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Cited by 3,834Diabetes Treatment and ManagementDiabetes Management and ResearchDiabetes, Cardiovascular Risks, and Lipoproteins

Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy

Open access
Nathan, David M., Buse, John B., Davidson, Mayer B., Ferrannini, Ele, Holman, Rury R., Sherwin, Robert, Zinman, Bernard·2009·Diabetes Care
DOI 10.2337/dc08-9025PMC PMC2606813
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Abstract

The consensus algorithm for the medical management of type 2 diabetes was published in August 2006 with the expectation that it would be updated, based on the availability of new interventions and new evidence to establish their clinical role. The authors continue to endorse the principles used to develop the algorithm and its major features. We are sensitive to the risks of changing the algorithm cavalierly or too frequently, without compelling new information. An update to the consensus algorithm published in January 2008 specifically addressed safety issues surrounding the thiazolidinediones. In this revision, we focus on the new classes of medications that now have more clinical data and experience.

AI snapshot

Written from the paper’s full text.

TL;DR

This 2009 consensus update reaffirms an A1C goal of <7% and recommends lifestyle intervention plus metformin at diagnosis, with rapid addition of a second medication—usually insulin or a sulfonylurea—and further insulin intensification if targets are not met. It reviews glucose-lowering drug classes and advises against rosiglitazone while placing exenatide or pioglitazone in a second tier for selected patients.

Key findings

  • The consensus recommends achieving and maintaining A1C <7.0%, initiating lifestyle intervention and metformin at diagnosis, and adding a second medication within 2–3 months if glycemic goals are not achieved or sustained.
  • Metformin and sulfonylureas each typically lower A1C by ∼1.5 percentage points; TZDs by 0.5–1.4; DPP-4 inhibitors by 0.6–0.9; exenatide by 0.5–1; pramlintide by 0.5–0.7; and α-glucosidase inhibitors by 0.5–0.8.
  • The ACCORD study found excess CVD mortality in the intensive group targeting A1C <6.0% versus <7.9%, while ADVANCE and the Veterans Affairs Diabetes Trial did not show excess mortality with intensive regimens; none demonstrated benefit on primary CVD outcomes.
  • The consensus group unanimously advised against using rosiglitazone; exenatide or pioglitazone may be considered in selected settings, such as when hypoglycemia is particularly undesirable or weight loss is a major consideration.

Methods

  • Consensus guideline/algorithm derived from two sources: clinical trials addressing effectiveness and safety of diabetes therapies, and the writing group’s clinical judgement weighing benefits, risks, and costs.
  • The writing group reviewed studies of drugs used as monotherapy or in combination to lower glycemia, but did not conduct a systematic review or meta-analysis and collected no new primary data.
  • Recommendations are organized into a tiered algorithm: Tier 1 well-validated core therapies (lifestyle plus metformin, then add insulin or sulfonylurea, then intensify insulin) and Tier 2 less well-validated therapies (e.g., exenatide or pioglitazone in selected patients).

Limitations

  • Stated: the paucity of high-quality, well-controlled clinical trials directly comparing different diabetes treatment regimens remains a major impediment to recommending one class or combination over another.
  • Stated: the most appropriate day-to-day blood glucose and A1C targets have not been systematically studied, and evidence-based review was supplemented by subjective value judgements about benefits, risks, and costs.
  • Evident: as a consensus statement rather than a systematic review or original trial, the recommendations reflect panel opinion and may not be reproducible by other groups with different judgements.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.2337/dc08-9025

Cites

108 of 108 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 113 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Intensive glycemic management resulting in lower A1C levels has a beneficial effect on cardiovascular disease complications in type 1 diabetes.

    “Intensive glycemic management resulting in lower A1C levels has also been shown to have a beneficial effect on cardiovascular disease (CVD) complications in type 1 diabetes (9,10)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group: Intensive diabetes therapy and carotid intima–media thickness in type 1 diabetes. N Engl J Med 348:2294–2303, 2003 source

      Not checked in the free run.

    • cites [10] Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group: Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 353:2643–2653, 2005 source

      Not checked in the free run.

