Insulin Analogs or Premixed Insulin Analogs in Combination With Oral Agents for Treatment of Type 2 Diabetes

Philip Levy, MD, FACE

April 16, 2007

Introduction

In 2005, 20.8 million adults in the United States were estimated to have diabetes mellitus.^[1] This number is expected to increase to 29 million by 2050.^[2] Most cases of diabetes (90% to 95%) are type 2,^[3] which has been increasing in prevalence everywhere in the United States in parallel with the obesity epidemic. All ages, ethnic groups, education levels, and both sexes are susceptible.^[4]

Several long-term randomized trials of diabetes care and outcomes demonstrated that achieving near-normal glycemia, in terms of fasting and postprandial plasma glucose and glycosylated hemoglobin (A1C) levels, is crucial for avoiding or delaying long-term microvascular complications such as retinopathy, nephropathy, and neuropathy.^[5,6,7] The evidence that intensive therapy also delays macrovascular disease is less compelling. However, after more than 17 years of follow-up in one of these trials, intensive insulin therapy that targeted normoglycemia was shown to reduce the risk of cardiovascular disease by 42%. Compared to conventional therapy (defined as 1-2 injections of insulin daily with no glycemic goals other than to prevent symptoms of hyperglycemia and hypoglycemia), the risk of nonfatal myocardial infarction, stroke, or death from cardiovascular disease was 57% lower with intensive therapy.^[8]

Maintenance of tight glycemic control in patients with type 2 diabetes requires timely adjustments and changes in therapy when goals are not met. While the majority are initially treated with oral antidiabetic drugs (OADs),^[9] most patients ultimately require insulin therapy to maintain glycemic control.^[10] Commonly used OADs and some newer therapies have limited potential to lower A1C, by just 0.5 to 1.5%. Insulin, when used in appropriate doses, can decrease any level of A1C to near goal, limited only by its potential to cause hypoglycemia.^[11] The aim of this article, therefore, is to provide evidence-based practical guidance for improving glycemic control in patients with type 2 diabetes. The emphasis is placed on how insulin therapy, in particular, with insulin analogs and premixed insulin analogs, can be initiated in patients who currently are inadequately managed with OADs alone.

References

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Glycemic Goals
Parameter	Normal	ADA Goals	ACE/AACE Goals
Fasting plasma glucose (mg/dL)	< 100	90-130	< 110
Postprandial plasma glucose (mg/dL)	< 120	< 180*	< 140**
A1C (%)	4-6	< 7***	≤ 6.5

*1-2 hours post-meal
**2 hours post-meal
***as close to normal as possible without undue risk of hypoglycemia

Noninsulin Pharmacotherapies for Management of Type 2 Diabetes
Insulin Secretagogues	Insulin Sensitizers	Other Agents
Sulfonylureas Chlorpropamide Glyburide Glimepiride Glipizide Gliclazide Tolbutamide Glinides Nateglinide Repaglinide	Metformin Thiazolidinediones Rosiglitazone Pioglitazone	alpha-Glucosidase Inhibitors Acarbose Miglitol GLP-1 Analogs* Exenatide DPP-IV Inhibitors* Sitagliptin Amylin Analog Pramlintide

Combination products are also available, most of which combine a secretagogue with a sensitizer; *several other agents in this class are in clinical development

Noninsulin Pharmacotherapies for Management of Type 2 Diabetes
Insulin Secretagogues	Insulin Sensitizers	Other Agents
Sulfonylureas Chlorpropamide Glyburide Glimepiride Glipizide Gliclazide Tolbutamide Glinides Nateglinide Repaglinide	Metformin Thiazolidinediones Rosiglitazone Pioglitazone	alpha-Glucosidase Inhibitors Acarbose Miglitol GLP-1 Analogs* Exenatide DPP-IV Inhibitors* Sitagliptin Amylin Analog Pramlintide

Combination products are also available, most of which combine a secretagogue with a sensitizer; *several other agents in this class are in clinical development

