Titration of Insulin Glargine in Patients with Type 2 Diabetes Mellitus in Asia: Physician- Versus Patient-Led? Rationale of the Asian Treat to Target Lantus Study (ATLAS)

Abstract

Objective:

The AT-LANTUS Study demonstrated that a simple subject-administered titration algorithm significantly improved glycemic control with a low incidence of severe hypoglycemia compared with a physician-managed titration. However, in the AT-LANTUS Study Asian patients were under-represented, and more than 70% of the patients were already treated with insulin. The Asian Treat to Target Lantus Study (ATLAS) will compare the effectiveness of a patient- versus physician-led initiation of insulin glargine-based basal management in the specific setting of Asia and Russia (as is routinely used in Western countries). This report presents the study design of ATLAS.

Methods:

Subjects are 40–75 years old (body mass index ≥20 and ≤40 kg/m²) with type 2 diabetes mellitus (T2DM) of >2 years in duration, suboptimally controlled (hemoglobin A1c [HbA1c] ≥7.0% and ≤11%) with stable doses of two oral antidiabetes drugs (OADs) (sulfonylureas, biguanides, α-glucosidase inhibitors, dipeptidyl peptidase-IV inhibitors, and glinides) for more than 3 months, and not using insulin. The subjects will be randomized to either the patient-led or the physician-led titration arm, where the insulin dose will be adjusted to achieve a target fasting plasma glucose (FPG) value of 110 mg/dL (6.1 mmol/L).

Study Outcomes:

The primary outcome will be change in mean HbA1c at 6 months from baseline. The analysis plan prespecifies a hierarchical testing procedure for the primary outcome. If noninferiority is achieved using a 0.3% HbA1c boundary, we will go on to undertake a test for superiority. Secondary outcomes will also include number of patients reaching American Diabetes Association target HbA1c with or without hypoglycemia and analysis of FPG profiles in the two groups.

Conclusions:

ATLAS will provide information on the relative safety and efficacy of a patient- versus physician-led titration strategy for insulin glargine-based basal insulin initiation in patients who are not controlled with two OADs in Asia and Russia. The results of the study may guide policymakers to translate data into clinical practice.

Introduction and Rationale for Study in Asia

T he worldwide prevalence of diabetes among adults (20–79 years old) is significantly projected to increase to >300 million subjects. This will be dominated by India and China. A recent nationwide survey has confirmed that diabetes has reached epidemic proportions in China, with up to 92.4 million people suffering from diabetes. China has the largest diabetes population in Asia,¹ which is larger now than India (50.8 million).² Unlike in the West, where older populations are most affected, the burden of diabetes in Asia is disproportionately high in young to middle-aged adults,³ and thus there is a longer risk of possible complications associated with diabetes. For a similar body mass index (BMI), South Asians have higher total body fat compared with white Caucasians.⁴ Obesity-related morbidities (such as diabetes, hypertension, and dyslipidemia) are more frequent at lower BMI levels in Asians than white Caucasians.³ Management of type 2 diabetes mellitus (T2DM) in Asia poses unique challenges: the International Diabetes Mellitus Practice Study (IDMPS), a multinational survey, confirmed the chasm between guidelines and practice in Asia. Asia lags behind Western and Latin American countries in the adoption of insulin, e.g., more patients in Latin America received oral antidiabetes drugs (OADs) with insulin treatment compared with patients in Asia.⁵ International guidelines recommend tight glycemic control in order to prevent the onset or to reduce the progression of complications associated with T2DM with the addition of basal insulin in OAD-uncontrolled T2DM patients.⁶ However, insulin use is delayed in Asian countries: patients were on insulin treatment for an average of 3.4 ± 4.2 years, although the average time since diagnosis was 11.8 ± 7.7 years.⁵ Failure to adequately intensify treatment to achieve glycemic targets has been termed clinical inertia. ⁷

When insulin is used, the premix insulin regimens are more popular and used more frequently than basal insulin.⁵ There is also a discrepancy between physicians' perception and actual achievement of treatment targets by patients with diabetes.⁵