  • Premisecitation

    The increased number of choices available to practitioners and patients has heightened uncertainty regarding the most appropriate means of treating type 2 diabetes.

    “the increased number of choices available to practitioners and patients has heightened uncertainty regarding the most appropriate means of treating this widespread disease (14)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Nathan DM: Finding new treatments for diabetes—how many, how fast . . . how good? N Engl J Med 356:437–440, 2007 source

      Not checked in the free run.

  • Premisecitation

    Maintaining glycemic levels as close to the nondiabetic range as possible has a powerful beneficial effect on diabetes-specific microvascular complications, including retinopathy, nephropathy, and neuropathy, in type 1 diabetes.

    “Maintaining glycemic levels as close to the nondiabetic range as possible has been demonstrated to have a powerful beneficial effect on diabetes-specific microvascular complications, including retinopathy, nephropathy, and neuropathy, in the setting of type 1 diabetes (4,5)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [4] Diabetes Control and Complications Trial Research Group: The effect of intensive diabetes treatment on the development and progression of long-term complications in insulin-dependent diabetes mellitus: the Diabetes Control and Complications Trial. N Engl J Med 329:978–986, 1993 source

      Not checked in the free run.

    • cites [5] Reichard P, Nilsson B-Y, Rosenqvist U: The effect of long-term intensified insulin treatment on the development of microvascular complications of diabetes mellitus. N Engl J Med 329:304–309, 1993 source

      Not checked in the free run.

  • Premisecitation

    In type 2 diabetes, more intensive treatment strategies reduce microvascular complications.

    “in type 2 diabetes, more intensive treatment strategies have likewise been demonstrated to reduce microvascular complications (6–8)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [6] UK Prospective Diabetes Study (UKPDS) Group: Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complication in patients with type 2 diabetes (UKPDS 33). Lancet 352:837–853, 1998 source

      Not checked in the free run.

    • cites [7] UK Prospective Diabetes Study (UKPDS) Group: Effect of intensive blood glucose control with metformin on complication in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854–865, 1998 source

      Not checked in the free run.

    • cites [8] Ohkubo Y, Kishikawa H, Araki E, et al.: Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with NIDDM: a randomized prospective 6-year study. Diabetes Res Clin Pract 28:103–117, 1995 source

      Not checked in the free run.

  • Premisecitation

    Controlled clinical trials in type 1 and type 2 diabetes have helped establish the glycemic goals of therapy that result in improved long-term outcomes.

    “Controlled clinical trials, such as the Diabetes Control and Complications Trial (DCCT) (4) and the Stockholm Diabetes Study in type 1 diabetes (5) and the UK Prospective Diabetes Study (UKPDS) (6,7) and Kumamoto study (8) in type 2 diabetes, have helped to establish the glycemic goals of therapy that result in improved long-term outcomes.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [4] Diabetes Control and Complications Trial Research Group: The effect of intensive diabetes treatment on the development and progression of long-term complications in insulin-dependent diabetes mellitus: the Diabetes Control and Complications Trial. N Engl J Med 329:978–986, 1993 source

      Not checked in the free run.

    • cites [5] Reichard P, Nilsson B-Y, Rosenqvist U: The effect of long-term intensified insulin treatment on the development of microvascular complications of diabetes mellitus. N Engl J Med 329:304–309, 1993 source

      Not checked in the free run.

    • cites [6] UK Prospective Diabetes Study (UKPDS) Group: Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complication in patients with type 2 diabetes (UKPDS 33). Lancet 352:837–853, 1998 source

      Not checked in the free run.

    • cites [7] UK Prospective Diabetes Study (UKPDS) Group: Effect of intensive blood glucose control with metformin on complication in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854–865, 1998 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. 8
  • May combine two claims. 23

  • Classified as probably not a substantial claim.

    Premisenone given

    The paucity of high-quality evidence in the form of well-controlled clinical trials that directly compare different diabetes treatment regimens remains a major impediment to recommending one class of drugs, or a particular combination of therapies, over another.

