Monday, December 4, 2023
This activity is intended for physicians and pharmacists.
This article reviews 3 current topics in the management of diabetes. The first presentation outlines new approaches in the treatment of diabetes in special populations, the second discusses the use of insulin in type 2 diabetes, and the third reviews the cardiovascular effects of thiazolidinediones beyond glycemic control.
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Several therapeutic combinations are used to target both fasting and postprandial blood glycemia in order to provide tight glycemic control throughout the day. These combinations include oral agents with insulins, rapid-acting insulin analogues with basal insulins, and premixed combination products of rapid-acting and intermediate-acting insulins.[42] Newer studies on combining a rapid-acting insulin analogue with a sulfonylurea suggest that even better control of both postprandial plasma glucose levels and HbA1c can be achieved in type 2 patients who have failed therapy with oral agents.[43]
Title/Slide 1 - Insulin Therapy in Type 2 Diabetes: When and How to Start
Slide 2 - Pathogenesis of Diabetic Complications
The complications of diabetes mellitus result from a complex interplay of factors, ultimately stemming from the underlying hyperglycemia. Sustained elevated blood glucose levels, or even glucose levels that wax and wane, cause toxic effects to tissues. Controlling both postprandial and fasting blood glucose levels is essential for efficient prevention of chronic complications.
Slide 3 - Effect of Hyperglycemia on the Vascular Wall
Postprandial elevation of glucose may exert both short-term and long-term effects on the vasculature. The hyperglycemic wave can trigger events ultimately contributing to vessel wall oxidative stress and atherosclerosis. Tight control of hyperglycemia can minimize these vascular effects and reduce the risk of cardiovascular complications in patients with diabetes.
Slide 4 - Extrapolation of Time to Deterioration of Beta-cell Dysfunction
Type 2 diabetes has an insidious onset. Data collected in the UKPDS have indicated that by the time type 2 diabetes is diagnosed, beta-cell function is no more than 50% of its total capacity. Since beta-cell function decreases linearly, by extrapolating backwards, it can be argued that the initial loss of beta-cell function begins, on average, 12 years before diagnosis. Therefore, the goal of therapy in type 2 diabetes is to compensate for beta-cell failure in order to achieve glycemic control.
Slide 5 - When Should We Start Insulin in Type 2 Diabetes?
One of the most difficult aspects of providing care for the patient with type 2 diabetes is deciding when to initiate insulin therapy. Administration of insulin before it is needed can result in increased hypoglycemic episodes. Conversely, waiting too long to administer insulin can hinder the patient's glycemic status. Careful monitoring of the patient's blood glucose levels with an eye toward initiating insulin therapy when necessary is key to good glycemic control.
Slide 6 - Targeting Postprandial Glucose
Studies have indicated that an effective way to achieve glycemic control in type 2 diabetes is to monitor postprandial glucose excursions and titrate insulin regimens accordingly. This method most closely mimics the normal physiology of glycemic control, whereby insulin is released in response to ingested glucose. The rapid-acting insulin analogues may be particularly suited to this method of glycemic control because their short onset and duration of action allows them to effectively target postprandial blood glucose levels.
Slide 7 - Daily Metabolic Conditions
There are 3 glycemic metabolic states. The postprandial state lasts for up to 3 hours after a meal, after which the metabolism switches to the postabsorptive state. A lack of glucose ingestion for 12 hours triggers the fasting state. Because studies have shown that postprandial blood glucose levels correlate with overall glycemic status, ensuring adequate insulin coverage for mealtime glucose ingestion is key.
Slide 8 - Correlation of 2-Hour Plasma Insulin Concentration and 30-Minute Plasma Insulin Response With 2-Hour Plasma Glucose
In patients with glucose intolerance, an inverse relationship was found between plasma insulin 30 minutes after the ingestion of an oral glucose load (OGTT) and 2-hour plasma glucose concentrations, suggesting that the loss of early phase insulin response plays a primary role in restraining glucose excursion. On the other hand, a positive correlation was found between 2-hour plasma glucose and insulin levels, suggesting an increased stimulation of the beta cell in response to the prevalent plasma glucose increase as well as a concomitant insulin resistance at the tissue level. Compensating for the lack of early-phase insulin through the use of a rapid-acting insulin may help to achieve glycemic control.
