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P E R S P E C T I V E S
Aspects of Insulin Treatment
ZACHARY T. BLOOMGARDEN, MD
system and a separate electronic controller,smaller than traditional pumps and with alarge insulin reservoir. Medtronic also may Thisisthesecondofaseriesofarticles periodsoflesserandgreaterinsulinsen- be developing a patch delivery system,
rhythm of insulin sensitivity characteris- tic of many type 2 diabetic patients. A re- port of use of the V-Go for 7 days in six peutics is the PassPort transdermal insu- control with significantly lower levels at provide constant basal insulin. This com- pany is also developing a transdermal ex- available for subjects with type 2 diabetes and pointed out that “the pumps work!” reservoir containing up to 200 units, de- being developed for delivery of glucagon- She predicted that several of these prod- like peptide-1 and pramlintide as well as side, with a double “squeeze” providing a fixed dose; different models deliver 1⁄2, 1,2, or 5 units per squeeze. The unit is thin, Chris Sadler (La Jolla, CA) gave an update been used to develop a V-Go insulin patch through clothing, lasting up to 3 days. Al- devices” and new design aspects of exist- both basal and bolus insulin, requiring a insulin, given the lack of adjustable basal fixed basal dose, which appears to be pre- doses in the other devices, this may not be a complete negative, and it can be used to 24 h. For bolus delivery, each click deliv- iological insulin delivery, decreased glu- ers 2 units up to a total of 36 units per risk of hypoglycemia, particularly during with an external device, with the backing electronic with a matchbox size patch and an external electronic controller, but it boluses to be delivered manually. This is a vices also use “smart features” to eliminate pressing a button on one side that releases full-featured insulin pump, with variable basal rates, allowing delivery of boluses in istered without taking into account resid- safety feature to prevent accidental bolus ual insulin delivered in previous boluses.
delivery. After 24 h, a button is pressed to withdraw the needle. The device is purely hand pump is designed for use in subjects vices will include reminders to check glu- with both type 1 and type 2 diabetes; it is cose levels, to change infusion sets, and to considerably smaller than currently avail- alarm for low insulin reservoir content.
able devices, with a remote controller, al- program, patients liked it and considered it to be easy to use, discrete, and comfort- insertions; and quick-release infusion sets insulin delivery; a patch pump from Star- mechanism, the single preset basal rate is tant benefit of CSII basal rates is the ability “needle phobia” for children. Tactile feed- back after delivery of insulin boluses and ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● external controllers that allow pumps, par- Zachary T. Bloomgarden, MD, is a practicing endocrinologist in New York, New York, and is affiliated with ticularly the “tubeless” patch pumps, to stay the Division of Endocrinology, Mount Sinai School of Medicine, New York, New York.
hidden will further improve ease of use.
2010 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.
org/licenses/by-nc-nd/3.0/ for details.
units/h, particularly important in pediat- DIABETES CARE, VOLUME 33, NUMBER 1, JANUARY 2010 Perspectives on the News
rics and for very insulin-sensitive adults, “skins” to allow patients to upload im- more intuitive interfaces and screens, per- past 2 decades furthering interest in such ratios, glucose correction factors, dura- tion of insulin action factors, and occlu- including a flat, flexible rechargeable bat- sion and safety alarms. Sadler pointed out that it is possible, unfortunately, to “out- rithm-based insulin controller, targeting a need to use the bolus calculators to fully benefit from these devices, so that they do not become just “a fancy syringe.” To use stable, rising, or falling. The Charmr and ularly test glucose levels and must accu- infusion protocols, although not avoiding gorithm is the “moving horizon concept,” and stresses, it is useful for patients using the devices to understand the use of tem- features and “to plan ahead.” A further diabetic patients. Insulin still is slow- about changes in the individual’s insulin acting, there are still infusion site failures sensitivity. The most difficult aspect of than falling into the trap of “reacting to stress of constant need for troubleshoot- ing, sensors not working, the need to wear min prior to food ingestion leads to much ment of basal rates that it is difficult to plies, leading for some patients to an over- to optimally use the devices, patients (and also a burden for clinicians, and Sandler trol, giving bolus doses ahead of the meal touched on the question, “How do we get data. Pumps capture a wealth of data, and it is important to organize the information “modal day” display particularly useful.
Data analysis with artificial intelligence with 85% of glucose levels in target range cussed approaches to “closing the loop” proach). Another aspect of true artificial providers to possible need for changes in basal or bolus doses, ideally with simpli- and a control program. “Why,” he asked, logical insulin patterns must be meal size fied and more rapid data downloading.
“aren’t we using closed loops today?” Is- leading to “stepwise progress to finally glucose sensors, probably physiologically 6 –7 min, but increased to 10 –11 min due to the filters in the devices, as well as the accuracy of sensor glucose measurement.