    “Unfortunately, the paucity of high-quality evidence in the form of well-controlled clinical trials that directly compare different diabetes treatment regimens remains a major impediment to recommending one class of drugs, or a particular combination of therapies, over another.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Neither the DCCT nor the UKPDS was able to maintain A1C levels in the nondiabetic range in their intensive treatment groups, achieving mean levels over time of approximately 7%, which is 4 SDs above the nondiabetic mean.

    “Neither study was able to maintain A1C levels in the nondiabetic range in their intensive treatment groups, achieving mean levels over time of ∼7%, which is 4 SDs above the nondiabetic mean.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [4] Diabetes Control and Complications Trial Research Group: The effect of intensive diabetes treatment on the development and progression of long-term complications in insulin-dependent diabetes mellitus: the Diabetes Control and Complications Trial. N Engl J Med 329:978–986, 1993 source

      Not checked in the free run.

    • cites [6] UK Prospective Diabetes Study (UKPDS) Group: Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complication in patients with type 2 diabetes (UKPDS 33). Lancet 352:837–853, 1998 source

      Not checked in the free run.

    • cites [7] UK Prospective Diabetes Study (UKPDS) Group: Effect of intensive blood glucose control with metformin on complication in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854–865, 1998 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metformin monotherapy is not usually accompanied by hypoglycemia and has been used safely, without causing hypoglycemia, in patients with prediabetic hyperglycemia.

    “Metformin monotherapy is not usually accompanied by hypoglycemia and has been used safely, without causing hypoglycemia, in patients with prediabetic hyperglycemia (50).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Diabetes Prevention Program Research Group: Reduction in incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346:393–403, 2002 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Metformin interferes with vitamin B12 absorption but is very rarely associated with anemia.

    “Metformin interferes with vitamin B12 absorption but is very rarely associated with anemia (27).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Bailey CJ, Turner RC: Metformin. N Engl J Med 334:574–583, 1996 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The UKPDS demonstrated a beneficial effect of metformin therapy on cardiovascular disease outcomes, which needs to be confirmed.

    “The UKPDS demonstrated a beneficial effect of metformin therapy on CVD outcomes (7), which needs to be confirmed.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] UK Prospective Diabetes Study (UKPDS) Group: Effect of intensive blood glucose control with metformin on complication in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854–865, 1998 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chlorpropamide and glibenclamide are associated with a substantially greater risk of hypoglycemia than other second-generation sulfonylureas (gliclazide, glimepiride, glipizide, and their extended formulations), which are preferable.

    “Chlorpropamide and glibenclamide (known as glyburide in the U.S. and Canada), are associated with a substantially greater risk of hypoglycemia than other second-generation sulfonylureas (gliclazide, glimepiride, glipizide, and their extended formulations), which are preferable (Table 1) (53,54).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [53] Holstein A, Plaschke A, Egberts E-H: Lower incidence of severe hypoglycemia in patients with type 2 diabetes treated with glimepiride versus glibenclamide. Diabetes Metab Res Rev 17:467–473, 2001 source

      Not checked in the free run.

    • cites [54] Gangji AS, Cukierman T, Gerstein HC, et al.: A systematic review and meta-analysis of hypoglycemia and cardiovascular events: a comparison of glyburide with other secretagogues and with insulin. Diabetes Care 30:389–394, 2007 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The upper limit of the nondiabetic range is 6.1% with the DCCT/UKPDS-standardized assay.

    “The upper limit of the nondiabetic range is 6.1% (mean ± SD. A1C level of 5 ± 2%) with the DCCT/UKPDS-standardized assay, which has been promulgated through the National Glycohemoglobin Standardization Program (NGSP) and adopted by the vast majority of commercially available assays (20).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Little RR, Rohlfing CL, Wiedmeyer H-M, et al.: The National Glycohemoglobin Standardization Program (NGSP): a five year progress report. Clin Chem 47:1985–1992, 2001

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lower levels of glycemia at the time of initial therapy are associated with lower A1C levels over time and decreased long-term complications.

