Insulin therapy in type 2 diabetes mellitus

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Diabetes mellitus is a disease of metabolic dysregulation, most notably abnormal glucose metabolism, accompanied by characteristic long-term complications. The complications that are specific to diabetes include retinopathy, nephropathy, and neuropathy. Patients with all forms of diabetes of sufficient duration, including type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), are vulnerable to these complications, which cause serious morbidity. These are microvascular complications. High plasma glucose is the driving force in microvascular complications of diabetes.

To achieve glycemic goals in patients with type 2 diabetes, multiple pharmacologic agents, including sulfonylureas, meglitinides, metformin, alpha-glucosidase inhibitors, thiazolidinediones, dipeptidyl peptidase IV (DPP-4) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonist and insulin are available. These agents can be used singly or in combination to achieve target glycaemic control. Unlike patients with type 1 diabetes who have no significant insulin secretion and hence require insulin therapy from the onset of their disease, in patients with type 2 diabetes insulin resistance with hyperinsulinemia is a prominent feature in the early stages of the disease. People with type 2 diabetes mellitus thus benefit from measures to improve insulin sensitivity such as dietary caloric restriction, exercise, and weight management early in their disease in combination with oral agents such as insulin sensitizers and insulin secretagogues to achieve the glycaemic target. With the progression of type 2 diabetes, there is ultimately progressive loss of pancreatic beta-cell function and reduction in endogenous insulin secretion. At this stage, most patients will require exogenous insulin therapy to achieve optimal glucose control.

Landmark clinical trials have been able to establish the fact that optimal glycaemic control can prevent/delay the progression of complications in people with diabetes mellitus1. The conclusions from these trials positioned insulin strategically as a very important agent in achieving reduced microvascular complications1,2.

Data from the UnitedKingdom Prospective Diabetes Study (UKPDS) suggest that early insulin treatment lowers macrovascular risk in type 2 diabetes mellitus3. These trials strive to achieve glycaemic control below which no complication would occur. However, better glycaemic control was associated with reduced risks of complications over the whole glycaemic range (“the lower the better”) in the UKPDS4.

In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, higher mortality was recorded in the intensive glycemia treatment arm while targeting HbA1C of <6.0% compared with the standard therapy group targeting HbA1C from 7.0 to 7.9% 5. The intensive arm recorded more episodes of hypoglycemia hence the increase in mortality recorded5. No additional benefit was recorded by lowering HbA1C <6.5% in the KUMAMOTO study 2.

Choosing from the wide variety of glucose-lowering interventions currently available could be a challenge for the healthcare provider and the patients in terms of effectiveness, tolerability, and cost of the various diabetes treatments. However, these should not be the case as risk reductions in long-term complications were related to the levels of glycaemic control achieved, rather than to a specific glucose-lowering agent 1. In the Steno-2 study, very few patients achieved the HbA1C target of 6.5% compared with the large number of patients who reached the intensive blood pressure and serum lipid goals6. The challenges of initiating and intensifying insulin therapy are quite enormous and could be daunting to health caregivers. This review contains an overview of the currently available insulin preparations and an outline of the merits and demerits 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.

The rationale for Insulin Therapy in Type 2 Diabetes

Three major pathophysiologic abnormalities contribute to hyperglycemia in type 2 diabetes: excessive hepatic glucose production, impaired pancreatic insulin secretion, and peripheral resistance to insulin action occurring principally in liver and muscle tissue1. Of these, peripheral resistance to insulin action and impaired pancreatic beta-cell secretion are early and primary abnormalities, whereas increased hepatic glucose production is a late and secondary manifestation. Early in their disease, patients with type 2 diabetes compensate for increased insulin resistance at the tissue level by increasing pancreatic beta-cell insulin secretion. When this compensation is no longer adequate to overcome the insulin resistance, blood glucose levels begin to rise. Over the course of the disease, however, insulin levels slowly begin to decrease, and eventually, most patients with type 2 diabetes mellitus are unable to achieve optimal glycaemic control with oral agents1. At this stage, the introduction of insulin is inevitable.

Human Insulin and Its Analogues

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 minutes 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. Secondly, 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 pharmacodynamics limitations predispose users to elevated glucose levels before breakfast and nocturnal hypoglycemia 7,8. To overcome these difficulties, insulin analogs with a modified amino acid sequence from the human insulin molecule were developed. The three rapid-acting analogs (apart, glulisine, lispro) are absorbed more quickly than regular insulin because of reduced self-association. Their onset of action is within 15 minutes after subcutaneous injection, and they have a faster and greater peak action. The 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)9-11. The pathophysiologic process in type 2 diabetes mellitus leaves the patient with residual insulin production on the background of insulin resistance. It is worthy to note that the long-acting insulin analogs have a pharmacokinetics that closely mimics the physiological insulin secretion in the body.

