Type 2 Diabetes: Where Do We Go From Here? Assessing Multi-drug Approaches

Case Studies
Stephen Clement, MD, Program Chair

Reported by Joelle Escoffery, PhD

In this case studies presentation, 3 different approaches to combination therapy in type 2 diabetes were explored using the same patient case information.

53 year old male with type 2 diabetes for 15 yrs
Stable coronary artery disease
Dyslipidemia and hypertension controlled with medication 
Current medications

Does not test blood glucose
Blood pressure = 125/85 mm Hg
BMI = 35
A1C = 9%
FPG = 220 mg/dL
LDL = 100 mg/dL

Dr Matthew Riddle, MD
Use of basal insulin

Excessive exposure to hyperglycemia can damage both large and small vessels in the body. Under conditions of hyperglycemia, approximately on half to two thirds of the glucose burden is attributable elevated fasting glucose levels. Because elevated fasting hyperglycemia is a significant contributor to the glucose burden, treatment strategies that address this issue are an important therapeutic option.

Portal insulin is the main determinant of hepatic glucose production, which in turn is the main regulator of fasting hyperglycemia. Injected insulin augments both portal and systemic insulin and suppresses basal overproduction of glucose. Insulin has also been shown to lower triglycerides, raise HDL, improve vasodilatory response, suppress inflammatory markers and reduce mortality in the inpatient setting.

One study that tested the efficacy of basal insulin in type 2 diabetes was the Treat to Target Trial. In this study, bedtime insulin glargine or NPH was added to existing oral agent regimens in poorly controlled patients with type 2 diabetes. The study included both a titration target of < 100  mg/dL and an overall glycemic target of A1C < 7%. At 16 weeks, mean A1C = 6.9%, 58% reached glycemic targets, and severe hypoglycemia was uncommon. Patients on insulin glargine experienced less mild to moderate hypoglycemia than patients on NPH insulin.

Basal insulin therapy is associated with a number of challenges, including timely initiation, finding and implementing the optimal titration strategy, and the need to add treatments that address postprandial hyperglycemia (PPG). According to one study, patients had an A1C above 8% for 26 months before further therapy was initiated. Furthermore, the Treat to Target trial demonstrated that when insulin is initiated at A1C < 8.5%, approximately 75% of patients achieved an A1C < 7%. Taken together, these results suggest that clinical inertia is a significant problem. In terms of dose titration strategies, many large trials that have used different titration strategies have achieved similar results. In terms of who should take on the responsibility for dose titration, both patients and providers need to play a role.  When the decision to begin basal insulin has been made, patients need proper education and phone or email follow-up, which should include teaching process. If PPG is limiting a patient’s ability to reach A1C targets, they can be switch to twice-daily premixed insulin, twice daily NPH or detemir injections, or prandial injections can be added at the largest meal. Premixed insulin regimens are associated with higher levels of hypoglycemia compared with basal insulin, and more weight gain is seen with NPH insulin as compared with insulin detemir.

Based on the available evidence, one strategy for this patient is to add glargine at 10 U and titrate up to approximately 50 U. If additional prandial control is needed, add a rapid analogue before dinner and titrate to 15 U. As is the case for all patients with diabetes, therapeutic lifestyle change should also be encouraged.

Philip Raskin, MD
Use of Premixed Insulin

The American Diabetes Association, the American Association of Clinical Endocrinologists, and the International Diabetes Federation have all established guidelines for diabetes control. In spite of the awareness of the importance of glycemic control, many patients are not meeting targets. Regardless of the treatment strategy used, glycemic control declines over time, and multiple therapies are needed as the insulin-producing ß cells decline over time. Early and aggressive glycemic control may attenuate ß-cell decline. 

When insulin is used in combination with oral therapies, drug synergy can occur, along with better glycemic control and better patient acceptance. One study showed that when insulin was used in conjunction with metformin, 59% of patients achieved A1C < 7%, compared with only 41% when insulin was used with placebo. Metformin may also attenuate weight gain commonly seen with insulin therapy. Insulin may also be used with more than one oral therapy. In one study, 100% of patients on insulin, metformin, and a thiazoladinedione (TZD) met glycemic targets, compared with 86% on insulin and TZD, and 64% with insulin and metformin. Although the combination of insulin and TZD generally results in better glycemic control, the combination of insulin and metformin results in less weight gain.