Several barriers (similar to those in Western countries) to insulin therapy are encountered by both the providers and the patients with T2DM. These barriers include the fear of the needles, the number of injections as well as the number of times of self-monitoring blood glucose (SMBG), fear of hypoglycemia, and weight gain, as well as the convenience, compliance, and cost.⁸

The Diabetes Attitudes, Wishes, and Needs study done in the United States highlighted that physicians significantly delayed insulin therapy compared with their counterparts from other countries, except for India and Japan.⁹

Another critical barrier to optimal insulin therapy is the suboptimal dose titration. Adequate titration of the insulin dose, by either physicians or patients, can help patients achieve and maintain treatment goals. Self-titration (where patients adjust the insulin dosage themselves) offers the potential for better blood glucose control than titration only at clinic visits. Several studies have demonstrated the success of patient-driven self-titration schemes for insulin analogs. The concept of patient self-titration was first validated in AT-LANTUS.¹⁰ In this study, more than 70% of the patients were already treated with insulin. This study demonstrated that a simple subject-administered titration algorithm significantly improved glycemic control with a low incidence of severe hypoglycemia compared with a physician-led titration. However, in AT-LANTUS Asian patients were under-represented. Evaluating self-titration for basal insulin initiation in insulin-naive patients would therefore provide important information for the daily management of T2DM patients and may also further support international guidelines implementation in Asia.

ATLAS Study Design

The aim of this study is to evaluate the effectiveness and safety of physician- versus patient-led initiation and titration of insulin glargine in Asian patients with T2DM. The study will also describe safety and efficacy of basal insulin (glargine) addition to OAD-uncontrolled patients. Its impact on quality of life and treatment satisfaction will be assessed. This is a prospective, randomized, multicenter, multinational (Japan, China, Russia, India, Philippines, and Pakistan), open-label, active-controlled, two-arm parallel-group, 24-week phase IV study. In order to obtain a consistently high level of quality throughout the study, a Steering Committee (responsible for the proper conduct of the study according to the protocol) and a Titration Committee (ensuring the appropriate titration algorithm is followed in both arms) have been established. The study will be conducted in accordance with the principles of the 18th World Medical Assembly (Helsinki, 1964) and all applicable amendments (including the 6^th revision, 59^th World Medical Association meeting, Seoul, Republic of Korea, 2008) laid down by the World Medical Assemblies and the International Conference on Harmonization guidelines for Good Clinical Practice.

Study population

Eligible subjects are 40–75 years old (BMI ≥20 and ≤40 kg/m²) with T2DM (for >2 years), suboptimally controlled (HbA1c ≥7.0% and ≤11%) with stable doses of two OADs (sulfonylureas, biguanides, α-glucosidase inhibitors, dipeptidyl peptidase-IV inhibitors, and glinides) for >3 months, and not using insulin (Table 1).

Table 1.

Asian Treat to Target Lantus Study: Overall Inclusion Criteria

1. Subjects with a diagnosis of type 2 diabetes mellitus for more than 2 years

2. Age ≥40 and ≤75 years

3. Insulin-naïve

4. Continuous treatment with stable doses of two oral antidiabetes drugs (sulfonylureas, biguanides, α-glucosidase inhibitors, dipeptidyl peptidase-IV inhibitors, and glinides) for >3 months prior to randomization

5. Hemoglobin A1c levels ≥7% and ≤11%

6. Body mass index ≥20 and ≤40 kg/m²

7. Willing and able to perform blood glucose monitoring using a blood glucose meter

8. Willing and able to complete study diaries and questionnaires

9. Willing and able to provide written informed consent prior to enrollment in the study

Exclusion criteria included use of concomitant medication known to interfere with glucose metabolism (such as systemic steroids, nonselective β-blockers, or monoamine oxidase inhibitors), use of glucose-lowering medication that was not indicated in combination with insulin (such as glucagon-like peptide-1 analogs), or impaired renal function (serum creatinine of ≥1.5 mg/dL [133 μmol/L; male] and ≥1.4 mg/dL [124 μmol/L; female]). The overall inclusion criteria are provided in Table 1, and major exclusion criteria are provided in Table 2.

Table 2.