Slide 9 - Plasma Insulin Profile After Regular Insulin and Insulin Lispro
Because one of the primary defects in type 2 diabetes is impairment of the early rise in plasma insulin concentration after the ingestion of glucose, its restoration is important in the attempt to improve glycemic control. Following subcutaneous injection, rapid-acting insulin analogues have demonstrated a faster rise in plasma insulin concentration, a higher peak of action, and a shorter duration of action compared with regular insulin. Therefore, a rapid-acting insulin analogue, such as insulin lispro, can be effectively used to mimic the physiologic insulin profile after the ingestion of a meal.
Slide 10 - Serum Insulin Profile After Regular Insulin and Insulin Aspart
Insulin aspart, the other available rapid-acting insulin analogue, has also demonstrated a shorter onset of action compared with regular insulin.
Slide 11 - First-Phase Insulin Response After Oral Glucose Tolerance Test
The need for replacement of the missing early-phase insulin response after an oral glucose tolerance test (OGTT) is readily apparent, even more so than under normal physiologic conditions. Compared with regular human insulin, administration of insulin lispro resulted in a significantly improved plasma insulin profile, lower plasma glucose levels, and lower plasma C-peptide levels over the course of nearly 6 hours.
Slide 12 - Benefits of Prandial Insulin Therapy: Effect on Serum Insulin Levels
The benefits of the rapid-acting insulin analogues as prandial therapy become apparent when evaluating their effects on serum insulin levels. Regardless of injection site, the time to peak insulin concentration was significantly shorter with insulin aspart, and the maximum concentration achieved was significantly higher with insulin aspart compared with regular insulin.
Slide 13 - Benefits of Prandial Insulin Therapy: Serum Glucose and Hypoglycemic Episodes
In addition to its ability to decrease serum glucose levels, trials with insulin lispro have also demonstrated a significant reduction of the incidence of hypoglycemic episodes (mainly nocturnal), indicating that the benefits of prandial insulin therapy extend beyond the immediate postprandial period to the postabsorptive and fasting states.
Slide 14 - Prandial Insulin Therapy: HbA1c
Despite the improvements in postprandial glucose control seen with insulin lispro compared with regular human insulin, HbA1c levels remained comparable in both groups, possibly due to insufficient attention to fasting glucose.
Slide 15 - Combination Therapy
Any diabetes therapy strategy must address all of the contributing factors to the development of disease. Regimens that include multiple therapies, ie, insulin plus oral agents, are therefore fairly common. At the same time, to simplify insulin regimens, the use of premixed insulins has been gaining ground, whereby a shorter-acting insulin, such as an insulin analogue, is premixed with an intermediate-acting insulin to better control both postprandial and fasting blood glucose levels.
Slide 16 - Combination Therapy: Bedtime Insulin + Daytime Sulfonylurea
The most common combination therapy regimen consists of bedtime insulin and daytime sulfonylurea. Insulin is given at bedtime to control overnight plasma glucose (ie, hepatic glucose production), whereas sulfonylurea is used during the day to stimulate insulin release. Appropriate administration and stimulation is expected to result in overall improvement of glucose control.
Slide 17 - Combination Therapy: Insulin + Sulfonylurea
The combination of insulin/sulfonylurea therapy has been widely studied. In a meta-analysis of clinical studies of patients with type 2 diabetes, the use of the insulin/sulfonylurea combination resulted in a significant decrease in mean HbA1c levels when compared with insulin therapy alone. However, it should be noted that HbA1c still remained high compared with the target value of 7.5%. The failure to meet the recommended standard may reflect a therapeutic intervention started too late, or it may reflect a relative inefficacy of the therapeutic strategy.
Slide 18 - Combination Therapy: Insulin Lispro + Sulfonylurea
The combination of a sulfonylurea with the rapid-acting analogue insulin lispro also reduced HbA1c levels, demonstrating significantly reduced postprandial and fasting plasma glucose levels compared with sulfonylurea alone.