There are numerous strategies for treating patient with type 2 diabetes. For patients presenting with significant hyperglycemia, one strategy is as follows:

For patients who have hyperglycemia despite other therapies, the following strategy was recommended:

The INITIATE Study tested the use of premixed insulin in patients with A1C > 8 and BMI > 40. There was a 40week run-in period where secretagogues and alpha-glucosidase inhibitors were discontinued, metformin was optimized, and patients who were on a TZD continued its use (although TZD use was not required. Patients were then randomized to receive either insulin glargine or 70-30 premixed insulin. Overall, better A1C reduction was achieved with the premixed insulin. However, among patients with A1C > 8.5, premixed yielded better results, but among patients with A1C < 8.5 there was no difference in A1C reduction seen between the 2 different types of insulin therapy. Although patients on insulin glargine had lower fasting glucose levels, patients receiving premixed insulin had better postprandial glycemic levels. More weight gain and more mild to moderate hypoglycemia were seen with the premixed insulin.

There are a number of important points to consider when starting insulin. Address patient concerns is key to successful initiation of insulin. Patients should be provided education and support to allay their initial anxiety regarding insulin initiation. Many patients view insulin initiation as a sign of personal failure. For such patients, the progressive nature of type 2 diabetes should be explained so that self-blame and guild don’t undermine treatment success. Patients with a fear of hypoglycemia should be educated on hypoglycemia treatment and prevention. For patients concerned with weight gain, adjustments to diet and exercise behaviors can be suggested. Finally, healthcare providers should communicate benefits of insulin as a safe, effective, and flexible strategy for reducing the risk of diabetic complications,

In conclusion, the combination of insulin and insulin sensitizers can be used to achieve glycemic control in many patients with type 2 diabetes. TZD used in conjunction with insulin provide better glycemic control but more weight gain. If metformin added first, weight gain may be attenuated.

Robert Ratner, MD
Use of Exenatide

There are numerous barriers to insulin use, including patient resistance, the stigma of worsening disease, physician resistance, side effects such as weight gain and hypoglycemia, inconvenience of treatment, and increased cost. Triple therapy is one strategy for meeting glycemic targets without the use of insulin. Adding a TZD can be an effective strategy if initiated before A1C reaches 9%. The addition of rosiglitazone to combination oral therapy at A1C < 8% can lower A1C 1%, allowing targets to be met. One study showed that triple oral therapy can be as effective as insulin therapy. Initiating triple therapy earlier is a strategy that may allow patients to postpone insulin therapy. However, over time triple therapy is not a durable. Approximately 50% of patients will fail to meet glycemic targets on triple therapy over 6 years.

One additional strategy for patients failing oral agents is to add the incretin mimetic exenatide. Exenatide has been tested among patients failing to meet glycemic targets with SU and metformin combination therapy. Patients on combination SU and metformin therapy were randomly assigned to placebo, 5 mcg exenatide therapy twice daily, or 10 mcg exenatide therapy. There was a dose dependent decrease in A1C on exenatide therapy. A1C improvements were approximately 1%. Patients on exenatide therapy also lost weight rather than gained weight, as is the case with many other therapies. Some hypoglycemia was seen early in the course of therapy, especially with SU use. When SU dose was reduced, risk of hypoglycemia was also reduced. Dose-dependent nausea was also observed with exenatide therapy, but the withdrawal rate in all 3 groups was comparable.

The efficacy of exenatide has been compared with insulin glargine, and no difference both groups showed comparable reduction in A1C. There was a weight gain of 2 kg seen in the insulin glargine group at 26 wks, compared with a weight lost of 2.5 kg loss at 26 weeks with exenatide therapy. The weight loss between the 2 groups was statistically significant beginning at the second week of the study.

There are numerous reasons why adding exenatide to existing oral therapies is viable therapeutic strategy. It has been shown to be effective, relatively simple compared with insulin, and provides durable treatment effects to at least 2 years. Additionally, it is safe, is associated with a decreased risk of hypoglycemia compared with insulin, and promotes weight loss rather than weight gain.