When should insulin therapy be initiated?

This question will arise at a point in the management of patients with type 2 diabetes mellitus, a progressive and chronic disease. The answer is not straightforward. It leaves room for controversy. Oral medications are traditionally introduced in a stepwise manner with insulin reserved as the final step in the management of type 2 diabetes mellitus. This may take up to 10 – 15 years after diagnosis before insulin is finally introduced. The fears of painful injections, weight gain, and hypoglycemia militate against the early initiation of insulin by both the physician and the patients13,14. Negative beliefs about insulin treatment and other socio-cultural factors also affect the acceptance of patients to accept insulin14, 15. This predisposes the patient to long-term complications due to exposure to many years of uncontrolled hyperglycaemia16. This, therefore, calls for a proactive approach to treatment failure. Lowering glycemia improves insulin resistance as well as insulin secretion17. Early initiation of insulin therapy in a newly diagnosed patient with type 2 diabetes mellitus restores and maintains ?-cell function17. We advocate that insulin should be initiated when stepwise approach failed to achieve the target HbA1C of <7%18. This initiation should be swift when the HbA1C <7% is not achieved at 2-3 months of maximally dosed dual oral therapy. For patients intolerant to one or more oral glucose-lowering agents and who do not achieve glycaemic control with oral monotherapy, as well as those with a personal preference, earlier initiation of insulin is indicated. It is noteworthy that rapid addition of insulin therapy is supported by numerous studies showing improved treatment satisfaction and quality-of-life for type 2 diabetic patients who had started using insulin19,20.

In what way should insulin therapy be initiated?

Good glycaemic control was achieved in the majority of patients with type 2 diabetes mellitus in the ‘treat-to-target’ clinical trials when basal insulin was added to their oral antidiabetic agents21-23. It should, however, be noted that the benefit of the long-acting insulin analogs is in the reduction of nocturnal hypoglycaemia24. According to the ADA/EASD algorithm for the management of type 2 diabetes, insulin could be initiated with either once-daily NPH insulin or a long-acting insulin analogue18. A meta-analysis that included six randomized comparisons of NPH and glargine found event rates for self-monitoring of blood glucose (SMBG) confirmed symptomatic hypoglycemia <65mg/dl of only 138 and 91 events per 100 patient-years for these insulins, respectively, in insulin-naive type 2 diabetic patients who achieved an A1C of 7.0%25. The NPH, insulin glargine and determine have been used as basal insulin to achieve glycaemic control in type 2 diabetes patients. As desirable as this may be, the cost implication of the newer insulins to the patient should not be lost on the physicians. In Africa (and in Nigeria), the cost of insulin has been a barrier to the acceptance of insulin therapy aside from socio-cultural issues15. The NPH is cost-effective and insulin therapy in type 2 diabetes can be initiated with NPH. The other issue to be considered is the frequency of dosing for basal insulin. In a “treat-to-target” trial with the twice-daily detemir administration, an endpoint A1C of 6.8% was reached.22 In other studies, a second daily detemir injection was required in 34–55% of study subjects because of pre-dinner hyperglycemia or nocturnal hypoglycemia. 23,26 In the only reported trial that investigated the efficacy of once-daily insulin detemir, A1C remained above the currently recommended glycaemic goal with an endpoint level of 7.4%, both for NPH insulin and detemir, 27 compared with an end of study A1C <7.0% with once-daily glargine and NPH in the original Treat-to-Target Trial.21

In the ACCORD study,5 the finding of increased mortality in the intensive glucose lowering therapy group will probably deter some practitioners from lowering glucose promptly. The ACCORD study solely included patients at high risk for cardiovascular disease, in whom low A1C levels were reached by using up to four or five different classes of glucose-lowering drugs. In contrast, in less selected patients treated with stable doses of one or two oral agents, simple titration algorithms targeting fasting plasma glucose =100 mg/dl (=5.6 mmol/l) can safely achieve A1C of 7.0%. 21 An algorithm, which is patient-driven, with patients increasing their insulin dose by 2 or 3 units every 3 days, as long as their fasting plasma glucose remains above target, constitutes a practical approach that has been shown to be equally or more effective than physician-led titration. 28,29 In the timing of once-daily basal insulin regimens, administration of NPH in the evening appears to be superior to morning injection7,19. There are conflicting results in the studies from studies examining the injection time of the long-acting insulin analogs. When morning and evening injection of insulin glargine were compared in one study, there was a greater reduction in HbA1c and nocturnal hypoglycemia when insulin glargine was given in the morning30, whereas in another larger study with identical design no significant difference was found in the timing31. A morning administration of insulin detemir was associated with lower glucose levels during the day and a trend toward a reduced risk of nocturnal hypoglycemia compared with evening injection27. What do all these mean? We can safely conclude from these discrepant data that when nocturnal hypoglycemia limits dose titration of evening detemir or glargine, administration in the morning could be attempted.

