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

Philip Levy, MD, FACE

April 16, 2007

Conclusions

Type 2 diabetes is a progressive disease. At the time of diagnosis, patients should be informed that insulin therapy is part of the natural course of diabetes, and not a last resort to be feared or avoided. Although initial treatment may begin with oral agents, the vast majority will transition to insulin therapy to achieve and maintain good glycemic control. Insulin therapy has become more flexible and convenient with insulin analogs (which more closely mimic physiologic insulin secretion than human insulins) and better insulin delivery systems. Addition of once- or twice-daily administration of long-acting insulin analogs to OADs effectively lowers A1C in patients with an elevated FPG, and with less risk for hypoglycemia compared with NPH. Mealtime administration of rapid-acting insulin analogs decreases postprandial glucose excursions and lowers A1C. Premixed insulin analogs provide an effective and convenient approach to controlling FPG and PPG and lowering A1C levels in patients with type 2 diabetes transitioning to insulin therapy. The reduction in regimen complexity achieved with premixed insulin analogs has the potential to overcome an important barrier to successful insulin therapy. Compared to conventional insulins, the insulin analogs also decrease the risk for hypoglycemia, which can prevent patients from adhering to insulin-based regimens. Selection of appropriate insulin analogs and convenient injection devices can facilitate the transition to insulin therapy. Patient education about insulin, its potential benefits, and how to manage symptoms of hypoglycemia are also important for decreasing patient anxiety and optimizing adherence. Ultimately, a physician's choice of insulin therapy should be individualized according to the patient's glycemic parameters, treatment preferences, and lifestyle.

References

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Acknowledgments

The author thanks Novo Nordisk for funding that helped support the preparation of this manuscript and Bob Rhoads for writing and editorial assistance.

Cite this: Insulin Analogs or Premixed Insulin Analogs in Combination With Oral Agents for Treatment of Type 2 Diabetes - Medscape - Apr 16, 2007.

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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