events (including oedema), and significantly more weight gain compared with the insulin glargine group (+1.6±0.4 kg vs 3.0±0.4 kg, p=0.02).24

With consideration given to clinical safety25 early introduction of a glitazone may be a way of avoiding the initiation of insulin if results from the Prospective pioglitAzone Clinical Trial in MacroVascular Events (PROactive) trial can be verified. This trial randomised 5,238 patients with Type 2 diabetes and evidence of macrovascular disease to receive either pioglitazone (titrated from 15-45mg) or placebo, in addition to their existing anti-diabetes regimen. In fact, approximately 33% of patients in the PROactive trial were on a regimen containing insulin plus pioglitazone. The use of glitazones plus insulin in this way reflects the latest thinking on glycaemic control, which is to progressively use dual and triple combinations of complementary antidiabetes therapies to reach appropriate glycaemic targets.

After a mean duration of follow-up of 34.5 months, pioglitazone reduced the risk of the composite secondary endpoint (all-cause mortality, non-fatal MI and stroke) by 16% (hazard ratio [HR] 0.84, 95% confidence interval [CI] 0.72-0.98; p=0.027). Furthermore, pioglitazone was associated with a 53% reduction in the risk of progression to permanent insulin use (HR 0.47, 95% CI 0.39-0.56; p<0.0001).26 However, the authors point out that this risk reduction may be partly explained by the increased use of insulin in the control arm, as a glitazone would not have been an option for patients with deteriorating glycaemic control.

While these results are encouraging, there is concern that agents of this class can cause oedema and increase the risk of congestive heart failure, especially when used in combination with other oral agents and insulin.27,28 Indeed, other experts have suggested that the benefits on cardiovascular events achieved by pioglitazone may be offset by the increased incidence of oedema, heart failure and degree of weight gain observed in the study (mean 3.6 kg) associated with this therapy.29 Therefore, insulin therapy remains a safe and effective means of maintaining tight glycaemic control in the long term in many patients with Type 2 diabetes.

Insulin analogues – a more physiological approach to insulin therapy

To maximise the effectiveness of insulin regimens, a balance between tight glycaemic control and the risk of hypoglycaemia is essential. It is known that episodes of hypoglycaemia can be as frequent in people with Type 2 diabetes treated with insulin as in those with Type 1 diabetes if matched for duration of disease and insulin therapy.30 Furthermore, it is established that fear of hypoglycaemia is a key barrier to initiating insulin therapy,13,19 and the DAWN study showed that it was not only those with Type 1 diabetes (48%) who feared hypoglycaemic episodes but also those with Type 2 (39%).31

Until recently, insulin formulations have been limited in their ability to mimic physiological insulin release. For example, regular human insulin (RHI), which is used to control prandial glycaemia, must be administered up to 45 minutes before a meal and has an inappropriately long duration of action. In contrast, neutral protamine Hagedorn (NPH) insulin, which is commonly used to supplement basal insulin requirements in those with Type 2 diabetes, has an undesirable peak of activity that can increase the risk of nocturnal hypoglycaemia and an inadequate duration of action that limits its ability to fully supplement basal insulin over a 24-hour period.32

These limitations led to the development of insulin analogues with pharmacokinetics and pharmacodynamics tailored to mimic either prandial or basal insulin delivery in a more physiological manner. For example, rapid-acting analogues are absorbed more quickly than RHI and have a much shorter duration of action.32

Two long-acting insulin analogues, insulin detemir and insulin glargine, are now available. There is now sufficient data available to assess the ability of insulin glargine to improve insulin regimens and facilitate the safe achievement of glycaemic goals. The remainder of this review assesses evidence for insulin glargine, and the practice implication of the evidence for using insulin glargine in clinical practice in Type 2 diabetes.

Broad approach to insulin therapy and the role of insulin glargine

A number of options exist for insulin contain ing regimens to treat patients with Type 2 diabetes. As discussed above, both insulin glargine and pre-mixed insulins can improve glycaemic control in those with suboptimal control on oral agents alone. As discussed below, NPH is also effective when used in this manner.33,34 An ‘intensive’ regimen of covering fasting and postprandial glycaemia using a basal-bolus regimen is also an option.

