Insulin Pump: C-Peptide Levels as a Criterion for Use

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CMS has determined that the evidence is adequate to conclude that continuous subcutaneous insulin infusion (CSII) is reasonable and necessary for treatment of diabetic patients: 1) who either meet the updated fasting C-peptide testing requirement or are beta cell autoantibody positive; and 2) who satisfy the remaining criteria for insulin pump therapy detailed in the Medicare National Coverage Determinations Manual (Medicare NCD Manual 280.14, Section A.5). CMS has determined that fasting C-peptide levels will only be considered valid when a concurrently obtained fasting glucose is ≤ 225 mg/dL. Insulinopenia is defined as a fasting C-peptide level that is less than or equal to 110 percent of the lower limit of normal of the laboratory’s measurement method. Alternatively, for patients with renal insufficiency and a creatinine clearance (actual or calculated from age, gender, weight and serum creatinine) ≤ 50 ml/minute, insulinopenia is defined as a fasting C-peptide level that is less than or equal to 200 percent of the lower limit of normal of the laboratory’s measurement method. Levels only need to be documented once in the medical records. CMS will also continue to allow coverage of all other uses of CSII in accordance with the Category B IDE clinical trials regulation (42 CFR 405.201 ) or as a routine cost under the clinical trials policy (Medicare NCD Manual 310.1).

Decision Memo: To: Administrative File CAG-00092R Insulin Pump: C-Peptide Levels as a Criterion for Use From: Steve Phurrough, MD, MPA Director, Coverage and Analysis Group Marcel Salive, MD, MPH Director, Division of Medical and Surgical Services Coverage and Analysis Group Elizabeth Koller, MD Medical Officer, Division of Items and Devices Coverage and Analysis Group Lawrence Schott, MD, MS Medical Officer, Division of Medical and Surgical Services Coverage and Analysis Group CDR Betty Shaw, USPHS Health Insurance Specialist, Division of Medical and Surgical Services Coverage and Analysis Group Elizabeth Truong Health Insurance Specialist, Division of Medical and Surgical Services Coverage and Analysis Group Subject: Coverage Decision Memorandum for C-Peptide Levels as a Criterion for Use of Insulin Pumps Date: December 17, 2004 I. Decision CMS has determined that the evidence is adequate to conclude that continuous subcutaneous insulin infusion (CSII) is reasonable and necessary for treatment of diabetic patients: 1) who either meet the updated fasting C-peptide testing requirement or are beta cell autoantibody positive; and 2) who satisfy the remaining criteria for insulin pump therapy detailed in the Medicare National Coverage Determinations Manual (Medicare NCD Manual 280.14, Section A.5). CMS has determined that fasting C-peptide levels will only be considered valid when a concurrently obtained fasting glucose is ≤ 225 mg/dL. Insulinopenia is defined as a fasting C-peptide level that is less than or equal to 110 percent of the lower limit of normal of the laboratory’s measurement method. Alternatively, for patients with renal insufficiency and a creatinine clearance (actual or calculated from age, gender, weight and serum creatinine) ≤ 50 ml/minute, insulinopenia is defined as a fasting C-peptide level that is less than or equal to 200 percent of the lower limit of normal of the laboratory’s measurement method. Levels only need to be documented once in the medical records. CMS will also continue to allow coverage of all other uses of CSII in accordance with the Category B IDE clinical trials regulation (42 CFR 405.201 ) or as a routine cost under the clinical trials policy (Medicare NCD Manual 310.1). II. Background On April 1, 2004, CMS began a national coverage determination (NCD) for reconsideration of C-peptide levels as a criterion for use of insulin pumps in diabetic patients. Diabetes is a disease in which insulin is absent or not functionally available in sufficient quantities to metabolic pathways including those for glucose utilization. Endogenous insulin, a hormone secreted by beta cells in the islets of Langerhans of the pancreas, is itself synthesized as a larger molecule called proinsulin that is subsequently cleaved into insulin and C-peptide. Serum C-peptide, measured by either radioimmunoassay or immunochemiluminometric assay techniques, is thus a marker for endogenous insulin release in diabetic patients. Historically, diabetes has been broadly classified as type 1 diabetes mellitus (T1DM; formerly called type I, insulin-dependent diabetes mellitus (IDDM) or juvenile diabetes) and type 2 diabetes mellitus (T2DM; formerly called type II, non-insulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes) with the distinguishing features largely based on clinical presentation. T1DM is generally associated with an earlier age of onset, thinner patients and ketosis, whereas T2DM is associated with a later age of onset and weight gain. T1DM accounts for 5 to 10% of diabetic patients and results from immune-mediated destruction of the pancreatic islet cells including pancreatic beta cells. T2DM accounts for 90 to 95% of diabetic patients and is generally characterized by insulin resistance. Grouped together to form a third etiologic classification are “other specific types” of diabetes mellitus, which include diabetic patients with genetic defects, diseases of the exocrine pancreas, endocrinopathies, drug-induced or chemical-induced diabetes, infections, uncommon forms of immune-mediated diabetes, and other genetic syndromes sometimes associated with diabetes. 1 , 2 Our understanding about the etiology of diabetes continues to evolve and has complicated this diagnostic schema. Specifically, diabetes appears to be polygenic. 3 , 4 , 5 This is consistent with the observation that some patients cannot be classified as T1DM, T2DM or “other specific types” of diabetes, but are rather type 1.5 diabetes, late autoimmune diabetes in adults (LADA) or slowly progressive type 1 diabetes. Indeed, in the United Kingdom Prospective Diabetes Study (UKPDS) in type 2 diabetic patients, glutamic acid decarboxylase (GAD) antibodies - a marker and possibly causative antibody for type 1 diabetes - were noted to be present in a significant number of patients, albeit more prevalent in the cohort diagnosed between the ages of 25 and 35 years (34%) than in those diagnosed between the ages of 55 and 65 years (7%). 