The background of diabetes mellitus

Introduction:

Diabetes mellitus is a metabolic disorder resulting from a defect in insulin secretion, insulin action, or both. A consequence of this is chronic hyperglycaemia (i.e. elevated levels of plasma glucose) with disturbances of carbohydrate, fat and protein metabolism. Long-term complications of diabetes mellitus include retinopathy, nephropathy, neuropathy, and increased risk of cardiovascular disease.

The prevalence of type 1diabetes has been quoted in literature as being 1 in every 300 children (Timoty et al) to 1 in 500 (NICE guidelines). It is one of the most common chronic condition affecting our children.

Type 1 diabetes mellitus is characterised by a progressive destruction of pancreatic beta cells, which leads to insulin deficiency and overt diabetes. The goals of therapy for type 1 diabetic patients are to eliminate the symptoms of hyperglycaemia, reduce the long term micro-vascular and macro-vascular complications and allow the patients to achieve a normal life-style.

The care of a type 1 diabetic patient requires, among other things, ongoing insulin replacement therapy. Various insulin regimens are available to match glucose intake and insulin requirements, and the right regimen for an individual patient should be tailored according to patient’s glycaemic status and patients’ needs. In most regimens, basal insulin replacement is achieved via intermediate or long acting insulin, with supplemental short acting insulin bolus injections during meals.

The Diabetic Control and Complications Trial (DCCT) demonstrated that “intensive” insulin therapy for patients with type 1 diabetes mellitus (T1DM) was associated with significantly improved glycemic control and decreased rates of co-morbidities such as retinopathy, nephropathy, and peripheral neuropathy1. Even marginal improvements in glycemic control are now known to be associated with reductions in microvascular complications.

Over the past several years, the definition of intensive therapy has changed as new insulin analogs have become available. The normal pancreas secretes a relatively constant basal amount of insulin into the circulation between meals and then responds to the ingestion of a meal by secreting a larger bolus of insulin to maintain euglycemia.

Long-acting insulin analogs such as insulin Glargine, paired with rapid-acting insulin analogs (RAIAs) (Lispro, Aspart, or Glulisine), allow subcutaneous insulin regimens to approximate normal endogenous secretory patterns more closely. The efficacy of such “basal-bolus” combinations, compared with more-traditional insulin regimens, has been studied extensively. Insulin glargine, paired with a RAIA, is at least as effective in maintaining glycemic control in children with T1DM as are more-conventional regimens using a combination of an intermediate-acting insulin (such as neutral protamine Hagedorn [NPH], levels of which peak _6 hours after injection) with the RAIAs mentioned above2.

Most studies have suggested equal efficacy with respect to glycemic control3-11, with significantly reduced rates of hypoglycemia for patients treated with basal-bolus regimens, whereas a few studies have suggested improved glycemic control in selected subpopulations12-16.

The subsequent Epidemiology of Diabetes Interventions and Complications Study (EDIC), an observational study that continues to follow the patients previously enrolled in the DCCT, demonstrates that benefit has continued since the DCCT trial ended in 1993.5  Not only do benefits include continued reductions in the rates of microvascular complications, additionally significant differences in cardiovascular events and overall mortality emerged. These benefits occurred in spite of the fact that subjects in the intensively treated group and those in the standard treatment group maintained similar A1C levels (approximately 8%) starting one year after the formal trial ended. Therefore, it is postulated that a “metabolic memory” exists, and that better early glycemic control sets the stage for outcomes many years in the future.

Although tight glycemic control is beneficial, an increased risk of severe hypoglycemia accompanies lower blood glucose levels. For many, the A1C target should be <7%, with pre-meal blood glucose level of 80-130 mg/dL. However, targets should be individualized. Individuals with recurrent episodes of severe hypoglycemia, CVD, advanced complications, substance abuse, or untreated mental illness may require higher targets, such as an A1c of <8% and preprandial glucose levels of 100-150 mg/dL.

Background:

Type-1 Diabetes has been conventionally managed by twice daily insulin. While this is convenient from administration point of view, the level of insulin achieved was not physiological, owing to the characteristics of the types of insulin used, and sometimes pose difficulty in food habit and exercise pattern especially in a young child. Rapid-acting analogue insulin, on the other hand, is more physiological, and can be better suited for the patient’s needs as well as food habits.

Glucose control in UK children with diabetes is below the EU average, as shown in several multicentre studies over the last 10 years. There are many reasons, from social factors such as high divorce rate in the UK, more single-parent families and more isolation. Medical causes include undue reliance on twice-daily premixed insulins, reluctant acceptance of poor HbA1c levels by some UK paediatricians and parents. Unfortunately, the long-term effects on shortened life expectancy, cardiovascular disease, blindness and renal failure mean that poor glucose control is no longer acceptable.