Comparison of Insulin Preparations by Pharmacodynamics and Cost
Insulin Preparation	PD Parameters			Cost*
Insulin Preparation	Onset (h)	T_{peak activity} (h)	Duration (h)	Per 10-mL Vial**
Rapid-acting analogs
Insulin aspart	0.17-0.33	1-3	3-5	$81
Insulin glulisine	0.25	0.5-1.5	5.3	$78
Insulin lispro	0.25-0.5	0.5-2.5	3-6.5	$78
Short-acting human
Regular human Insulin (RHI)	0.5-1	1-5	6-10	$35
Intermediate-acting human
Neutral protamine Hagedorn (NPH)	1-2	6-14	16-24	$35
Long-acting analogs
Insulin detemir	0.8-2	6-8	Up to 24	$84
Insulin glargine	1.1	2-20	Up to 24	$76
Premixes (human)
NPH/RHI 70/30 or 50/50	0.5	1.5-12	Up to 24	$32-36
Premixes (analogs)
Biphasic insulin aspart 70/30	0.17-0.33	1-4	Up to 24	$84 ($153 for five 3-mL pens)
Insulin lispro 75/25	0.25-0.5	≤ 2	Approx. 22	$84 ($148 for five 3-mL pens)
Insulin lispro 50/50	0.25-0.5	0.5-1.5	Approx. 22	$156 (five 3-mL pens)
Inhaled insulin	0.17-0.33	0.5-1.5	Approx. 6	$134 for kit that contains 90 × 1 mg plus 90 × 3 mg blister packs***

*Except for pen devices, does not include the cost of the needles and syringes, or, in the case of inhaled insulin, the inhaler, chamber, or release unit that must be replaced every 2 weeks; **unless otherwise noted; ***approximately equivalent to 990 units of RHI (ie, one 10-mL vial of 100 unit/mL); pharmacodynamic data from respective prescribing information. Cost data from Red Book 2006^[83] and www.drugstore.com, accessed December 14, 2006. Prices are for comparison and could vary considerably, depending on source.

Starting and Titration Schedule for a Basal Insulin Analog
Self-Monitored FPG (mg/dL)	Dosage Increase (units/day)
≥ 180	8
≥ 140 to < 180	6
≥ 120 to < 140	4
> 100 to < 120	2

FPG = fasting plasma glucose; *no increase if FPG is < 72 mg/dL in the preceding week; decrease dosage (2-4 units/day) if FPG is < 56 mg/dL or severe hypoglycemia (requiring assistance) occurred within the preceding week; copyright 2003 American Diabetes Association. From Diabetes Care 2003;26:3080-3086; reprinted with permission from The American Diabetes Association.

Starting and Titration Schedule for a Premixed Insulin Analog
Blood Glucose Values	Starting Dose	Dose Titration*
Baseline FPG < 180 mg/dL FPG ≥ 180 mg/dL	5 units before breakfast and supper 6 units before breakfast and supper
After Initial Therapy FPG < 80 mg/dL FPG 80-110 mg/dL FPG 111-140 mg/dL FPG 141-180 mg/dL FPG > 180 mg/dL		Reduce by 2 units No change Increase by 2 units Increase by 4 units Increase by 6 units

FPG = fasting plasma glucose; *increase in total daily dose should not exceed the greater of 10 units or 10% of the total daily dose; morning dose is based on pre-supper blood glucose reading; supper dose is based on pre-breakfast blood glucose reading; the dose titration is based on blood glucose values from the preceding 3 days; reprinted from Rolla AR, Rakel RE. Practical approaches to insulin therapy for type 2 diabetes mellitus with premixed insulin analogues. Clin Ther. 2005;27:1113-1125, with permission from Excerpta Medica, Inc.

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Insulin Analogs or Premixed Insulin Analogs in Combination With Oral Agents for Treatment of Type 2 Diabetes

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