Asian Treat to Target Lantus Study Major Exclusion Criteria

1. Diabetes other than type 2 diabetes mellitus (e.g., secondary to pancreatic disorders, drug or chemical agent intake)

2. Current or previous use of insulin (except for previous treatment of gestational diabetes or brief treatment with insulin for <1 week)

3. Current treatment with thiazolidinediones

4. Current or previous use (within the last 3 months) of glucagon-like peptide-1 receptor agonists or glucagon-like peptide-1 analogs

5. Current or previous (within the last 3 months) use of any treatment for weight loss

6. Active proliferative diabetic retinopathy

7. Patient with no written history of an eye examination in the past 6 months

8. History of ketoacidosis or hyperosmolar hyperglycemic state

9. History of stroke, myocardial infarction, angina pectoris, coronary artery bypass graft, or percutaneous transluminal coronary angioplasty within the previous 12 months

10. History of congestive heart failure

11. History of hypoglycemia unawareness

12. Unexplained hypoglycemia in the past 6 months

13. Any medical condition that may have an influence on hemoglobin A1c measurements (e.g., sickle cell anemia, thalassemia)

14. Treatment with systemic corticosteroids in the 3 months prior to study entry

15. Currently receiving treatment with nonselective β-blockers

16. Currently receiving treatment with monoamine oxidase inhibitors

Study procedure

A total of 554 patients with T2DM will be randomized with a 1:1 ratio to the two arms: usual standard of care group with a physician-led titration (physician-led group) or intervention group with a patient-led titration (patient-led group).

In each of the two groups, patients will be initiated on insulin glargine, 10 units/day. Slightly different starting doses will be used in India and in Japan to take into account the local practices: 8–10 units/day for India and 4 units/day for subjects in Japan. Insulin glargine will be self-administered, using the SoloSTAR^® (sanofi-aventis, Paris, France) disposable pen, once daily at bedtime (preferably between 9:00 PM and 11:00 PM), by subcutaneous injection in the abdomen.

The titration regimens for each study arm will be as follows:

Physician-led group (titration performed at every visit, managed by physician). The patient will be reviewed by a physician at every visit, either in person or over the telephone. The middle value of the last three consecutive fasting plasma glucose (FPG) values will be used to perform the titration.

Patient-led group (titration every 3 days, managed by subject). The patient will be empowered to adjust his or her insulin doses, under strict investigator's supervision. The patients will use the middle value of their last three consecutive FPG values to perform the titration.

Both groups will follow the same titration regimen as provided in Table 3.

Table 3.

Asian Treat to Target Lantus Study Treatment Algorithm

Fasting blood glucose
mg/dL	mmol/L	Insulin dose
FPG ≤56	FPG ≤3.1	Dose decrease at physician's discretion and upon physician's clinical judgment
≤70 or symptomatic hypoglycemia^*	≤3.9 or symptomatic hypoglycemia^*	−2 U
70 < FPG ≤110	3.9 < FPG ≤6.1	No change
110 < FPG ≤160	6.1 < FPG ≤8.9	+2 U
FPG >160	FPG >8.9	+4 U

Occurring independently of the fasting plasma glucose (FPG) and defined as symptoms of hypoglycemia responding to ingestion of carbohydrate or an episode associated with a blood glucose level of ≤56 mg/dL (≤3.1 mmol/L).

A total of 15 study visits will be completed (seven face-to-face clinic visits; eight telephone contact visits) over a 24-week period (Fig. 1).

FIG. 1.

Asian Treat to Target Lantus Study visits.

Participants will be required to keep a daily study diary to collect information on FPG, medications taken, and other adverse events. All patients will be asked to attend an “end of study visit” at Week 25. In addition to the study visits (clinical or phone call visits) the patient may contact the investigator/provider for counseling at any time.

As of December 2010, Japan and China are actively enrolling patients in this study, and other countries will initiate enrollment soon.

Concomitant treatment

OADs prescribed before study entry will remain the same and stable throughout the trial. However, in the event of hypoglycemia, participants taking sulfonylureas or glinides may have these therapies either discontinued or have the dose reduced at the discretion of the investigator.