Slide 19 - Combination Therapy: Insulin Lispro, NPH, Sulfonylurea
When compared with NPH plus a sulfonylurea (s) in patients who were uncontrolled on sulfonylurea alone, the insulin lispro/sulfonylurea combination (n) resulted in lower preprandial and postprandial blood glucose levels. The combination of insulin lispro plus NPH (l) was approximately equivalent to or less efficacious than the insulin lispro plus sulfonylurea combination, suggesting that the addition of a rapid-acting insulin can help to stabilize blood glucose levels in patients with poorly controlled diabetes.
Slide 20 - Combination Therapy: Bedtime Sulfonylurea + Daytime Insulin
Given the ability of the insulin lispro/sulfonylurea combination to control blood glucose effectively, a revised model is now being explored: bedtime sulfonylurea and daytime insulin. This model relies on the long-acting sulfonylurea to provide fasting glycemic control and the rapid-acting insulin analogue to provide postprandial glycemic control. The combination of insulin analogues and metformin also is an attractive combination, given the advantages of this insulin sensitizer.
Slide 21 - Pre-mixed Insulins: Regular/NPH vs Insulin Lispro/NPL
Premixed regular human insulin and NPH has been used successfully in patients with type 2 diabetes, providing glycemic control while minimizing the number of injections of insulin required each day. Premixed insulin lispro and NPL (neutral protamine lispro; an intermediate-acting neutral insulin lispro-protamine suspension) demonstrated significantly lower mean blood glucose values at 2 of the 3 postprandial measurements, and equivalent or slightly lower values at all other measured points.
Slide 22 - Pre-mixed Insulins: Regular/NPH vs Insulin Aspart/NPA
The pharmacodynamic properties of premixed rapid-acting insulin aspart and NPA (neutral protamine aspart; an intermediate-acting neutral insulin aspart-protamine suspension) was compared with a mixture of regular human insulin and NPH. The insulin aspart/NPA mixture demonstrated a significantly shorter onset and peak of action.
Slide 23 - Weight Gain in Diabetes
Many patients with type 2 diabetes are overweight, so issues of weight gain as a result of therapy must be addressed. Because insulin therapy is associated with weight gain, identification of its precise mechanisms may help to devise strategies to minimize weight gain.
Slide 24 - Insulin Therapy and Weight Gain
Weight gain in patients with type 2 diabetes on intensive insulin therapy was directly correlated with both mean serum insulin levels and total insulin dose. Alternative regimens that provide sufficient insulin for glycemic control while minimizing circulating insulin doses could potentially limit therapy-associated weight gain.
Slide 25 - Insulin Therapy and Weight Gain: Effect of Insulin Lispro
In multiple studies, the addition of insulin to a sulfonylurea regimen has resulted in weight gain, which probably results from improved glucose utilization. However, the benefits of improved glycemic control overshadow the negative effects of weight gain.
Slide 26 - Body-Weight and Long-term Complications in UKPDS
Over the course of the UKPDS (> 10 years), significant reductions were seen in all diabetes complications, on a macro and on a micro level. At the same time, however, body weight increased approximately 5%. These data suggest that unwanted effects, such as weight gain, may be inevitable in order to achieve the dramatic morbidity and mortality benefits seen with intensive insulin therapy.
Slide 27 - Treatment Algorithm
Effectively managing type 2 diabetes can be challenging. Each patient's treatment regimen must be tailored specifically to meet metabolic demands. Although an algorithm for care may seem complex, the 2 main principles guiding all algorithms is the need to monitor regularly to ensure adequate glycemic control and the need to initiate insulin therapy when warranted.
Slide 28 - Conclusions
Given the proven benefits of intensive insulin therapy for type 2 diabetes, insulin should be added to the therapeutic regimen as soon as it is needed to maintain glycemic control. Early in the stages of type 2 diabetes, patients demonstrate an abnormal early-phase insulin response. For patients with type 2 diabetes on oral agents, the early sign of deteriorating metabolic status is usually the loss of postprandial control.
Slide 29 - Conclusions (cont'd)
Rapid-acting insulin analogues, because of their more rapid time to onset and shorter duration of action compared with regular insulin, may help to minimize postprandial glucose excursions and reduce the risk of hypoglycemic episodes. Concerns about the negative effects of weight gain should not limit the use of insulin in patients with type 2 diabetes because it is far more important to consider the beneficial effects of tight glycemic control on macrovascular and microvascular complications.