6 , 7 Takeda, et al.’s (2002) cross-sectional study (N = 4980 adult onset diabetic patients screened, N = 190 control without diabetes in first degree relatives) also identified such hybrid patients and further delineated markers associated with progression to insulin dependence. 8 GAD antibodies were detected in 188 (3.8%) screened patients and only 1 control. Of the patients with GAD antibodies and C-peptide data before and after a meal or after glucagon, 43% were considered insulin deficient and 57% were considered insulin sufficient. Certain haplotypes (HLA Class II genes), including the type 1 diabetes susceptibility alleles DRB1*0405 and DRB1*0901, were more common in the GAD positive-insulin deficient cohort than in controls. DRB1*0405 was more common in the GAD positive-insulin sufficient cohort than in controls. Putative protective genotypes DRB1*1502 and DQB1*0601 were more common in the GAD positive-insulin sufficient cohort than the GAD positive-insulin deficient cohort, but no more common than in controls. Insulinoma antigen (IA2) antibodies were more prevalent in the GAD positive cohort. GAD positive-insulin deficient patients were younger at the age of diagnosis and had lower maximal body mass indices and higher levels of GAD antibodies than GAD positive-insulin sufficient patients. 100% of GAD positive-insulin deficient patients used insulin whereas 38% of GAD positive-insulin sufficient patients were treated with insulin. Two strategies for managing diabetic patients requiring insulin use either conventional or intensive insulin therapy; both strive to maintain blood glucose levels near the normal range. With conventional therapy, insulin replacement is provided by 1 to 2 subcutaneous injections of insulin daily, usually with a combination of short-acting and long-acting preparations. With intensive therapy, insulin replacement is provided by 3 to 5 multiple daily injections (MDI) of insulin or by CSII. CSII attempts to more closely replicate the normal pattern of secretion of endogenous insulin by supplying insulin at a baseline rate augmented by pre-meal insulin boluses. CSII delivery systems involve a battery-powered pump, which holds a reservoir of buffered regular insulin or approved short-acting insulin analog. The pump propels insulin from the reservoir through an infusion set into a catheter inserted in the subcutaneous tissue of the abdomen (or alternatively the thigh or hip). The CSII systems do not measure blood glucose levels or automatically adjust insulin delivery rates. For proper effect, the CSII user must measure blood glucose several times per day and program the pump to deliver an appropriate basal rate and pre-meal boluses of insulin. Because of these requirements, not all patients are candidates for intensive therapy. CSII should be used only in diabetic patients who have been demonstrated to have T1DM or to be insulinopenic. With T1DM, most or all insulin producing capacity is lost within 12 months of presentation. C-peptide is typically low or absent in T1DM. With T2DM, insulin capacity may not be impaired initially. Patients typically have insulin resistance and can produce high levels of endogenous insulin, but the insulin is biologically less effective. The presence of this endogenous insulin permits therapies with various oral agents, which either cause more insulin to be released or improve the effectiveness of available insulin. Over time, however, the beta cells become exhausted, and oral agents become less effective. 9 This can be documented by decreased C-peptide during the fasted state or after a challenge by glucose, glucagon, Sustacal or a mixed meal. Although C-peptide levels are useful for assessing beta cell reserve, there are important considerations to their use for these purposes. 10 High glucose levels can cause glucose toxicity and impair both insulin and C-peptide release. This can be reversed with improved glycemic control. Renal dysfunction can also alter clearance of insulin and especially C-peptide. The effect on C-peptide levels appears most prominent when the creatinine clearance is < 50 ml/min. C-peptide levels may be artifactually high in this setting. 11 In the absence, however, of a clear algorithm or diagnostic gold standard to separate the two major forms of diabetes, CMS chose in both prior NCDs for insulin pump therapy to utilize C-peptide testing as the best available method of measuring insulin secretory ability, assessing residual beta cell function and ensuring appropriate use of CSII. 12 , 13 The current decision memorandum for reconsideration is an attempt to recognize and incorporate new data about the pathophysiology of diabetes and factors affecting C-peptide into a workable algorithm for Medicare beneficiaries. III. History of Medicare Coverage CMS’s Center for Medicare Management (CMM) has determined that the subcutaneous insulin infusion pump falls within the benefit category set forth for “Durable Medical Equipment” in Section 1861(n) of the Social Security Act. On August 26, 1999, HCFA (now CMS) issued the first decision memorandum (CAG-00041N) for “Continuous Subcutaneous Insulin Infusion Pumps” that utilized a C-peptide testing requirement for Medicare coverage of CSII pump therapy. 14 On May 11, 2001, CMS issued a second decision memorandum (CAG-00092N) for “Insulin Pump: C-Peptide Levels as a Criterion for Use” and on January 1, 2002, revised the cut-point for the C-peptide testing requirement for Medicare coverage of CSII pump therapy. 