Current practice:

Children and young people with suspected type 1 diabetes should be offered immediate (same day) referral to a multidisciplinary paediatric diabetes care team that has the competencies needed to confirm diagnosis and to provide immediate care.

At the time of diagnosis, children and young people with type 1 diabetes should be offered home-based or inpatient management according to clinical need, family circumstances and wishes, and residential proximity to inpatient services. Home-based care with support from the local paediatric diabetes care team (including 24-hour telephone access to advice) is safe and as effective as inpatient initial management1

Target glucose levels

The fact that chronic hyperglycemia is associated with an increased risk of microvascular complications of type 1 diabetes was demonstrated in the Diabetes Control and Complications Trial (DCCT)4.

 In that trial, intensive therapy designed to maintain normal blood glucose levels greatly reduced the development and progression of retinopathy, micro-albuminuria, proteinuria, and neuropathy, as assessed over the period of 7 years.

The subsequent Epidemiology of Diabetes Interventions and Complications Study (EDIC), an observational study that continues to follow the patients previously enrolled in the DCCT, demonstrates that benefit has continued since the DCCT trial ended in 1993.5  Not only do benefits include continued reductions in the rates of microvascular complications, additionally significant differences in cardiovascular events and overall mortality emerged. These benefits occurred in spite of the fact that subjects in the intensively treated group and those in the standard treatment group maintained similar A1C levels (approximately 8%) starting one year after the formal trial ended. Therefore, it is postulated that a “metabolic memory” exists, and that better early glycemic control sets the stage for outcomes many years in the future.

Although tight glycemic control is beneficial, an increased risk of severe hypoglycemia accompanies lower blood glucose levels. For many, the A1C target should be <7%, with pre-meal blood glucose level of 80-130 mg/dL. However, targets should be individualized. Individuals with recurrent episodes of severe hypoglycemia, CVD, advanced complications, substance abuse, or untreated mental illness may require higher targets, such as an A1c of <8% and preprandial glucose levels of 100-150 mg/dL.

Self-monitoring of glucose levels

Optimal diabetic control requires frequent self-monitoring of blood glucose levels. Frequent monitoring allows for rational adjustments in insulin doses. Most patients with type 1 diabetes require 2 or more injections of insulin daily with doses adjusted based on self-monitoring of blood glucose levels. In general, individuals with type 1 diabetes should test a minimum of 4 times per day-before each meal and at bedtime.

Subcutaneous continuous glucose sensors are now available, making the continuous glucose monitor (CGM) possible. These devices measure interstitial glucose levels every 1-5 minutes, providing alarms when glucose levels are too high or too low or are rapidly rising or falling.

CGM transmits to a receiver, which is either a pager like device or is integral to an insulin pump. Looking at the continuous glucose graph and responding to the alarms can help patients avoid serious hyperglycaemia or hypoglycaemia.

Several drawbacks exist:

First, there is a lag between glucose levels in the interstitial space and capillary blood, so the levels recorded by the CGM may differ from a finger stick glucose.

For that reason, the trends tend to be more helpful. Second, patients may over treat hyperglycaemia (repeatedly giving insulin because the glucose levels do not fall rapidly enough-a phenomenon known as stacking) as well as over treat lows (the glucose levels rise slowly with ingestion of carbohydrate).

Patients using CGM and/or insulin pumps can often provide very detailed information as to their insulin regimens as well as recent alterations in blood glucose levels.

Monitoring glycaemic control:

Children and young people with type 1 diabetes and their families should be informed that the target for long-term glycaemic control is an HbA1c level of less than 7.5% without frequent disabling hypoglycaemia and that their care package should be designed to attempt to achieve this.

Children and young people with type 1 diabetes and their families should be encouraged to perform frequent blood glucose monitoring as part of a continuing package of care

that includes dietary management, continued education and regular contact with their diabetes care teams.

Diabetic service at our trust:

In our own trust, we have a shifted from the traditional twice a day approach to multidose regime. Over the last 18 months, overwhelming majority of our patients have been shifted to this regime (46 out of 58). In the remainder, we have not been successful, owing wide range of causes, one of the main being patient choice.

The average HbA1C of children on multi dose regime was 8.2 while that on twice a day was 9.6.

3 of those 12 children have shown at least one complication including, hyper cholestrenemia and microalbuminuria in 3, Diabetic retinopathy changes in 2 and necrobiosis lipodica in one child.

We have further developed for all our children

An out patient checklist pro forma

An individualised spreadsheet,

glucose diary,

an individualized insulin dose schedule.