    “Lower levels of glycemia at the time of initial therapy are associated with lower A1C levels over time and decreased long-term complications (38).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] Colagiuri S, Cull CA, Holman RR, et al.: Are lower fasting plasma glucose levels at diagnosis of type 2 diabetes associated with improved outcomes? U.K. Prospective Diabetes Study 61. Diabetes Care 25:1410–1417, 2002 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The most recent glycemic goal recommended by the American Diabetes Association is, in general, an A1C level of <7%.

    “The most recent glycemic goal recommended by the American Diabetes Association, selected on the basis of practicality and the projected reduction in complications over time, is, in general, an A1C level of <7% (1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] American Diabetes Association: Standards of medical care in diabetes—2008 (Position Statement). Diabetes Care 31(Suppl. 1): S12–S54, 2008 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Renal dysfunction is considered a contraindication to metformin use because it may increase the risk of lactic acidosis, an extremely rare but potentially fatal complication.

    “Renal dysfunction is considered a contraindication to metformin use because it may increase the risk of lactic acidosis, an extremely rare (less than 1 case per 100,000 treated patients) but potentially fatal complication (51).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51] Salpeter S, Greyber E, Pasternak G, et al.: Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev 1:CD002967, 2006 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Weight loss and exercise improve coincident cardiovascular disease risk factors, such as blood pressure and atherogenic lipid profiles, and ameliorate other consequences of obesity.

    “In addition to the beneficial effects of weight loss on glycemia, weight loss and exercise improve coincident CVD risk factors, such as blood pressure and atherogenic lipid profiles, and ameliorate other consequences of obesity (41,46,47).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [41] Look AHEAD Research Group: Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes: one-year results of the Look AHEAD trial. Diabetes Care 30:1374–83, 2007 source

      Not checked in the free run.

    • cites [46] Diabetes Prevention Program Research Group: Impact of intensive lifestyle and metformin therapy on cardiovascular disease risk factors in the Diabetes Prevention Program. Diabetes Care 28:888–894, 2005 source

      Not checked in the free run.

    • cites [47] Hadden DR, Montgomery DAD, Skelly RJ, et al.: Maturity onset diabetes mellitus: response to intensive dietary management. BMJ 3:276–278, 1975 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Type 2 diabetes is a progressive disease characterized by worsening glycemia; higher doses and additional medications are required over time if treatment goals are to be met.

    “Type 2 diabetes is a progressive disease characterized by worsening glycemia; higher doses and additional medications are required over time if treatment goals are to be met.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The risk of weight gain with glinides is similar to that for sulfonylureas, but hypoglycemia may be less frequent, at least with nateglinide, than with some sulfonylureas.

    “The risk of weight gain is similar to that for the sulfonylureas, but hypoglycemia may be less frequent, at least with nateglinide, than with some sulfonylureas (58,59).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [58] Gerich J, Raskin P, Jean-Louis L, et al.: PRESERVE-beta: two year efficacy and safety of initial combination therapy with nateglinide or glyburide plus metformin. Diabetes Care 28:2093–2099, 2005 source

      Not checked in the free run.

    • cites [59] Damsbo P, Clauson P, Marbury TC, et al.: A double-blind randomized comparison of meal-related glycemic control by repaglinide and glyburide in well-controlled type 2 diabetic patients. Diabetes Care 22:789–794, 1999 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Many patients may be managed effectively with monotherapy; however, the progressive nature of the disease will require the use of combination therapy in many, if not most, patients over time, to achieve and maintain glycemia in the target range.

    “Many patients may be managed effectively with monotherapy; however, the progressive nature of the disease will require the use of combination therapy in many, if not most, patients over time, to achieve and maintain glycemia in the target range.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Exenatide is associated with weight loss of approximately 2-3 kg over 6 months, some of which may be a result of its gastrointestinal side effects.

    “In published trials, exenatide is associated with weight loss of ∼2–3 kg over 6 months, some of which may be a result of its gastrointestinal side effects.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Exendin-4 appears to lower A1C levels by 0.5-1 percentage points, mainly by lowering postprandial blood glucose levels.