15 Coverage of CSII for the treatment of diabetic patients in the home setting is currently defined by the criteria outlined in Section A.5 of Medicare NCD Manual 280.14. On March 19, 2004, CMS received a request for reconsideration of the NCD for insulin pumps. In this letter Medtronic MiniMed requested removal of the C-peptide testing requirement as a condition of Medicare coverage for insulin pumps. The complete formal request letter is available on our tracking sheet at http://www.cms.hhs.gov/mcd/viewtrackingsheet.asp?id=109 . IV. Timeline of Recent Activities January 1, 2004 CMS began its modified NCD process on January 1, 2004. See “Changes to the National Coverage Determination Process” available electronically at http://www.cms.hhs.gov/coverage/8a4.asp April 1, 2004 CMS accepted Medtronic MiniMed’s formal request and initiated review. CMS also began, as of this posting date, its standard, initial 30-day comment period on this NCD to obtain public and scientific input relevant to the issue under consideration. April 29, 2004 CMS teleconference with Office of Compliance in Center for Devices and Radiological Health (CDRH) at the Food and Drug Administration (FDA) regarding history of past and present device recalls for insulin pumps. July 9, 2004 Initial public comments posted to tracking sheet available electronically at http://www.cms.hhs.gov/mcd/viewtrackingsheet.asp?id=109 July 13, 2004 CMS meeting with AACE Intensive Insulin Management Task Force and Medtronic MiniMed. September 30, 2004 Proposed Decision Memorandum posted to the tracking sheet, available at http://www.cms.hhs.gov/mcd/viewtrackingsheet.asp?id=109 , for final 30-day public comment period. October 28, 2004 CMS teleconference with Medtronic MiniMed regarding the requestor’s submitted written comments on the Proposed Decision Memorandum. V. FDA Status Medtronic MiniMed’s 508 insulin infusion pump received 510(k) marketing approval as a class II device on August 18, 2000. Medtronic MiniMed’s Paradigm insulin infusion pump received 510(k) marketing approval as a class II device on June 8, 1999. These pumps are indicated for use at set and variable rates for the management of diabetes mellitus in persons requiring insulin. In an April 2004 teleconference with CMS, the FDA’s Office of Compliance (OC) noted serious problems and recalls 16 involving Medtronic MiniMed’s insulin pump products. CMS reviewed Medtronic MiniMed’s regulatory history, which included several Class II and III recalls for potential timing problems, software lock-ups, development of pump case cracks and software errors in insulin infusion pumps. The OC reported that in October 2003, an FDA inspection revealed Medtronic MiniMed had conducted recall actions without the FDA’s knowledge, and that in April 2004, the FDA had requested Medtronic MiniMed present a plan or procedure for alerting customers about new or changed products. In May 2004, Medtronic MiniMed issued a Class I recall of its Paradigm Quick-set Plus Insulin Administration Sets for potential leakage or interruption of insulin flow that could go unnoticed due to no accompanying alarm to alert users. 17 In May 2004, the FDA also initiated a full quality system inspection of Medtronic MiniMed due to the OC’s serious concerns about recent adverse event reports and recalls. The OC suspected possible serious deviations from the Quality System Regulation and judged this inspection to be a critical assignment due to the life-saving nature of the device and Medtronic MiniMed’s large share of the insulin infusion pump market. The OC additionally noted that other insulin pump manufacturers have experienced serious problems and recalls. This included a Class I recall of Disetronic’s D-TRON insulin pump initiated in June 2002 for potential delivery of an unintended insulin bolus. 18 VI. General Methodological Principles When making national coverage determinations, CMS evaluates relevant clinical evidence to determine whether or not the evidence is of sufficient quality to support a finding that an item or service is reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member. The overall objective for critical appraisal of the evidence is to determine to what degree we are confident that: 1) the specific assessment questions can be answered conclusively; and 2) the intervention will improve net health outcomes for Medicare patients. Evidence may consist of external technology assessments, internal review of published studies, recommendations from the Medicare Coverage Advisory Committee (MCAC), evidence-based guidelines, professional society position statements, expert opinion, and public comments. A fully detailed account of “General Methodological Principles of Study Design” that CMS staff utilizes to assess the relevant literature on the therapeutic or diagnostic item or service for specific conditions follows the conclusion and references for this decision memorandum (see Appendix A). VII. Evidence A. Introduction This summary represents the body of evidence describing C-peptide levels and other laboratory measures as critical selection criteria for continued rational study and use of CSII pump therapy in diabetic Medicare patients. The health outcomes of interest to CMS include changes in the incidence of complications such as neuropathy, retinopathy, nephropathy or infection; the number of hypoglycemic or diabetic ketoacidotic episodes; and cardiovascular, non-cardiovascular or all-cause mortality. In analyzing the evidence, CMS focused upon the following question: “Is there adequate evidence to further refine the criteria for a diagnosis of T1DM or insulinopenia sufficient to support the use of CSII in the Medicare population?" B. Discussion of Evidence Reviewed The evidence reviewed includes summaries of CMS’s 1999 and 2001 insulin pump decision memorandums, an external technology assessment, CMS’s internal technology assessment of new or reconsidered evidence, as well as professional society position statements and expert opinion. 1. Prior CMS Decision Memorandums for Insulin Pump Use In the 1999 decision memorandum “Continuous Subcutaneous Insulin Infusion Pumps (CSII)” (CAG-00041N), CMS outlined the description and treatment of diabetes mellitus, reviewed the history of Medicare's coverage policies on diabetes management, analyzed the relevant scientific data related to the CSII pump, and delineated reasons supporting a positive national decision to cover the device for T1DM. The 1999 decision memorandum required physicians to document T1DM with a C-peptide level less than 0.5ng/ml for CSII coverage. 19 In the 2001 decision memorandum for “Insulin Pump: C-Peptide Levels as a Criterion for Use” (CAG-00092N), CMS additionally discussed the use of C-peptide as a means to distinguish T1DM versus T2DM, reviewed the scientific and clinical literature on the use of C-peptide levels as a method of determining beta-cell activity, and delineated reasons for revising the C-peptide requirement for CSII pump therapy. The review of the scientific literature and subsequent discussions with clinicians, researchers and specialty groups formed the basis for CMS’s decision to initiate the C-peptide requirement as a reasonable method for distinguishing between T1DM and T2DM. The 2001 decision memorandum revised the cut-point for the C-peptide testing requirement to less than or equal to 110% of the lower limit of normal of the lab's measurement method. 