A sample of the copy of pro forma looks like:

The key message here is that we need to intensify diabetes treatment in the UK to bring it up to the levels of the best European centres. This will be achieved only by the wholehearted acceptance of this approach by paediatric diabetes teams, and willingness of children and families to invest time and energy into learning and implementing more complex insulin-adjustment regimens.

We are now encouraging all newly diagnosed diabetic children to start on multi dose regime from the beginning. We have developed proforma for the diabetic clinic to emphasise the importance of regular investigations and screening procedures in the prevention of complications. We will re-audit in a years time to complete the audit cycle and to improve the HbA1C levels in our children.

Review of literature:

Multidose insulin regime has been in use for the last 2 decades, and progessvely many countries have switched over to this regime from a conventional 2 dose insulin.

There is vast amount of literature available on the importance/ advantages and benefits of using multi dose regime.

On reviewing the international literature, numerous documents have given clear guidelines to assist management pathway. These documents have highlighted various aspects of the multidose regimes.

DCCT trial:

Frank Macdonald RN et al performed a multicentre prospective randomised clinical trial.

DCCT trial was a landmark trial based on 1441 volunteers over a period of 10 years( 1983-1993). The study showed the importance of keeping glucose levels as close to normal ( physiological levels). This study was conducted over 29 medical centres based in USA and Canada.

Multicentre studies over the last two decades have shown that MDI are better than twice a day insulin regimes. The main issues with twice daily insulin injections were having high HbA1C levels, which in turn led to long term complications:

There was early development of hyper cholestrenemia, diabetic retinopathy, micro vascular renal disorder and peripheral neuropathy.

The second main issue with twice a day insulin regime was children’s lifestyle had to be quite rigid since they had to wake up every morning to have their insulin, have their breakfast, then have a mid day snack, later lunch, post lunch snack, tea with their evening insulin and later another snack before going to bed. This also led to obesity, over weight and other complications associated with it.

Given the need for sticking to a rigid diet, which often was not possible, lead to fluctuating intake, leading to a fluctuating glucose levels.

With the multiple daily regime, the child is noted to have better quality of flexible lifestyle, the insulin and glucose control is more physiological. Their diet can be more variable, no need to snack in-between meals, less long term complications and better control of HbA1C noted.

The only drawback of multidose regime is the need for constant monitoring of glucose level and the need for giving multiple injections per day.

With twice daily regime the child has to run behind the insulin, whereas in multiple daily dosing the insulin runs behind the child.

Intermediate acting versus long acting insulin for type 1 diabetes mellitus

In 2008, Vardi M, et al have reviewed intermediate versus long acting insulin’s.

The objective was to assess the effects of intermediate acting versus long acting insulin preparations for basal insulin replacement in type 1 diabetic patients.

Twenty-three randomised controlled trials were identified. A total of 3872 and 2915 participants in the intervention and in the control group, respectively, were analysed. Trials duration was no longer than one year. The level of glycosylated haemoglobin, a marker of diabetes control, was lower in the long acting insulin group, but the observed difference was of doubtful clinical significance. Longer acting insulins were superior mostly in their nocturnal effect, which resulted in a lower level of fasting glucose levels and fewer episodes of nocturnal hypoglycaemia. No data on long term complications were available.

Continuous glucose monitoring-guided insulin adjustment in children and adolescents on near-physiological insulin regimens:

In 2006, a landmark study by Yates et al ( American diabetes association), assessed the importance of continuous glucose monitoring to achieve near physiological glucose levels.

A randomized control trail of 36 subjects were done on the basis of 72hrs of CGMS every 3 weeks or intermittent self-monitoring of blood glucose (SMBG) for 3 months. HbA1C and fructosamine were measured at baseline, 6 and 12 weeks and followed up at 6 months.

It was concluded that CGMS was no more useful then intermittent fingerstick SMBG in improving diabetic control in reasonably well controlled diabetic patients in outpatient clinical setting.

Predictors of Insulin Regimens and Impact on Outcomes in Youth with Type 1 Diabetes: The SEARCH for Diabetes in Youth Study

In a study in 2009 by Carolyn et al, impact of different insulin regimes and thier outcomes were analysed.

The objective was to explore factors related to insulin regimen and to describe the association between insulin regime and clinical outcome, particularly glycemic control.

A total of 2743 youths diagnosed with Type 1 DM participated in an observational based study conducted at 6 centres in the United States. Data collected during the study included clinical and socio-demographic information, body mass index, laboratory measures and insulin regimen.

The results suggested that children with type 1 DM may have better long term outcome if treated with more intensive insulin regimes and encouraged to monitor blood glucose levels more frequently.