Other medications

Changes to other concomitant medications will be kept to a minimum during the study. However, if these are considered necessary for the patient's safety and are unlikely to interfere with the study treatments, they may be given at the discretion of the investigator and recorded in the case record forms.

Study outcome assessments

Efficacy

The primary outcome measure is change in mean HbA1c level from baseline to end of study for the patient-led titration group compared with patients receiving the conventional physician-led titration schedule. A hierarchical testing procedure is prespecified, where the groups will first be compared using a noninferiority boundary of 0.3% HbA1c for the patient-led titration scheme. If noninferiority is achieved a test for superiority of patient-led titration versus physician-led titration will be performed. Principal analyses for the primary and secondary outcomes will follow the intention-to-treat principle. Statistical analyses will follow a prespecified statistical analysis plan.

Secondary outcome measures will include percentage of patients achieving HbA1c levels <7.0% without severe hypoglycemia. In addition, the number of patients having a drop in HbA1c by at least 1% and/or a drop of at least 0.5% from baseline, mean change in FPG, postprandial blood glucose, body weight, and insulin dose from baseline to end point will be evaluated.

In addition, treatment satisfaction and patient's health-related quality of life^11,12 will be assessed in the study. Treatment satisfaction data collection will be done using Diabetes Treatment Satisfaction Questionnaire Status and Change versions (DTSQs and DTSQc, respectively). The eight-item questionnaires measure treatment satisfaction and how this satisfaction has changed on a 7-point Likert scale. Health-related quality of life will be measured with the EuroQol (EQ-5D)¹³ questionnaire assessing the current health status looking at five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each with three levels.

Statistical analyses and power

Efficacy will be analyzed in an intent-to-treat approach. A sample of 554 patients randomized using a 1:1 allocation strategy will provide an overall 5% significance level (two-sided) and 90% statistical power to exclude a difference of 0.3% HbA1c difference between the two arms, based on an expected baseline adjusted HbA1c decrease of 1.8% in the intervention and usual care arms and a 15% rate of non-evaluable patients. Similarly, the study will have 90% power to detect an HbA1c difference of 0.3%, which will be tested if the noninferiority criterion is met.

Discussion

Most Asian countries are undergoing a socioeconomic, lifestyle, and nutrition transition. Increasing levels of modernization, industrialization, and economic changes adversely affect biological and environmental risk factors for diabetes. Asian populations have low thresholds for conventional risk factors such as BMI and upper body adiposity.⁴ Diabetes develops at least a decade earlier in Asian than in white people.¹⁴ Youth-onset diabetes and T2DM in children are common, and their rising trend is linked to epigenetic factors, such as maternal imprinting, and to unhealthy lifestyle changes leading to high rates of obesity. Both the thrifty genotype and the thrifty phenotype might be operative in Asian groups.³ These populations also have high rates of clustering of cardiovascular risk factors (i.e., metabolic syndrome) even at a young age.³

Self-titration is commonly not practiced by patients in Asia. The IDMPS study⁵ also demonstrated that a large majority of Asian patients did not self-monitor blood glucose or self-adjust insulin, compared with patients in Europe, the United States, and Latin America. Hence, the Asian patients perhaps underestimate the importance of SMBG and do not perceive T2DM to be a serious disease.⁵

There is an ongoing debate as to whether and when it is most beneficial to treat patients, to target postprandial blood glucose concentrations with meal-related prandial insulin, or continue to target fasting blood glucose concentrations with basal insulin that is restricted only by hypoglycemia levels. Monnier et al.¹⁵ showed that fasting glucose is the predominant contributor to HbA1c in patients as soon as HbA1c is ≥7.3%. This finding was also further substantiated by a recent study conducted in Japanese patients.¹⁶

Evidence from the APOLLO study¹⁷ suggests that although prandial insulin (lispro) may provide control of the large postprandial glucose excursions that are thought to contribute most at HbA1c levels <7.3%, it would involve three (or more) injections of insulin plus six (or more) SMBG measurements. On the other hand, a once-daily injection of basal insulin (glargine) plus one SMBG measurement was equally effective and served as a simple and effective option that is more satisfactory to patients for early initiation of insulin therapy, as it was associated with a lower risk of hypoglycemia, fewer injections, less SMBG, and greater patient satisfaction.