    “exendin-4 appears to lower A1C levels by 0.5–1 percentage points, mainly by lowering postprandial blood glucose levels (78–81).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [78] Kendall DM, Riddle MC, Rosenstock J, et al.: Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care 28:1083–1091, 2005 source

      Not checked in the free run.

    • cites [79] DeFronzo RA, Ratner RE, Han J, et al.: Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 28:1092–1100, 2005 source

      Not checked in the free run.

    • cites [80] Buse JB, Henry RR, Han J, et al.: Effects of exenatide on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 27:2628–2635, 2005 source

      Not checked in the free run.

    • cites [81] Heine RJ, Van Gaal LF, Johns D, et al.: Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes. Ann Int Med 143:559–569, 2005 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Recent reports have suggested a risk for pancreatitis associated with use of GLP agonists; however, the number of cases is very small and whether the relationship is causal or coincidental is not clear at this time.

    “Recent reports have suggested a risk for pancreatitis associated with use of GLP agonists; however, the number of cases is very small and whether the relationship is causal or coincidental is not clear at this time.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    DPP-4 inhibitors lower A1C levels by 0.6-0.9 percentage points and are weight neutral and relatively well tolerated.

    “In clinical trials performed to date, DPP-4 inhibitors lower A1Clevels by 0.6–0.9 percentage points and are weight neutral and relatively well tolerated (83,84).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [83] Raz I, Hanefeld M, Xu L, et al.: Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia 49:2564–2571, 2006 source

      Not checked in the free run.

    • cites [84] Goldstein B, Feinglos M, Lunceford J, et al.: Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care 30:1979–1987, 2007 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Insulin analogues with longer, nonpeaking profiles decrease the risk of hypoglycemia modestly compared with NPH, and analogues with very short durations of action reduce the risk of hypoglycemia compared with regular insulin.

    “Insulin analogues with longer, nonpeaking profiles decrease the risk of hypoglycemia modestly compared with NPH, and analogues with very short durations of action reduce the risk of hypoglycemia compared with regular insulin (76,77).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [76] Zammitt NN, Frier BM: Hypoglycemia in type 2 diabetes. Diabetes Care 28:2948–2961, 2005 source

      Not checked in the free run.

    • cites [77] Miller CD, Phillips LS, Ziemer DC, et al.: Hypoglycemia in patients with type 2 diabetes mellitus. Arch Int Med 161:1653–1659, 2005 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The need for and number of required self-monitoring of blood glucose measurements are not clear and depend on the medications used.

    “The need for and number of required SMBG measurements are not clear (85) and are dependent on the medications used.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [85] Welschen LMC, Bloemendal E, Nijpels G, et al.: Self-monitoring of blood glucose in patients with type 2 diabetes who are not using insulin: a systematic review. Diabetes Care 28:1510–1517, 2005 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exenatide is not associated with hypoglycemia but causes a relatively high frequency of gastrointestinal disturbances, with 30-45% of treated patients experiencing one or more episodes of nausea, vomiting, or diarrhea.

    “It is not associated with hypoglycemia but causes a relatively high frequency of gastrointestinal disturbances, with 30–45% of treated patients experiencing one or more episodes of nausea, vomiting, or diarrhea (78–81).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [78] Kendall DM, Riddle MC, Rosenstock J, et al.: Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care 28:1083–1091, 2005 source

      Not checked in the free run.

    • cites [79] DeFronzo RA, Ratner RE, Han J, et al.: Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 28:1092–1100, 2005 source

      Not checked in the free run.

    • cites [80] Buse JB, Henry RR, Han J, et al.: Effects of exenatide on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 27:2628–2635, 2005 source

      Not checked in the free run.

    • cites [81] Heine RJ, Van Gaal LF, Johns D, et al.: Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes. Ann Int Med 143:559–569, 2005 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Amylin agonists, α-glucosidase inhibitors, glinides, and DPP-4 inhibitors have lower or equivalent overall glucose-lowering effectiveness compared with first- and second-tier agents and/or limited clinical data or relative expense.