Institution of Basal-Bolus Therapy at Diagnosis for Children With Type 1 Diabetes Mellitus.

Soumya Adhikari et al, researched the instituion of basal bolus therapy.

The objective was to note whether institution of basal bolus therapy immediately after diagnoses improved glycemic control in the 1st year after diagnoses in children type 1 DM.

They reviewed 459 children aged 6yrs who were diagnosed with Type 1 DM between 1st July 2002 and 30th June 2006. 212 treated with basal bolus therapy and 247 treated with more conventional neutral protamine Hagedom regime.

It was noted that glargine treated subjects had a lower HbA1c levels at 3, 6, 9 and 12 months compared to NPH treated subjects. Average HbA1c was 7.05% with glargine and 7.63% with NPH. Treatment difference was 0.58%.

It was concluded the institution of basal bolus therapy with insulin glargine at the time of diagnoses was associated with improved glycemic control in comparison with more conventional neutral protamine Hagedom regime.

Parent’s health literacy among high-risk adolescents with insulin dependent diabetes.

Janisse HC et al, conducted a trial in May 2010 on the parents of diabetic children.

The objective was to describe the health literacy of parents with type 1 diabetes and to examine the relationship between parents health literacy and treatment adherence.

93 parents were included in the trial and it was concluded, parents with low health literacy may struggle to help their children to the increasingly complex diabetic regimes.

Such families may benefit from more intensive diabetic education and different approaches to diabetic management skills.

Cost-effectiveness of insulin detemir compared with neutral protamine Hagedorn insulin in patients with type 1 diabetes using a basal-bolus regimen in five European countries.

Gschwend MH et al, in June 2009 found that it was more cost effective to use detemir in basal bolus regimes. It was 2 yr randomised control trial and events were projected for a time horizon of 50 yrs.

The objective of this study was to evaluate the long term clinical and economical out come using insulin detemir and NPH in combination with aspart in Type 1 DM in Belgium, France, Gremany, Italy and Spain.

The basal bolus therapy was noted to improve quality adjusted life expectancy by 0.45 years versus NPH in Germany, with similar results in other countries. Insulin detemir was also cost effective in Belgium, Germany and Spain.

In France and Italy, lifetime costs were slightly higher in the detemir arm, leading to incremental cost-effectiveness ratios of 519 euro per QALY gained and 3,256 euro per

QALY gained, respectively

Comparison of glycemic variability associated with insulin glargine and intermediate-acting insulin when used as the basal component of multiple daily injections for adolescents with type 1 diabetes.

White NH et al, in March 2009 performed an randomized, active controled and open study.

The objective was to compare glucose variability associated with glargine and NPH/Lente as basal insulin in MDI regime in the treatment of type 1 DM.

An active controlled, randomized, open labelled study was conducted involving 90 children.

It demonstrated a significant reduction in glucose variability measured by the SD of glucose values while using glargine in children with type 1 DM.

Insulin glargine is associated with greater reductions in glucose variability than NPH/Lente insulin in paediatric patients with type 1 diabetes.

Long-term efficacy and safety of insulin detemir compared to Neutral Protamine Hagedorn insulin in patients with Type 1 diabetes using a treat-to-target basal-bolus regimen with insulin aspart at meals: a 2-year, randomized, controlled trial.

Bartley PC et al, in April 2008 performed a randomized control trial

497 children with type 1 DM were involved in a 24 month, randomized, multinational, open labeled, parallel group trial to investigate the safety and efficacy of insulin determir and NPH in combination with aspart. 331 children were in group detemir, and 166 children were in neutral protamine Hagedron group.

It was noted that long term treatment with insulin analogues detemir and aspart were superior to NPH and aspart in reducing HbA1c, and less major and nocturnal hypoglycemia and less weight gain.

Flexibility of rapid-acting insulin analogues in children and adolescents with diabetes mellitus.

Danne T presented in XIXth World Diabetes Congress, 3rd December 2006 Cape Town.

Every year, approximately 70,000 children aged<15 years develop type 1 diabetes mellitus (DM) worldwide. Achieving glycosylated hemoglobin control is a very important aim, but quality-of-life concerns for the child and the family should also have high priority in the management of paediatric DM.

This review article was based on a presentation at a satellite symposium entitled “Realising the Value of Modern Insulins: Reaching Further with Rapid-Acting Insulin Analogues “that was convened during the XIXth World Diabetes Congress, December 3, 2006, in Cape Town, South Africa.