20 2. External Technology Assessment CMS identified a 2003 National Institute for Clinical Excellence (NICE) technology appraisal on “Guidance on the Use of Continuous Insulin Infusion for Diabetes”. 21 NICE, an independent organization responsible for developing guidance documents for healthcare professionals and patients, is part of the United Kingdom National Health Service (NHS). While not specifying diagnostic criteria, the NICE appraisal defined T1DM as follows: “In type 1 diabetes, the pancreas makes little or no insulin because the islet b cells, which produce insulin, have been destroyed through an autoimmune mechanism. Therefore, people with type 1 diabetes usually depend on daily insulin injections to survive.” (Section 2.2 of NICE guidance document) In defining T2DM, the NICE appraisal wrote: “Type 2 diabetes results from failure of insulin production to overcome reduced tissue sensitivity to insulin (known as insulin resistance). Type 2 diabetes is a progressive disease in which insulin production declines as the disease progresses.” (Section 2.3 of NICE guidance document) Guidance for T1DM NICE recommended CSII as an option for T1DM provided that MDI therapy failed and that those receiving the treatment had the commitment and competence to effectively use CSII. (Section 1.1 of NICE guidance document) Guidance for T2DM The 2003 NICE technology appraisal noted that there was insufficient evidence with which to draw conclusions from studies comparing the effect of CSII with MDI treatment in T2DM. NICE concluded that CSII is not recommended for patients with T2DM requiring insulin therapy. (Section 1.6 of NICE guidance document) 3. Internal Technology Assessment Literature Search CMS extensively searched PubMed (1990 to present) for new randomized controlled trials (RCTs) and systematic reviews evaluating the use of clinical laboratory criteria to differentiate major types of diabetes and ensure appropriate use of CSII in patients with T1DM, T2DM and other specific types of diabetes requiring insulin. CMS likewise searched the Cochrane Collaboration, the NHS Centre for Reviews and Dissemination, and the INAHTA databases for all systematic reviews and technology assessments. Keywords used in CMS’s search included C-peptide, diabetes, T1DM, T2DM, insulin pump, intensive insulin management and CSII. RCTs must have presented original data, included greater than or equal to 10 patients, examined health outcomes, and been published as full-length articles in peer-reviewed, English language journals. Uncontrolled studies and abstracts were excluded. Summary of Evidence Using the aforementioned search strategy to supplement the latest technology appraisal from NICE (2003), CMS identified 65 articles, 1 current health plan policy, 2 professional society position statements, 124 expert opinions from practitioners and 7 public comments from patients and family members. Articles subsequently reviewed have either been newly published since CMS’s 2001 decision memorandum or are previously published relevant articles now being reconsidered or referenced for the first time. Scientific Articles Pickup, et al.’s (2002) meta-analysis studies performed between 1975 and 2000 identified 12 randomized controlled trials of insulin pump therapy compared with optimized insulin injection therapy for T1DM. This meta-analysis did not specifically define T1DM and also did not include trials of pregnant women or trials of newly diagnosed T1DM. All but Hanaire-Broutin’s (2000) study were performed during the 1980s and were not part of CMS’s literature search for new RCTs or systematic reviews of CSII. Outcome measures in Pickup’s meta-analysis were glycemic control measured by mean blood glucose concentration and percentage of glycated hemoglobin, as well as total insulin dose. Glycemic control was slightly better during CSII compared with optimized injection therapy, including both a standardized mean blood glucose concentration difference of 0.56 (95% confidence interval of 0.35 to 0.77) equivalent to a difference of 1.0 mmol/l, and a lower percentage of glycated hemoglobin equivalent to a difference of 0.51%. CSII achieved this improved control with an average reduction of 14% in insulin dose equivalent to 7.58 units/day. Pickup and colleagues concluded the “difference in control between the two methods is small but should reduce the risk of microvascular complications.” 22 Weissberg-Benchell’s (2003) meta-analysis of insulin pump therapy reported on 52 studies of T1DM, the majority of which were published before 1987. A total of 11 studies (1 with random assignment procedures) were classified as parallel group design comparing CSII pump therapy with MDI and conventional insulin therapy, and 41 studies (5 using random assignment and the remainder enrolling self-selected patients) were classified as paired design assessing the same patients before and after initiation of CSII. This study concluded that CSII was associated with improved glycemic control compared to MDI and conventional insulin therapy and did not appear to be associated with significant adverse outcomes. Weissberg-Benchell and colleagues, however, noted that the majority of studies in their meta-analysis were published before 1987 and that relatively few studies reported after the 1993 Diabetes Control and Complications Trial (DCCT) specifically examined the relative risks and benefits of CSII therapy. The authors recommended standardized and systematic reporting of outcomes data in future research and cautioned that their results “should not be viewed as a definitive statement about the efficacy of CSII therapy.” 23 The landmark DCCT (1993), which compared conventional and intensive insulin therapy, measured insulin dependence based on deficient C-peptide secretion of < 0.2 pmol/ml and used this as a major patient eligibility criterion. Other major DCCT inclusion criteria included an age of 13 to 39 years; exclusion criteria included hypertension, hypercholesterolemia, and severe diabetic complications or medical conditions. In this study of T1DM patients, the DCCT research group reported that intensive therapy administered either with three or more daily insulin injections or an external insulin pump effectively delayed the onset and slowed the progression of diabetic retinopathy, nephropathy and neuropathy (microvascular complications) in patients with insulin-dependent diabetes. 