The 4-T Trial¹⁸ evaluated if prandial or premixed insulins can be used as successfully as basal insulin for starting insulin. All three regimens improved glycemic control significantly, and a low 1-year dropout rate (about 6%) indicated good acceptance of insulin therapy. Severe hypoglycemia was uncommon, and few serious adverse events occurred. However, hypoglycemia was more frequent with the premixed and prandial regimens than with basal insulin. Similarly, the mean weight gain with premixed and prandial insulins was much greater than with basal insulin. Referring to the study results, an accompanying editorial¹⁹ concluded that “prandial and biphasic insulin formulations are suboptimal choices for insulin initiation” and that “the best approach is to continue metformin and add a basal insulin,” as currently advised by American Diabetes Association/European Association for the Study of Diabetes consensus guidelines.

A recent 6-month trial²⁰ compared a premix strategy or a glargine basal strategy for insulin initiation in insulin-naive T2DM patients. Premix was given twice daily prior to morning and evening meals, whereas glargine was given once daily. Compared with the insulin glargine arm, a slightly lower HbA1c level and a moderately higher percentage reaching the HbA1c target of <7.0% were found at 24 weeks in the premix arm. However, patients receiving premix insulin had more weight gain, needed an increased insulin dose, and had higher rates of overall hypoglycemia.

ATLAS will evaluate an insulin glargine-based basal strategy for starting insulin in patients failing OADs in Asian countries and Russia. Important information for improving the daily management of T2DM patients is expected from this trial. As ATLAS is not a large pragmatic trial, therefore a full extrapolation of the study results to the real-life setting may not be totally possible. In addition, even if the ethnicity of the population will be dominated by Asians, the overall population will be ethnically mixed with Asians and Caucasians. This may limit a complete translation of the results to a defined ethnic category. On the other hand, ATLAS will be the first randomized controlled trial looking into key questions for improving care of T2DM patients with basal insulin in this part of the world.

Any optimal insulin management is based on a treat-to-target approach to ensure full effectiveness while no compromise is done on safety. A specific and simple treat-to-target titration algorithm has been developed for ATLAS. This titration algorithm will support the basal insulin implementation in the study population and will be used in the two study arms. As a result, it is likely that ATLAS will add another piece of evidence on the critical nature of insulin titration to get patients to target HbA1c.

In conclusion, ATLAS will provide further evidence about insulin titration that can be safely used in Asian patients with T2DM. The results of this study would help to translate a treat-to-target approach in a bigger community and allow policymakers to make new guidelines for achieving better glycemic targets in type 2 diabetes.

Footnotes

Acknowledgments

This study was supported by sanofi-aventis. Editorial support was funded by sanofi-aventis (Asia-Pacific & Japan Region).

Author Disclosure Statement

M.O. has received lecture fees and research funding from sanofi-aventis, Novo Nordisk, and Eli Lilly. A.M. has received lecture fees and research funding from sanofi-aventis, Merck, Novartis, AstraZeneca, GSK, BMS, and Ranbaxy. M.S. has received lecture fees and funding from sanofi-aventis, Novo Nordisk, Eli Lilly, and Novartis. C.-Y.P. has received lecture fees and research funding from sanofi-aventis, Novo Nordisk, Eli Lilly, Novartis, and Bayer. A.J. has received lecture fees and research funding from sanofi-aventis and Eli Lilly. N.F. has received lecture fees and research funding from sanofi-aventis, Novo Nordisk, Eli Lilly, and Pfizer. K.A. is currently employed in the capacity of Diabetes Medical Director for the Asia-Pacific & Japan Region by the sponsor of this study, sanofi-aventis.

References

China National Diabetes and Metabolic Disorders Study Group. Prevalence of diabetes among men and women in China. N Engl J Med, 2010; 362:1090–1101.

Shaw

, Sicree

, Zimmet

. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract, 2010; 87:4–14.

Chan

J CN

, Malik

, Jia

, Kadowaki

, Yajnik

, Yoon

, Hu

. Diabetes in Asia: epidemiology, risk factors, and pathophysiology. JAMA, 2009; 301:2129–2140.