    “The amylin agonists, α-glucosidase inhibitors, glinides, and DPP-4 inhibitors are not included in the two tiers of preferred agents in this algorithm, owing to their lower or equivalent overall glucose-lowering effectiveness compared with the first- and second-tier agents and/or to their limited clinical data or relative expense (Table 1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Table 1

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Unlike other blood glucose-lowering medications, there is no maximum dose of insulin beyond which a therapeutic effect will not occur.

    “Unlike the other blood glucose–lowering medications, there is no maximum dose of insulin beyond which a therapeutic effect will not occur.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Alpha-glucosidase inhibitors are less effective in lowering glycemia than metformin or the sulfonylureas, reducing A1C levels by 0.5-0.8 percentage points.

    “They are less effective in lowering glycemia than metformin or the sulfonylureas, reducing A1C levels by 0.5–0.8 percentage points (29).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Van de Laar FA, Lucassen PL, Akkermans RP, et al.: Alpha-glucosidase inhibitors for type 2 diabetes mellitus. Cochrane Database Syst Rev 2:CD003639, 2005 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The most common adverse effects with thiazolidinediones are weight gain and fluid retention, with peripheral edema and a twofold increased risk for congestive heart failure.

    “The most common adverse effects with TZDs are weight gain and fluid retention, with peripheral edema and a twofold increased risk for congestive heart failure (61,62).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [61] Home PD, Pocock SJ, Beck-Nielsen H, et al.: Rosiglitazone evaluated for cardiovascular outcomes--an interim analysis. N Engl J Med 357:28–38, source

      Not checked in the free run.

    • cites [62] Singh S, Loke YK, Furberg CD: Thiazolidinediones and heart failure: a teleoanalysis. Diabetes Care 30:2248–2254, 2007 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The potential for DPP-4 inhibitors to interfere with immune function is of concern; an increase in upper respiratory infections has been reported.

    “The potential for this class of compounds to interfere with immune function is of concern; an increase in upper respiratory infections has been reported (34).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Richter B, Bandeira-Echtler E, Bergerhoff K, et al.: Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus. Cochrane Database Syst Rev 2:CD006739, 2008 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Addition of a third oral agent is no more effective in lowering glycemia, and is more costly, than initiating or intensifying insulin.

    “Although addition of a third oral agent can be considered, especially if the A1C level is close to target (A1C <8.0%), this approach is usually not preferred, as it is no more effective in lowering glycemia, and is more costly, than initiating or intensifying insulin (91).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [91] Schwartz S, Sievers R, Strange P, et al.: Insulin 70/30 mix plus metformin versus triple oral therapy in the treatment of type 2 diabetes after failure of two oral drugs. Diabetes Care 26:2238–2243, 2003 source

      Not checked in the free run.

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  • The authors state this as an assumption.

    The writing group's collective clinical judgement is an appropriate source for the recommendations.

    “The second source of material that informed our recommendations was clinical judgement, that is, our collective knowledge and clinical experience, which takes into account benefits, risks, and costs in the treatment of diabetes.”

  • The authors state this as an assumption.

    Value judgements are necessary to weigh the benefits of treatment against risks and costs in a subjective fashion.

    “As in all clinical decision making, an evidence-based review of the literature must also be supplemented by value judgements, where the benefits of treatment are weighed against risks and costs in a subjective fashion.”

  • The authors state this as an assumption.

    The recommendations made in this new iteration of the treatment algorithm will guide therapy and result in improved glycemic control and health status over time.

    “While we realize that others may have different judgements, we believe that the recommendations made in this new iteration of our treatment algorithm will guide therapy and result in improved glycemic control and health status over time.”

  • The authors state this as an assumption.

    There are enough data regarding the characteristics of the individual interventions to provide the guidelines despite the absence of rigorous, comprehensive studies that directly compare the efficacy of all available glucose-lowering treatments and their combinations.

    “However, even in the absence of rigorous, comprehensive studies that directly compare the efficacy of all available glucose-lowering treatments and their combinations, we feel that there are enough data regarding the characteristics of the individual interventions to provide the guidelines below.”

  • The paper relies on this without support.