24 , 25 Building upon the DCCT’s original design, selection criteria and C-peptide testing protocol, the investigators subsequently published a 1998 DCCT follow-up study of annually measured stimulated C-peptide levels in a subgroup of patients it termed “responders”. Among 855 of the 1441 DCCT participants who had T1DM for 1 to 5 years at baseline, 303 (35%) of those 855 patients were C-peptide “responders” defined as having a C-peptide level of 0.2 to 0.5 pmol/ml after ingestion of a standardized, mixed meal. Development of retinopathy, HbA1c levels and episodes of hypoglycemia were also measured. The results of the C-peptide screening during the feasibility phase of the DCCT provided insight into the natural history of residual beta cell function in T1DM, and this follow-up 1998 study showed responders receiving intensive therapy maintained a higher stimulated C-peptide level than those receiving conventional therapy. This 1998 analysis concluded that intensive therapy for T1DM helps sustain endogenous insulin secretion, which in turn was associated with improved metabolic control and decreased risk of hypoglycemia and chronic complications. 26 In Hanaire-Broutin’s (2000) randomized study of T1DM, inclusion criteria were HbA1c < 10%, negative C-peptide level and experience of intensified insulin therapy. A total of 41 C-peptide negative T1DM patients were studied to compare the efficacy of CSII versus MDI using the short-acting insulin lispro. In this unblinded crossover study comparing two successive periods of intensive insulin therapy by CSII and MDI, patients were randomly assigned to either CSII or MDI therapy for 4 months then switched to the other treatment for 4 months. Mean insulin dose and the frequency of hypoglycemic events were recorded. Hanaire-Broutin, et al. concluded that CSII pump therapy required lower doses of insulin lispro than MDI and did not increase the risk of hypoglycemia. 27 In DeVries and colleagues’ (2002) multicenter, open-label, double 16-week crossover trial of CSII (N = 39) and intensive insulin injection therapy (N = 40), inclusion criteria were T1DM patients between 18 and 70 years of age, with persistent poor control on three or more insulin injections a day, who were diagnosed at or before age 30 years, with a C-peptide level ≤ 0.2 nmol/l and glucose level ≥ 7.0 mmol/l. 28 In this study, CSII improved glycemic control and some aspects of health-related quality of life in patients with a history of long-term poor glycemic control. 29 Linn, et al. (2003) also published the protocol for a study evaluating the effect of conventional versus intensive insulin therapy on residual beta cell function in T1DM, with anticipated three-year follow-up. In this ongoing study of newly diagnosed T1DM subjects, the presence of diabetes related antibodies was not mandatory for inclusion, but a negative C-peptide level at diagnosis is among the exclusion criteria. The authors noted that, while the bulk of uncontrolled trials in the past 20 years suggested that residual C-peptide might be beneficial for the prevention of diabetes related vascular disease, their trial will help settle whether preservation of residual insulin/C-peptide facilitates stable glucose levels. 30 In patients with T2DM, a multicenter, randomized, parallel-group, 24-week study (N = 127) by Raskin and colleagues (2003) compared the efficacy, safety and patient satisfaction of CSII with MDI therapy. The study’s inclusion criteria required that enrolled patients ≥ 35 years had at baseline a fasting C-peptide level > 0.2 nmol/l, BMI ≤ 43 kg/m 2 and HbA1c level ≥6% and ≤ 12%. Exclusion criteria were patients with impaired hepatic, renal or cardiac function, as well as recurrent hypoglycemia. 31 Raskin’s study concluded that insulin aspart in CSII pump therapy showed efficacy and safety comparable to MDI for T2DM, and that patients with T2DM can be trained as outpatients to use CSII and prefer CSII to injections. As described by one of the study’s co-authors (BB), a respondent in CMS’s initial 30-day public comment period, the “main benefit in the CSII group of patients was improvement in quality of life and greater acceptance of intensive insulin therapy.” Five additional studies of CSII pump therapy examined by CMS for this reconsideration utilized inclusion or exclusion criteria other than a C-peptide level (see also Table 1). For example, in Jennings, et al.’s (1991) randomized trial to compare CSII (N = 10) with conventional insulin therapy consisting of twice daily regular and NPH insulin (N = 10) in T2DM patients poorly controlled on sulfonylureas, inclusion criteria included all Caucasian patients attending diabetes clinic, aged 40 to 65 years, without severe diabetic complications, who had previously been satisfactorily treated with sulfonylureas for at least 1 year. Patients were excluded if they had features of T1DM (including those with islet cell antibodies), retinopathy requiring laser therapy, serum creatinine > 200 μM, severe neuropathy, severe cardiovascular disease, an uncorrected endocrine abnormality, or another life-threatening disease. No additional definition of T1DM or specification of excluded T1DM patients was made. In this study of patients < 65 years of age without severe microvascular or macrovascular disease, the proportion of patients achieving satisfactory glycemic control was greater with CSII than conventional insulin therapy. Weight gain, insulin dosage and prevalence of hypoglycemia were similar in the two treatment groups. 32 In Bode, et al.’s (1996) unblinded study comparing the incidence of severe hypoglycemia in T1DM patients (N = 55) crossed over from MDI to CSII, inclusion criteria included a minimum of 12 months on MDI before crossover and 12 months on CSII-based intensive therapy after crossover. These 55 patients were selected from “a population of 255 patients using CSII”, and no other definition or specification of included T1DM patients was made. Criteria for switching from MDI to CSII included suboptimal glycemic control to intermediate-acting insulin, HbA1c > 8%, history of recurrent severe hypoglycemia, or hypoglycemic unawareness. In Bode’s study, the incidence of severe hypoglycemia during MDI declined from 138 to 22 events per 100 patient-years during the first year of CSII (P < 0.0001) and remained significantly lower in years 2, 3 and 4 on CSII therapy. The difference in diabetic ketoacidosis rates between the MDI year and the CSII period (14.6 versus 7.2 events per 100 patient-years, respectively) was not statistically significant. 