Another option is the use of prandial insulin injections, with short or rapid-acting insulin being administered three times daily, before meals. However, Queale et al reported that the use of such a regimen, in the absence of basal supplementation, increases the risk of poor glucose control.35

The important question of the efficacy of pre-mixed versus basal versus prandial insulin regimens is being addressed by the current Treat-to-Target Trial (T4).36 This ongoing trial recruited 708 patients with Type 2 diabetes who were poorly controlled on oral agents. Patients were randomised to receive one of three treatments: Biphasic insulin aspart twice daily, Prandial insulin aspart three times daily or Basal insulin detemir once daily (twice daily if required).

At one year HbA1c levels were similar in the biphasic (7.3%) and prandial (7.2%) (p=0.08) groups but higher in the basal group (7.6%, p<0.001 for both comparisons), however lower rates of hypoglycaemia and weight gain were seen in the basal group. The authors concluded that the basal insulin analogue detemir added to metformin and sulphonylurea was insufficient to optimise HbA1c in the majority of patients, suggesting that the majority of patients receiving this regimen will require more than one type of insulin to achieve optimal glycaemic targets. The final two years of this study will examine complex insulin regimens in this group of patients and the 3 year results are planned to report in 2009.

Basal only insulin regimens have become more popular since the introduction of basal insulin analogues. Evidence suggests that fasting, rather than postprandial glycaemia, plays the major role on overall glycaemia when glucose control is poor.37 Therefore, while postprandial glycaemia is an important consideration in all patients with diabetes, the use of basal insulin to address fasting glucose levels is likely to be a valuable tool for many of the diabetes patients encountered in primary care. The attributes of insulin glargine that make it an attractive option for basal insulin therapy include a duration of action that allows once-daily injection for most patients, and a peakless time-activity profile38,39 and a lower risk of hypoglycaemia than NPH insulin.40

Janka et al compared the addition of insulin glargine to metformin and sulphonylurea therapy with discontinuation of oral agents and the initiation of twice-daily pre-mix 70/30 insulin, in a 24-week trial of 742 insulin-naïve people with Type 2 diabetes.41 At study end, HbA1c had reduced more substantially (-1.64 vs -1.31; p=0.0003) and more patients reached a HbA1c of ≤7.0% without confirmed nocturnal hypoglycaemia (4.5.5 vs 28.6%; p=0.0013) with oral agents and insulin glargine, compared with the pre-mix regimen one. A second 28-week study compared the addition of twice-daily pre-mix 70/30 insulin or once-daily insulin glargine to metformin in 209 insulin-naïve patients. In this study, unlike the previous one, MF was compared in the premix arm and the premix included short-acting insulin analogue. Significant HbA1c reductions were seen in both arms, but were greater in the pre-mix than the insulin glargine arm (-2.79±0.11 vs -2.36±0.11%, p<0.01). However, weight gain was significantly greater in the pre-mix versus insulin glargine group (5.4±4.8 vs 3.5±4.5 kg, p<0.01) as was the rate of minor hypoglycaemia (3.4±6.6 vs 0.7±2.0 episodes/year, p<0.05).42

These two latter studies demonstrate the fine balancing act and individualistic approach that must be employed when initiating insulin therapy. Both regimens were shown to be effective. Insulin glargine, in addition to oral agents, was very effective in lowering HbA1c, however adding pre-mix insulin was also very effective but was associated with an increased risk of minor hypoglycaemia and additional weight gain.