There is biological variability in insulin to detect presumed meal-related increases control of insulin infusion rates by small devices, Sleep Sentry devices with remote could be quite useful in pediatrics to then and a very interesting concept will be of affect glucose levels, “so you’re at least a deliver insulin. “There’s an explosion of data integrators. A service under develop- more rapidly acting insulin preparations, failure of either the sensor or the insulin tivity is another issue, with a study using the Actical multidirectional piezoelectric change recommendations to address this.
trollers are also being developed. Future 1976 led to interest in the development of judge changes in activity, and studies sug- termed “cool factors,” such as colored and gest this to be potentially useful as well.
DIABETES CARE, VOLUME 33, NUMBER 1, JANUARY 2010 Bloomgarden
Table 1—Controlled trials of CSII for type 2 diabetes
the sensors give optimal results andwhether more than one sensor should be used at one time. Buckingham observedthat fluorescent sensors appear to be an tions of the artificial pancreas might be the use of glucagon to provide a brake to gated in a porcine model (5), or the use of pramlintide to delay gastric emptying.
to the design of algorithms may be to use “in-silico” computer modeling of type 1 diabetes rather than doing animal studies to allow development of approaches thatwould reduce glycemic variation in hu-man studies and, ultimately, in patient A number of further studies described ap- tainly show feasibility of this approach, use of insulin pumps for type 2 diabetes.
al. (abstract 230) infused insulin lispro There are, he stated, 5.6 million insulin- with CSII at 0.5, 1.0, and 2.0 units/h for treated diabetic individuals in the U.S., of 4 h periods in 10 type 1 diabetic men and whom 4.5 million have type 2 diabetes.
treatment “clearly improves glucose con- He cited estimates that 31% of type 1 but Ͻ5% of type 2 diabetic patients use CSII quality of life and satisfaction, and may be progressively over each period. The re-and that 71% of patients on multiple-dose the preferred therapy for type 2 [diabetic] patients not at goal.” He suggested that neuver of reducing basal insulin infusion sulin outside the home, particularly those with type 2 diabetes. The goal of insulin low glucose levels may not, then, rapidly treatment is, however, to duplicate phys- lead to desired effects. Recognizing this delivered by CSII, Castle et al. (abstract certainment of cost-effectiveness will be 207) reported reduction in late postpran- will, Bode stated, deliver better glycemic glucagon rates based on the difference be- glucose rate of change. Russell et al. (ab- certainly offer an effective approach in re- ous insulin were presented at the meeting.
stract 235) similarly reported use of glu- ticipated was presented by Edelman et al.
betic patients taken off oral medications tion of action of insulin lispro failed to tration for type 2 diabetes and to be cost effective, with comparable expense to that eters might be required in such cases. Ko- trolled with two basal rates. Although not requiring large insulin doses, U-500 insu- 57-year-old patients with duration of di- (6), although one should be careful of the potential for occlusion of the very concen- A1C from 8.4 to 7.2% was of interest.
algorithms and reporting a fivefold reduc- trated insulin in the tubing. Medicare al- kg, but there was no weight gain in those creasing the time spent within the 3.9 – unawareness, the need for a flexible insu- DIABETES CARE, VOLUME 33, NUMBER 1, JANUARY 2010 Perspectives on the News
85 type 1 diabetic subjects viewing versus not viewing results of their CGM, and Jen- kins et al. (abstract 209) showed that type 1 diabetic adults but not adolescents had a significant predictor of glycemic change.
8.5% to a significantly greater extent with Similarly, Riddle et al. (abstract 468) re- ported an analysis of 12 studies of 2,193 1.1 vs. 0.5 times yearly; weight increased with insulin glargine and found that with 1.7 kg with both agents. Vora et al. (ab- stract 211) reported that, with four visits progressively greater amounts of 0.9, 1.4, biphasic insulin aspart twice daily or in- sulin glargine once daily plus insulin glu- lisine three times daily before meals for 52 0.1% increase with less frequent monitor- 0.8 vs. 1.3%. Although the latter regimen ing. Raccah et al. (abstract 205) reported of the cost of more frequent capillary glu- lispro three times daily before meals, 104 with conventional capillary glucose self- 448, respectively, receiving biphasic in- 135 type 2 diabetic subjects with insulin 9.3 to 8.7%. Hovorka et al. (abstract 206) sulin lispro three times or twice daily. For glargine and oral agents, titrating to fast- all groups, lower A1C levels prior to the predicted the ability to achieve target lev- ized to addition of insulin glulisine prior weight also predicting success in glycemic to the main meal or to continuation of oral agents plus glargine alone, with the single prandial insulin dose leading to improve- units/kg body wt either as separate injec- tients randomized to glargine versus CSII tions or mixed and found that mixing vir- quate control with glargine plus orals af- latter, although glucose variability did not to addition of insulin glulisine before one, two, or all three meals for 24 weeks, re- ␮g) to eight type 1 diabetic adolescents 7.3%, respectively, with similar changes in body weight, although with a trend for ϳ90% reduction in glucose excursions more frequent hypoglycemia with the gon suppression, but with delay in gastric play a role in both types of diabetes.
betic patients randomized to glargine plus Technosphere insulin for prandial control insulin ratio following a mixed meal; it is prandial administration of a rapid-acting versus biphasic insulin aspart twice daily insulin analog or pramlintide in 112 type vs. 0.3 kg weight loss, with greater hypo- determinants of treatment effect of pran- glycemia frequency in the insulin-treated cemia, respectively. Bergenstal et al.