33 In Boland, et al.’s (1999) nonrandomized study to evaluate psychosocial outcomes in adolescents with established T1DM utilizing CSII versus MDI, inclusion criteria included youths aged 12 to 20 years, with no other health problem except treated thyroid disease, treatment with insulin for ≥ 1 year, recent HbA1c between 7 – 14%, no more than two severe hypoglycemic events within the past 6 months, and in a school grade appropriate to within 1 year of their age. Patients were selected from a diabetes clinic caring for children, adolescents and young adults with T1DM. No other definition or specification of included T1DM patients was made. Data was reported on the first 75 patients enrolled in the study who completed 12 months of follow-up. Self-reported questionnaires demonstrated improvement in self-efficacy, depression and quality of life in both CSII and MDI treated patients. 34 In Maniatis, et al.’s (2001) nonrandomized study (N = 56) to determine the feasibility and efficacy of CSII in routine pediatric diabetes care, inclusion criteria were HbA1c levels available ≥ 6months before and after CSII initiation, as well as duration of CSII ≥ 6 months. The children and adolescents selected were all cared for in a pediatric clinic for childhood diabetes, and no additional definition or specification of included T1DM patients was made. The mean duration of CSII therapy was 12.2 months (range: 6 – 35 months). Results for the entire cohort demonstrated a decrease in HbA1c from 8.5% to 8.3%, including 36 patients (64.3%) who maintained or achieved an HbA1c < 8.0% or at least 1% lower than their pre-CSII level. Of concern were 10 of 17 patients with an initial HbA1c ≥ 9% who remained ≥ 9% on CSII, as well as 6 patients (10.7%) who demonstrated a clinically significant increase in HbA1c from 8.3% to 9.6% on CSII. Analysis of HbA1c subgroups could not identify any distinguishing features predictive of outcome on CSII, and Maniatis, et al. noted that additional study is underway to prospectively identify predictors for those at risk for metabolic deterioration on CSII therapy. 35 In Tsui, et al.’s (2001) RCT to evaluate glycemic control, hypoglycemic events and quality of life in patients treated for 9 months with CSII (N = 13) versus MDI (N = 14), inclusion criteria included adults between 18 and 60 years of age with T1DM for > 2 years, onset of diabetes on or before age 40, and ability to comply with treatment. Patients considered for inclusion in Tsui’s trial had an “endocrine diagnosis of type 1 diabetes”, but no other definition or specification of T1DM was stated for those selected. Patients were excluded if they had a history of more than two hypoglycemic episodes within the previous year; hemoglobinopathy; insulin resistance; extreme obesity (BMI > 35 kg/m 2 ); severe late complications of diabetes; evidence of significant cardiovascular, hepatic disease, cancer, or cerebrovascular or severe peripheral vascular disease; or alcohol or drug abuse. In Tsui’s study, no statistically significant differences in glycemic control, reported hypoglycemic events or quality of life were found. 36 Table 1: Characteristics of Insulin Pump Studies Study Type C-Peptide Inclusion Criterion Age DCCT Group (1993) T1DM < 0.2 pmol/ml 13 to 39 years Bode, et al. (1996) T1DM None 39.2 ± 12.9 DCCT Group (1998) T1DM 0.2 to 0.5 pmol/ml 13 to 39 years Boland, et al. (1999) T1DM None 12 to 20 years Hanaire-Broutin, et al. (2000) T1DM Negative C-peptide 21 to 65 years Maniatis, et al. (2001) T1DM None 7 to 23 years Tsui, et al. (2001) T1DM None 18 to 60 years DeVries, et al. (2002) T1DM ≤ 0.20 nmol/l (if ≤ 30 years) ≤ 0.05 nmol/l (if ≤ 40 years) 18 to 70 years Linn, et al. (2003) T1DM Negative C-peptide excluded 18 to 40 years Jennings, et al. (1991) T2DM None 42 to 65 years Raskin, et al. (2003) T2DM > 0.2 nmol/l 55.1 ± 10.2(CSII) 56.0 ± 8.18(MDI) Literature has been published since CMS’s last decision memorandum exploring new concepts about the pathophysiology, diagnosis and treatment of diabetes. Defining diabetes as the result of long-lasting, immune-mediated destruction of pancreatic beta cells, Batstra and colleagues (2001) noted “autoantibodies originating from this process can be applied in the diagnosis and clinical discrimination of autoimmune diabetes as well as in the prediction of this disease.” Over 85% of recently diagnosed patients with T1DM and only about 3.5% of patients with T2DM are said to be positive for beta cell autoantibodies. The most significant of these are islet cell antibodies (ICA), which were first described in T1DM in 1974, followed by later discovery of insulin autoantibodies (IAA), glutamic acid decarboxylase (GAD) autoantibodies and insulinoma antigen (IA2) autoantibodies. According to Batstra’s review, GAD and to a lesser degree ICA autoantibodies can be utilized “for the differential diagnosis of diabetes in adult patients and have a better predictive value than biochemical (C-peptide, HbA1c) or clinical parameters (age of diagnosis, BMI). 37 On behalf of the Immunology of Diabetes Society, Greenbaum and Harrison also proposed that subjects in standardizing protocols for intervention trials in newly diagnosed T1DM should have at least one of the above four islet autoantibodies. These authors also clarified that although up to 10% of patients presenting with clinical T1DM are antibody negative and 10 to 15% of patients with clinical T2DM are autoantibody positive, autoantibody measurements remain the best indication that diabetes is immune-mediated and that the presence of one or more islet autoantibodies (i.e., GAD, IAA, IA2 or ICA) is a sufficient criterion for study enrollment. 