Insulin glargine in Type 2 diabetes – achieving targets while reducing hypoglycaemia

The concept of triple therapy, discussed earlier, represents a new focus in treating Type 2 diabetes, as it makes treating-to-target possible. The ability of insulin glargine to improve glycaemic control in people with Type 2 diabetes who are failing on oral antidiabetes therapy, was assessed by Riddle et al in the Treat-to-Target trial. This 24-week trial randomised 756 patients (over 80% of whom were failing on dual oral antidiabetes therapy), to receive insulin glargine or NPH insulin in addition to pre-existing regimen.33 The study involved systematically titrating bedtime insulin to achieve a HbA1c level of <7.0%, a target that was achieved by 60% of patients in each group. However, nearly 25% more patients in the insulin glargine group achieved this level of control without experiencing an episode of documented nocturnal hypoglycaemia (≤4.0 mmol/l) compared with NPH insulin (33.2% vs 26.7%; p<0.05).

This ability to improve glycaemia without increasing the risk of hypoglycaemia was also demonstrated in a year-long trial of similar design.34 In this case, 426 people with Type 2 diabetes poorly controlled on oral agents were randomised to receive bedtime insulin glargine or bedtime NPH insulin. HbA1c was reduced by a similar amount in both groups (9.1±0.1 to 8.34±0.09 and 8.9±0.1 to 8.24±0.09 for insulin glargine and NPH insulin, respectively; p<0.001 for both observations). However, there was less hypoglycaemia and in particular, nocturnal hypoglycaemia, with insulin glargine than NPH insulin (Fig. 1). Furthermore, postprandial hyperglycaemia was better controlled with insulin glargine than NPH insulin (post-dinner glucose concentrations 9.9±0.2 vs 10.7±0.3 mmol/L; p<0.02).

 

 

Fig. 1. Percentage of patients treated with insulin glargine or NPH insulin with symptomatic hyperglycaemia34

 

A meta-analysis encompassing these and two other trials, further supports the assertion that insulin glargine reduces the risk of hypoglycaemia.40 The study included 1,142 patients treated with insulin glargine and 1,162 patients treated with NPH insulin. Compared with NPH insulin, insulin glargine reduced the risk of overall symptomatic hypoglycaemia by 11% (p=0.0006) and nocturnal hypoglycaemia by 26% (p<0.0001). Importantly, the risk of severe hypoglycaemia and severe nocturnal hypoglycaemia were reduced by 46% (p=0.0442) and 59% (p=0.0231), respectively (Table 1).

Table 1. Percentage of patients reporting one or more hypoglycaemic episodes and degree of risk reduction
achieved with insulin glargine versus NPH insulin4

Type of documented
symptomatic hypoglycaemia
Insulin glargine
(% of patients)
NPH insulin (%
of patients)
% risk reduction
(where significant)
P value
Overall   
54.2 61.2 11 0.0006
Nocturnal 28.4  
28.4 38.2 26 <0.0001
Non-nocturnal 
49.6 51.7 - -
 Severe   
1.4
2.6
46
0.0442
 Severe nocturnal 0.7 1.7 
0.7 1.7 59
0.0231
 Severe non-nocturnal 
0.8
0.9
 -  -

Advantages of insulin glargine in perspective

NICE recommends insulin glargine for Type 1 diabetes patients and for certain patients with Type 2 diabetes, including those who require assistance from a carer or healthcare professional to administer insulin and those whose life is restricted by recurrent episodes of symptomatic hypoglycaemia.43,44

A major advantage of insulin glargine is the fact that most patients will only require a once-daily injection to provide basal insulin requirements. In fact, the Treat-to-Target trial showed that both insulin glargine and NPH insulin can improve glycaemic control with a once-daily regimen.33 In these situations, titration becomes easier as the dose can be adjusted according to a single blood measurement taken in the morning. The simplicity of this regimen facilitates its management in the community setting and is an easy concept to discuss in groups of patients initiating insulin. These are important considerations as the burden of routine care for diabetes patients moves from being hospitals based. Furthermore, insulin glargine based therapy can be safely and effectively initialised in sub-optimally controlled subjects with Type 2 diabetes in both hospitals and in the community setting.45

A study involving 120 individuals with poor glucose control despite treatment with maximal doses of oral agents has provided evidence that a group education strategy is effective for the initiation of insulin. In this study, patients were randomised to receive education on an individual basis, or in groups of 4–8 patients.46 The education programme comprised visits before initiation of insulin glargine and at 0, 6, 12 and 24 weeks after initiation. Regular phone calls, preceded by electronic transfer of fasting glucose values, were also carried out to encourage self-adjustment of the insulin dose. The algorithm involved adjusting the dose of insulin glargine by 2 insulin units (IU) every 3 days to reach a fasting glucose of 5.5 mmol/L.