Ͻ6.5% at 24 weeks were given both treated type 1 diabetic patients to prandial pating in the Hyperglycemia and its Effect pramlintide or prandial insulin in combi- nation, with little evidence of additional benefit over the succeeding 12 weeks.
480 insulin-naïve subjects with biphasic insulin aspart before dinner versus insulin weight loss vs. 1.4 kg weight gain. Given DIABETES CARE, VOLUME 33, NUMBER 1, JANUARY 2010 Bloomgarden
its greater A1C reduction, it is not surpris- lin covalently conjugated to Cys34 of re- ing that the injected analog was associated the difference increasing with duration of glargine in a diabetic rat model, suggest- ing that this form of insulin might require similar. Arnolds et al. (abstract 528) per- administration less often than once daily.
insulin with insulin lispro prior to a stan- dardized meal in 18 insulin-treated type 2 nondiabetic subjects after administration diabetic subjects and found that the nadir glargine and 4 studies of insulin detemir.
during initial 30 min after administration three preparations, suggesting the former insignificant difference, although the ad- to have potential benefit in reducing post- ministered insulin dose was significantly insulin effect was identical at 90 min with less with glargine at 37 vs. 52 units daily.
both products. Bolli et al. (abstract 555) jects to 0.2 units/kg insulin aspart versus glulisine prior to a test meal, finding glu- were significantly lower with the inhaled al. (abstract 492) in patients who received with addition of miglitol. Chun et al. (ab- investigators may be reducing evidence of stract 450) treated type 2 diabetic subjects diabetic patients, showing that with fast- with insulin glargine titrated to fasting these parameters; the frequency of reduc- glucose Ͻ120 mg/dl; 75 patients received a meglitinide plus ␣-glucosidase inhibi- some other clinically relevant amount was similarly reduced with both insulin treat- ments, but glargine was more effective af- despite similar premeal glucose of 116 vs.
treated 204 previously insulin-naı¨ve type following 75 g oral glucose in 15 subjects was 209 vs. 255 mg/dl, suggesting benefit and mealtime repaglinide with insulin de- al. (abstract 424), Kidron et al. (abstract Boothe et al. (abstract 5LB) produced re- preparations in type 2 diabetic patients, meta-analysis of 12 trials of 3,553 diabetic subjects randomized to insulin aspart ver- base for 10,667 versus 2,009 oral agent– glucose levels after breakfast, lunch, and treated type 2 diabetic subjects receiving evidence of fewer microvascular events in nocturnal hypoglycemia. Heller et al. (ab- the former group after adjusting for base- stract 505) reported a similar analysis of line differences in age, A1C, sex, and co- 10 trials of 3,727 diabetic subjects receiv- hypoglycemic events, bruising, or pain.
combined analysis of four trials, compar- lower postprandial glucose levels, and re- 34 type 2 diabetic subjects with A1C 7% on zero to two oral agents with insulin detemir hospitalized subjects treated with insulin plus premeal aspart for 4 – 8 weeks, exam- glargine at bedtime to receive either hu- that A1C decreased 1.2% with glargine vs.
ining a 4-h meal test before and 1 day after the completion of the intensive treatment protocol. Twenty-three patients had fast- DIABETES CARE, VOLUME 33, NUMBER 1, JANUARY 2010 Perspectives on the News
Takeda, Merck, AtheroGenics, CV Therapeutics, sion in patients with type 2 diabetes and peptide levels through the meal test than Daiichi Sankyo, BMS, and AstraZeneca; holds stock in Abbott, Bard, Medtronic, Merck, Milli- pore, Novartis, and Roche; and has served as a 7. Jennings AM, Lewis KS, Murdoch S, Tal- consultant for Novartis, Dainippon Sumitomo Pharma America, Forest Laboratories, and Nas- tech. No other potential conflicts of interest rel- insulin infusion and conventional insulin toxicity. Li et al. (abstract 499) random- evant to this article were reported.
therapy in type II diabetic patients poorly patients to intensive insulin treatment ver- sus the sulfonylurea gliclazide, with or with- References
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has served on advisory panels for Medtronic, DIABETES CARE, VOLUME 33, NUMBER 1, JANUARY 2010

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