38 Other recent evidence regarding C-peptide as a surrogate outcome measure has been published since CMS’s 2001 memorandum. For example, beta cell function in newly diagnosed T1DM was recently reported as a “measurable outcome that likewise predicts long-term clinical status.” At an American Diabetes Association workshop held in October 2001, participants concluded that: “Measurement of C-peptide under standardized conditions provides a sensitive, well accepted, and clinically validated assessment of beta cell function. C-peptide measurement is the most suitable primary outcome for clinical trials of therapies aimed at preserving or improving endogenous insulin secretion in type 1 diabetes patients.” Participants further noted “relatively low variability and high reproducibility of C-peptide measurements make the assay suitable for precisely assessing the durability of a beta cell effect over long periods of time.” 39 New articles have also quantified the prevalence of T2DM and need for additional study of CSII in the target Medicare population. As calculated from a 5% nationally representative random sample of claims from beneficiaries aged ≥ 65 years in the 1999 Medicare Standard Analytic Files, 94.8% of elderly diabetic patients identified had T2DM and only 5.2% had T1DM. Furthermore, it has been estimated that 96% of all Medicare beneficiaries with T2DM have at least one other chronic condition and 46% of all Medicare beneficiaries ≥ 65 years with T2DM have ≥ 5 comorbid conditions. The most prevalent comorbid conditions among these Medicare T2DM patients are hypertension (66%), lipid disorders (36%), coronary atherosclerosis (33%), congestive heart failure (23%) and cardiac dysrhythmias (19%). 40 Despite this health burden for elderly T2DM patients, a recent review of insulin pump therapy observed that: 1) Outcome data are “almost non-existent for use in type 2 diabetes”; 2) “There have been no large-scale randomized, controlled trials examining the use of external insulin pumps in patients with type 2 diabetes”; and 3) “When considering both cost-effectiveness and risk-benefit, there are no compelling reasons to widely use insulin pumps in patients with type 2 diabetes at this time.” 41 As introduced in the background section, C-peptide levels can be useful in the assessment of beta cell reserve. There are, however, limits to their use in patients with hyperglycemia or renal disease. Investigators observed that the beta cell response in both animal and human subjects could recover with improvements in glycemic control. The restoration of euglycemia or near euglycemia was more important than the specific modality (pharmacological intervention, diet, weight loss) used to achieve glycemic control. 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 50 , 51 , 52 , 53 In an attempt to identify the pathophysiology, Brunzell, et al. (1976) delineated impairment of the first phase insulin response (insulin release within 10 minutes) of beta cells in T2DM patients with fasting glucose levels > 6.4 mmol/l. 54 Pfeifer, et al. (1981) demonstrated an impaired insulin response to non-glucose stimuli in diabetic subjects. 55 Dimitriadis, et al . (1985) and Goodner, et al. (1969) observed abnormal islet cell responses to short-term infusion of glucose in normal volunteers. 56 , 57 Islet cell impairment after glucose infusion was also observed in animal studies of cats by Dohan and Lukens (1948), dogs by Imamura, et al. (1988), and rats by Leahy, et al . (1987). 58 , 59 , 60 This is supported by pancreatic fibrosis and islet cell disarray observed in rats after 3 months of hyperglycemia (≥ 10 mmol/l) 61 and the impaired insulin secretion by islet cells incubated for 1 week in glucose (16.7 mmol/l versus 5.6 mmol/l). 62 Although the endocrinology community has generally accepted the concept of glucose toxicity 63 , 64 , there have been studies in which insulin secretion in non-diabetic subjects increased in response to hyperglycemia. 65 , 66 , 67 , 68 , 69 , 70 In many of these studies, the duration of hyperglycemia was relatively short and/or the magnitude of hyperglycemia relatively mild (≤ 7.2 mmol/l). Thus, this may not be a contradiction but rather the manifestation of a threshold effect. These methodological shortcomings were, in fact, addressed by Boden, et a l. (1996) in a 4-day triphasic study in normal volunteers. 71 Patients were assessed at baseline with a euglycemic clamp using [6,6- 2 H 2 ] glucose for glucose disposal studies. Patients were randomized to either euglycemic (5 mmol/l) or hyperglycemic (~ 8.8 or 12.6 mmol/l) clamps lasting 68 hours. Glucose levels were then normalized for all patients in another euglycemic clamp. C-peptide levels were low at baseline, but were elevated for all 3 days of the ~ 8.8 mmol/l hyperglycemic clamp. Insulin levels were even more elevated after initiation of the ~ 12.6 mmol/l hyperglycemic clamp, but decreased markedly over the 3 days. Insulin secretion was blunted by 35% (p < 0.05). There was a concomitant decrease in insulin clearance, but it only partially compensated for the impairment in secretion as demonstrated by the incremental decreases in the mean daily glucose infusion rates over time in the ~ 12.6 mmol/l hyperglycemic clamp cohort. For only the ~ 12.6 mmol/l cohort was insulin-mediated glucose disposal lower (36%) and basal glucose disposal higher (55%) during the terminal euglycemic clamp. These findings suggested an increase in peripheral insulin resistance and residual hyperstimulation of the islet cells induced by the recent hyperglycemia. Additional C-peptide studies were not reported so it is not known how long normalization of beta cell secretion would take. Renal function also affects C-peptide levels. Altered insulin pharmacokinetics and pharmacodynamics with renal impairment have been studied primarily in patients with end-stage disease. 72 , 73 , 74 , 75 Hyperinsulinemia was observed in 29 patients with a variety of renal diseases and a mean glomerular filtration rate of 25 ml/min/1.73 m 2 . 76 Pharmacokinetic studies conducted for insulin products also support decreased rates of insulin clearance in such patients (see product inserts). The magnitude of any effect from renal impairment is likely to be larger with C-peptide because of its longer serum residence time. 77 The effect of renal function on insulin and C-peptide has been most systematically studied in untreated hypertensive, non-diabetic patients (N = 321 patients, N = 92 normotensive controls) by Sechi, et al. (2002) using oral glucose tolerance testing. 