Misra

, Khurana

. Obesity and the metabolic syndrome in developing countries. J Clin Endocrinol Metab, 2008; 93,11 Suppl 1:S9–S30.

Chan

J CN

, Gagliardino

, Baik

, Chantelot

, Ferreira

SRG

, Hancu

, Ilkova

, Ramachandran

, Aschner

. Multifaceted determinants for achieving glycemic control: the International Diabetes Management Practice Study (IDMPS) Diabetes Care, 2009; 32:227–233.

Nathan

, Buse

, Davidson

, Ferrannini

, Holman

, Sherwin

, Zinman

. Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care, 2009; 32:193–203.

Philips

, Branch

Jr , Cook

, Doyle

, El-Kebbi

, Gallina

, Miller

, Ziemer

, Barnes

. Clinical inertia. Ann Intern Med, 2001; 135:825–834.

Kabadi

. Starting insulin in type 2 diabetes: overcoming barriers to insulin therapy. Int J Diabetes Dev Ctries, 2008; 28:65–68.

Peyrot

, Rubin

, Lauritzen

, Skovlund

, Snoek

, Matthews

, Landgraf

, Kleinebreil

. Resistance to insulin therapy among patients and providers: results of the cross-national Diabetes Attitudes, Wishes, and Needs (DAWN) study. Diabetes Care, 2005; 28:2673–2679.

10.

Davies

, Storms

, Shutler

, Bianchi-Biscay

, Gomis

. Improvement of glycemic control in subjects with poorly controlled type 2 diabetes: comparison of two treatment algorithms using insulin glargine. Diabetes Care, 2005; 28:1282–1288.

11.

Bradley

. The Diabetes Treatment Satisfaction Questionnaire: DTSQ. Bradley

. Handbook of Psychology and Diabetes: A Guide to Psychological Measurement in Diabetes Research and Practice. Chur, Switzerland: Harwood Academic Publishers, 1994; 111–132.

12.

Howorka

, Pumprla

, Schlusche

, Wagner-Nosiska

, Schabmann

, Bradley

. Dealing with ceiling baseline treatment satisfaction level in patients with diabetes under flexible, functional insulin treatment: assessment of improvements in treatment satisfaction with a new insulin analogue. Qual Life Res, 2000; 9:915–930.

13.

The EuroQol Group. EuroQol—a new facility for the measurement of health related quality of life. Health Policy, 1990; 16:199–208.

14.

Ramachandran

, Ma

RCW

, Snehalatha

. Diabetes in Asia. Lancet, 2010; 375:408–418.

15.

Monnier

, Lapinski

, Colette

. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA_1c . Diabetes Care, 2003; 26:881–885.

16.

Kikuchi

, Nezu

, Shirakawa

, Sato

, Togashi

, Kikuchi

, Aoki

, Ito

, Kimura

, Terauchi

. Correlations of fasting and postprandial blood glucose increments to the overall diurnal hyperglycemic status in type 2 diabetic patients: variations with levels of HbA1c. Endocr J, 2010; 57:259–266.

17.

Bretzel

, Nuber

, Landgraf

, Owens

, Bradley

, Linn

. Once-daily basal insulin glargine versus thrice-daily prandial insulin lispro in people with type 2 diabetes on oral hypoglycaemic agents (APOLLO): an open randomised controlled trial. Lancet, 2008; 371:1073–1084.

18.

Holman

, Thorne

, Farmer

, Davies

, Keenan

, Paul

, Levy

. Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes. N Engl J Med, 2007; 357:1716–1730.

19.

McMahon

, Dluhy

. Intention to treat—initiating insulin and the 4-T Study. N Engl J Med, 2007; 357:1759–1761.

20.

Buse

, Wolffenbuttel

BHR

, Herman

, Shemonsky

, Jiang

, Fahrbach

, Scism-Bacon

, Martin

. The DURABLE Trial 24-week results: safety and efficacy of insulin lispro mix 75/25 versus insulin glargine added to oral antihyperglycemic drugs in patients with type 2 diabetes. Diabetes Care, 2009; 32:1007–1013.