While patients had an average HbA1C level of approximately 8.8% at baseline, both groups were below 7.0% at 24 weeks (6.9±0.1% and 6.8±0.1% for individual and group education, respectively) and levels of symptomatic hypoglycaemia were similar in both groups (3.1 episodes per patient for both groups). Treatment satisfaction was also equal in both groups. Importantly, the total time spent by healthcare professionals addressing diabetes cares was reduced by 49% with group education.46

As well as being a simple regimen, the initiation of insulin therapy with insulin glargine may have other benefits. The initiation of insulin glargine or NPH insulin in combination with metformin was compared in the LANMET study.47 This 36-week study involved 110 insulin-naive type 2 diabetes patients with poor glycaemic control on oral agents. Patients were taught to self-adjust their insulin dose to achieve FPG levels of 4.0–5.5 mmol/l. During the last 12 weeks, FPG levels were 5.75±0.02 versus 5.96±0.03 mmol/l (p<0.001) in the insulin glargine and NPH insulin groups, respectively. The corresponding insulin doses and HbA1C levels were 68±5 versus 70±6 IU/day (p=NS) and 7.14±0.12 versus 7.16±0.14% (p=NS), respectively. While good glycaemic control was achieved with both types of insulin, the incidence of symptomatic hypoglycaemia was significantly lower during the first 12 weeks in the insulin glargine group than in the NPH insulin group (4.1±0.8 versus 9.0±2.3 episodes/patient-year, p<0.05). Furthermore, better control of postprandial glucose was achieved with insulin glargine (8.6±0.3 versus 10.1±0.3 mmol/l, p=0.002).

Optimising insulin glargine regimens

One area of diabetes management that has received little attention is insulin dose titration. Indeed, optimizing the titration algorithm is

likely to facilitate the long-term acceptance of insulin therapy for many patients. Two approaches to titration of basal insulin analogues have been reported in the literature that have both been effective, but differ in terms of initiation dose, titration algorithm and extent of patients self-management in the titration process.48-50 The AT.LANTUS study is one of the largest prospective studies in Type 2 diabetes and its primary aim was to compare the effects of these different titration strategies in more general clinical practice.51

This multicentre, multinational, open-label, 24-week trial included 4,961 patients with Type 2 diabetes who were poorly controlled with any oral and/or insulin therapy. These patients were switched to insulin glargine plus oral therapy or to insulin glargine plus prandial insulin and randomised to one of two initiation/maintenance algorithms (Table 2).

Table 2. Design of the AT.LANTUS study51

Algorithm 1
(n=2493)
Algorithm 2
(n=2468)
Physicians-led insulin dose titration
Insulin doses adjusted on a weekly basis during
practice visits or through telephone contact
Patients self-adjusted insulin dose Insulin dosage self-adjusted every three daysDose adjustments reviewed at clinical visits or over
the telephone

Target FPG ≤5.5 mmol/l. Insulin glargine was administered once daily at bedtime. The starting dose for insulin-naïve
subjects was 10 IU/day for algorithm 1. For algorithm 2, the dose was numerically equivalent to the highest FPG value in millimols per litre over the previous 7 days. In those switching from once-daily intermediate- or long-acting insulin to insulin glargine, an equivalent dose was recommended. For those switching from twice-daily NPH, a reduction by 20–30% from the total NPH dose was recommended.