Other options exist for initiation of insulin therapy. The treating to target in type 2 diabetes (4-T) study compared various options for insulin initiation. Basal insulin introduced at bedtime was compared with either biphasic insulin twice daily or prandial insulin before meals26. It was found that regimens using biphasic or prandial insulin reduced HbA1c to a greater extent than basal, but were associated with greater risks of hypoglycemia and more weight gain26. The HbA1c lowering with biphasic insulin is equivalent to Prandial insulin. However, there is greater weight gain and more hypoglycemia than with Basal insulin but less for both than with Prandial insulin26. Initiation with prandial insulin is not a first choice approach when initiating insulin in type 2 diabetes mellitus. Credence was lent to this in the study comparing once-daily insulin glargine versus thrice daily insulin lispro in insulin-naive patients32. Thus the addition of once basal insulin will reduce the frequency of injection and promote acceptability by patients of insulin initiation. Combination of basal insulin with oral agents have been shown to minimize adverse effects of insulin therapy (i.e. hypoglycemia and weight gain)33. Combination of insulin with metformin is indeed associated with better glycaemic control, fewer hypoglycemic events, and less weight gain than treatment with insulin alone33. Therefore, metformin should be continued when patients are initiated on insulin therapy (i.e., providing there are no intolerable side effects).

Intensification of Insulin Therapy

There is a progressive decline in ? cell function in type 2 diabetes mellitus. With progression, once-daily basal insulin alone will eventually fail to maintain glycaemic control in a large number of patients with type 2 diabetes mellitus. When the recommended A1C level of <7.0% is not reached or maintained despite successful basal insulin dose titration maintaining fasting plasma glucose =100 mg/dl, or when the aggressive titration is limited by hypoglycemia, treatment should be intensified by adding insulin injections. This can be achieved by intensifying the basal insulin or addition of prandial or biphasic insulin. This is individualized based on the patient’s diurnal glucose profile. Two studies established that in patients not achieving adequate glycaemic control with once-daily basal insulin, basal-bolus therapy results in greater A1C reductions than biphasic insulin twice or thrice daily34,35. 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 glargine35. For prandial insulins, rapid-acting insulin analogs are not superior to regular insulin in reducing HbA1C levels or rates for overall and nocturnal hypoglycemia, despite improving postprandial control36. Intensive insulin therapy can also be introduced in a patient with type 2 diabetes mellitus who are already on at least once daily insulin injection. Introducing subcutaneous insulin infusion resulted in comparable glycaemic control, weight gain and hypoglycaemic risk as multiple daily injections therapy37,38. Multiple daily injection therapy is, however, best administered in selected patients and experienced centers.

Disadvantages of Insulin Therapy

Hypoglycemia is one of the major disadvantages of insulin therapy. Many clinicians are reluctant to initiate insulin therapy for this reason alone. Increased rate of hypoglycemia occurs in intensive glucose-lowering therapy. The was confirmed in the ACCORD study5. Iatrogenic hypoglycemia hampers tight glycaemic control and is considered the limiting factor in diabetes management39. In type 2 diabetes, the frequency of hypoglycemia is generally lower than that in type 1 diabetes39. 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 glycaemic thresholds for counter-regulatory and symptomatic responses to hypoglycaemia40.

Weight gain is another disadvantage of insulin therapy. Approximately 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 glycaemic control is improved18,41. Other explanations are snacking to prevent or in response to, hypoglycemia.

Although insulin has no upper dose limit and numerous trials established that glycaemic goals can be attained by using adequate doses, in clinical practice, many patients experience years of uncontrolled hyperglycemia. 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. For successful insulin therapy, timely initiation and rapid titration are very important. The risk of hypoglycemia is low among type 2 diabetes patient just commencing insulin therapy. When glycaemic goals are not attained despite successful basal insulin dose titration (i.e., fasting plasma glucose =100 mg/dl), or when the titration is limited by hypoglycemia, treatment should be intensified by the addition of prandial or biphasic insulin.