Treating children and adolescents with DM is a challenge that should not be

ignored. Furthermore, DM in children is quite different from that in adults. Numerous

factors have to be taken into account when evaluating treatment for children with DM in

comparison with treatment for adult DM: sleep patterns; unpredictable activities,

especially eating behaviors; limited size of injection sites, making it difficult to rotate

injections; higher insulin sensitivity; and frequent infectious diseases. In addition,

achieving normal psychosocial development may be just as important as achieving strict

metabolic control in this population. Rapid-acting insulin analogues can be used

effectively in these individuals with type 1 DM. The pharmacokinetic profile of insulin

aspart suggests that it is suitable for flexible mealtime administration in children and

adolescents. Indeed, clinical studies in children and adolescents have shown the efficacy

and tolerability of postprandial administration of insulin aspart, particularly in comparison

with soluble human insulin. Postprandial administration of insulin aspart, compared with

preprandial soluble human insulin, has also been studied in very young children (aged 2-6

years); similar metabolic control and increased parent preference for insulin aspart were

reported.

Rapid-acting insulin analogues in children and adolescents with type 1 DM are effective and well tolerated; they can be injected postprandially, and this is a reliable option that can be recommended to patients and their families.

Cost-effectiveness of detemir-based basal/bolus therapy versus NPH-based basal/bolus therapy for type 1 diabetes in a UK setting: an economic analysis based on meta-analysis results of four clinical trials.

Palmer AJ et al, performed a meta analysis in 2004 about cost effectiveness of bolus therapy.

A meta-analysis of results from four clinical trials in type 1 diabetes patients showed that insulin detemir based basal bolus treatment of type 1 diabetes led to improved HbA1c (0.15%-points lower), reduced risk of major hypoglycaemic events (by 2%) and reduction in body mass index (BMI) (0.26 kg/m2) compared to protamine Hagedorn human (NPH) insulin-based basal bolus therapy in type 1 patients.

The results showed an improved glycaemic control decreased hypoglycaemic events and BMI with detemir based basal bolus therapy led to fewer diabetes-related complications, an increase in quality-adjusted life expectancy of 0.09 years, increased total lifetime costs/patient of 1707 pounds sterling and an incremental cost-effectiveness ratio of 19,285 pounds sterling per QALY gained.

The conclusions from the study were; Short-term improvements seen with detemir combinations versus NPH combinations led to decreased complications, improvements in QALYs and reductions in complication costs, which partially offset the additional costs of detemir, leading to a cost-effectiveness ratio which fell within a range considered to represent excellent value for money (< 35,000 pounds sterling/QALY gained).

Summary & conclusion:

Multicentre studies over the last two decades have shown that MDI are better than twice a day insulin regimes. The main issues with twice daily insulin injections were having high HbA1C levels, which in turn led to long term complications:

There was early development of hyper cholestrenemia, diabetic retinopathy, micro vascular renal disorder and peripheral neuropathy.

The second main issue with twice a day insulin regime was children’s lifestyle had to be quite rigid since they had to wake up every morning to have their insulin, have their breakfast, then have a mid day snack, later lunch, post lunch snack, tea with their evening insulin and later another snack before going to bed. This also led to obesity, over weight and other complications associated with it.

Given the need for sticking to a rigid diet, which often was not possible, lead to fluctuating intake, leading to a fluctuating glucose levels.

With the multiple daily regime, the child is noted to have better quality of flexible lifestyle, the insulin and glucose control is more physiological. Their diet can be more variable, no need to snack in-between meals, less long term complications and better control of HbA1C noted.

The only drawback of multidose regime is the need for constant monitoring of glucose level and the need for giving multiple injections per day.

With twice daily regime the child has to run behind the insulin, whereas in multiple daily dosing the insulin runs behind the child.

Majority of the European countries have since then, joined the bandwagon of multi dose regime, and have demonstrated fall in HbA1C and hence reduced number of complications. This has also lead to increased quality of life. Most of the European countries have been able to achieve the target HbA1C of around 7.5.

UK has not been able to switch over to multi dose regime from twice a day. There are multiple causes for this, and lack of resources being the main cause. The uptake of multidose regime has been patchy throughout the UK.

Parents and education of parents regarding the need of multidose regime is a key factor in achieving successful implementation of multi-dose regime.

In our own trust, we have a shifted from the traditional twice a day approach to multidose regime. Over the last 18 months, overwhelming majority of our patients have been shifted to this regime (46 out of 58). In the remainder, we have not been successful, owing wide range of causes, one of the main being patient choice.

The average HbA1C of children on multi dose regime was 8.2 while that on twice a day was 9.6.

3 of those 12 children have shown at least one complication- including; hyper cholestrenemia and microalbuminuria in 3, Diabetic retinopathy changes in 2 and necrobiosis lipodica in one child.