HbA1c levels were reduced by >1% in both arms, despite 72% of participants already being on insulin at baseline. However, the patient-led algorithm (Algorithm 2) was associated with a significantly greater improvement in glycaemic control at study end, with HbA1c being lowered to a significantly greater degree in algorithm 2 versus algorithm 1 (–1.22% vs. –1.08%; p<0.001). Furthermore, fasting blood glucose (FBG) levels were lowered to a significantly greater degree in algorithm 2 versus algorithm 1 (–3.4 vs. 3.1, p<0.001 and Figure 1). Importantly, although glycaemic control was improved to a greater degree with algorithm 2, the incidence of severe hypoglycaemia was similar between arms (0.9% and 1.1% for algorithm 1 and algorithm 2, respectively). Both algorithms were associated with a low incidence of hypoglycaemia, although rates of overall (29.8% vs. 33.3%; p<0.01), symptomatic (26.3% vs. 29.7%, p<0.05) and nocturnal (3.2% vs. 4.1%, p<0.05) hypoglycaemia were lower in algorithm 1 versus algorithm.2 In addition, improvements in glycaemic control were achieved with only marginal mean increases in body weight (+1.0 kg and +1.3 kg in algorithm 1 and algorithm 2, respectively). Figure 2 shows how individuals using algorithm 2 intensified their treatment to a greater degree than those in algorithm 1, resulting in significantly greater reductions in fasting blood glucose (FBG) (Fig. 2).

 

Fig. 2. Mean decrease in FBG throughout the study compared with mean insulin glargine dose (IU) in the AT.LANTUS study51

Although this study was limited by the absence of a control group, the results indicate that patients with Type 2 diabetes can safely and effectively be involved in the management of their disease. Not only does this increase patient empowerment, but also has the potential to reduce the burden on healthcare professionals.

 Ensuring optimal control – adding prandial to basal insulin

While a single dose of insulin glargine will effectively control glycaemia in some patients, evidence suggests that in others basal insulin alone will not be sufficient to improve or maintain glycaemia to acceptable levels. Monnier pooled evidence from six studies to show that for people below a baseline HbA1c of 9%, good glycaemic control (HbA1c <7%) can be achieved by titrating basal insulin up to 0.5U/kg body weight/day.52 However, for those above the HbA1c 9% threshold, further increments in basal insulin cause less improvement in glycaemic control. (Fig. 3)

 

Fig. 3. Relationship between insulin doses (unit/kg bodyweight/day) and decrements in HbA1c52

 

 

It is essential that patients are up-titrated to an adequate level of basal insulin. Although the upper limit of this titration is open to debate, and needs further explorations, doses of 0.5–0.7 U/kg body weight/day may be required. If, at this point, HbA1C and FPG levels rise or cannot be brought into line with targets, then prandial insulin may be added, although the exact timings and optimal methods of introducing prandial insulin therapy remain to be defined.

Conclusions

The quest for effective pharmacotherapy to achieve tight glycaemic control continues and the stricter glycaemic goals recommended by the IDF emphasie the need to achieve these. Evidence suggests that fasting glucose levels play a primary role in overall glycaemia when glucose control is poor. The ability of basal insulin therapy to effectively address fasting glucose levels means that this therapy is likely to occupy an increasingly important role as a tool to improve and maintain tight glycaemic control in people with Type 2 diabetes. Insulin glargine fulfils much of the requirements for a once-daily, peakless basal insulin and clinical trials have demonstrated that insulin glargine achieves the same degree of glycaemic control as NPH insulin with significantly reduced rates of hypoglycaemia.

Studies such as AT.LANTUS have demonstrated that low rates of hypoglycaemia allow patients to improve their self-management; glycaemic control can, therefore, be safely improved using a simple patient-led titration algorithm based on an insulin dose adjustment of 2 units every 3 days. However, it is important that titration to adequate insulin dose (often 0.5-0.7

units per kg) is achieved. Furthermore, evidence that group initiation of insulin therapy is as effective as individual patient education and may help manage the ever-increasing burden of diabetes. These studies allow the conversion of the evidence of the clinical efficacy of insulin glargine into practical methods of optimising insulin therapy for the type of patients healthcare professionals routinely encounter.

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