78 Fasting insulin, fasting C-peptide, and area-under-the-curve(AUC) insulin levels did not differ by renal function until the creatinine clearance was < 50 ml/min. At that level of dysfunction, fasting insulin levels increased by ~ 20%, fasting C-peptide levels increased by ~ 100%, and AUC insulin increased by ~ 60%. Current Health Plan Policy In the submitted summary analysis for this reconsideration, the requestor stated it was unaware of any commercial payer policy in the United States currently implementing C-peptide testing as a criterion for insulin pump use. Additionally, in a May 26, 2004 follow-up letter to CMS, the requestor estimated 400 Medicare patients a year failed to meet the C-peptide criterion and that of those patients approximately 15 to 25% (that is, 60 to 100 patients) were unable to continue CSII once enrolling in Medicare because of the C-peptide testing requirement. Aetna’s (2004) Clinical Policy Bulletin # 0161 explicitly requires documentation of a C-peptide level < 0.5 [ng/mL] for determination of the medical necessity of external insulin infusion pumps for T1DM patients who have been on a pump prior to enrollment in Aetna and have a documented frequency of glucose self-testing an average of at least 4 times per day during the month prior to Aetna enrollment. By way of comparison, this Aetna policy bulletin closely parallels CMS’s original 1999 decision memorandum for CSII. 79 Matching that reported by the 2003 NICE technology appraisal on CSII, Aetna also concluded that “there is inadequate evidence of the effectiveness of continuous subcutaneous insulin infusion pumps for persons with type 2 diabetes (formerly known as non-insulin dependent diabetes mellitus (NIDDM)). Subcutaneous insulin infusion pumps are considered experimental and investigational for all persons with type 2 diabetes, including insulin-requiring type 2 diabetics.” In their bulletin’s introductory paragraph, Aetna noted these conclusions were reached “based upon a review of currently available clinical information, including clinical outcome studies in the peer-reviewed published medical literature, regulatory status of the technology, evidence-based guidelines of public health and health research agencies, evidence-based guidelines and positions of leading national health professional organizations, views of physicians practicing in relevant clinical areas, and other relevant factors.” 80 4. Medicare Coverage Advisory Committee (MCAC) This issue was not referred to the MCAC. 5. Evidence-Based Guidelines CMS was unable to identify any guidelines for the use of CSII or insulin pumps in T2DM. A 1999 Blue Cross Blue Shield of California “Treatment Guideline for T2DM” submitted by the requestor is not hyperlinked or referenced in the peer-reviewed literature. Its bibliography for “elements of intensive insulin management” referenced only the DCCT’s study of T1DM, and the document provided no evidence-based guidelines for the use of insulin pumps in T2DM. 6. Professional Society Position Statements CMS received one position statement, but no formal professional society guidelines, from the American Association of Clinical Endocrinologists (AACE). The AACE requested that CMS remove the C-peptide criterion from the NCD for insulin pump therapy but provided no new articles or guidelines. The AACE additionally commented: “Outside of the C-peptide test, we agree the Medicare clinical criteria for insulin pump coverage is consistent with clinical practice, payer policies and professional society recommendations.” Members of the AACE Intensive Insulin Management Task Force and representatives of Medtronic MiniMed also met with CMS on July 13, 2004 to discuss the AACE’s intent to specifically design and publish practice guidelines for intensive insulin management. A first draft outline of the categories of evidence to be examined by AACE task force included: 1) evidence that intensified insulin delivery may be necessary for T1DM, T2DM, Pediatrics, Obstetrics and Geriatrics, as well as any potentially contraindicated populations; 2) insulin delivery protocols, including basal-bolus concept, MDI, CSII pumps and insulin mixtures; 3) evidence that protocols achieve normoglycemia, target A1C levels and improved outcomes; 4) targets for intensified insulin delivery including pre-prandial, post-prandial and continuous glucose monitoring; 5) diabetes education programs; 6) role of the endocrinologist and rationale for referrals for hyperglycemia; 7) barriers to insulin therapy including low literacy, indigent and transplants; and 8) pharmaceutical issues. An ADA position statement on CSII, originally approved in 1985 and most recently re-published in the January 2004 supplement of Diabetes Care , was last formally reviewed and/or revised in 2002. 81 This one page position statement generally addresses intensive diabetes management but does not provide formal guidelines or otherwise detail the appropriate use of CSII in T2DM. The American Academy of Family Physicians (2004), while not providing an official position statement, did note in its home study self-assessment program that if the diagnosis between T1DM and T2DM remains uncertain: “A fasting insulin level, a C-peptide level or a beta cell autoantibody measurement usually can remove any diagnostic uncertainty (Table 11)”. 82 7. Expert Opinion CMS received 124 comments from practitioners, including physicians, nurse practitioners, registered nurses, certified diabetes educators and registered dieticians, who favored the modification or removal of Medicare’s C-peptide testing requirement. One university endocrinologist, who is both a clinical research unit and fellowship training program director, stressed that he did not support widespread use of insulin pumps for the treatment of T2DM, specifically “the unjustified widespread use of insulin pumps for patients with true insulin resistant T2DM.” He considered CSII to be “an unnecessarily expensive form of treatment” which should be reserved only for those T2DM patients for whom there were strict but well-designed and fair criteria to allow use in those “few situations” where special needs or circumstances exist. Another physician wrote that he had no question that “if studied properly the few number of type 2 patients who truly require insulin pumps to properly control their disease would save the system money” due to fewer short and long-term complications. 8. Public Comments A. Initial 30-Day Comment Period In addition to professional society position statements and expert