    For most individuals with type 2 diabetes, lifestyle interventions fail to achieve or maintain metabolic goals because of failure to lose weight, weight regain, progressive disease, or a combination.

    “The authors recognize that for most individuals with type 2 diabetes, lifestyle interventions fail to achieve or maintain the metabolic goals either because of failure to lose weight, weight regain, progressive disease, or a combination of factors.”

  • The paper relies on this without support.

    Antihyperglycemic drugs with different mechanisms of action have the greatest synergy.

    “In general, antihyperglycemic drugs with different mechanisms of action will have the greatest synergy.”

  • The paper relies on this without support.

    Some patients with severely uncontrolled diabetes have unrecognized type 1 diabetes; others have type 2 diabetes with severe insulin deficiency.

    “Some patients with these characteristics will have unrecognized type 1 diabetes; others will have type 2 diabetes with severe insulin deficiency.”

  • The paper relies on this without support.

    Insulin can be titrated rapidly and is associated with the greatest likelihood of returning glucose levels rapidly to target levels.

    “Insulin can be titrated rapidly and is associated with the greatest likelihood of returning glucose levels rapidly to target levels.”

  • The paper relies on this without support.

    After symptoms are relieved and glucose levels decreased, oral agents can often be added and insulin may be withdrawn.

    “After symptoms are relieved and glucose levels decreased, oral agents can often be added and it may be possible to withdraw insulin, if preferred.”

  • The paper relies on this without support.

    Current-day management has failed to achieve and maintain the glycemic levels most likely to provide optimal healthcare status for people with diabetes.

    “Although new classes of medications and numerous combinations have been demonstrated to lower glycemia, current-day management has failed to achieve and maintain the glycemic levels most likely to provide optimal healthcare status for people with diabetes.”

  • The paper relies on this without support.

    10–20% of patients with type 2 diabetes are not obese or overweight.

    “For the 10–20% of patients with type 2 diabetes who are not obese or overweight, modification of dietary composition and activity levels may play a supporting role, but medications are still generally required early in the course of diabetes (see special considerations/patients below).”

  • The paper relies on this without support.

    Metformin has a favorable profile: effect on glycemia, absence of weight gain or hypoglycemia, generally low side effects, high acceptance, and relatively low cost.

    “Metformin is recommended as the initial pharmacological therapy, in the absence of specific contraindications, for its effect on glycemia, absence of weight gain or hypoglycemia, generally low level of side effects, high level of acceptance, and relatively low cost.”

  • The paper relies on this without support.

    Insulin secretagogues (sulfonylurea or glinides) are not synergistic with insulin.

    “When insulin injections are started, insulin secretagogues (sulfonylurea or glinides) should be discontinued, or tapered and then discontinued, since they are not considered to be synergistic.”
13 of 13

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • A reduction of ≥0.5% in HbA1c is typically considered clinically meaningful and associated with a lower risk of diabetes-related complications.

    “While a reduction of ≥ 0.5% is typically considered clinically meaningful and associated with a lower risk of diabetes-related complications [193, 194]”

    From Effects of Skeletal Muscle Hypertrophy on Fat Mass and Glucose Homeostasis in Humans and Animals: A Narrative Review with Systematic Literature Search (2025) · cites this paper as [194]

    The Glycemic goals of therapy section says that decreasing glycemia reduces long-term microvascular and neuropathic complications, and the Effectiveness in lowering glycaemia section links mean A1C levels with retinopathy and nephropathy. Neither section identifies a ≥0.5-percentage-point HbA1c reduction as the threshold for clinical significance or for lower complication risk. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Metformin is the most commonly used therapy in patients with type 2 diabetes, often prescribed as initial or combination therapy.

    “The biguanide metformin is the most commonly used therapy in patients with type 2 diabetes, often prescribed as initial or combination therapy (79).”

    From Diabetes and Cancer (2010) · cites this paper as [79]

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Related

Authors
Nathan, D. M., Buse, J. B., Davidson, M. B., Ferrannini, E., Holman, R. R., Sherwin, R., & Zinman, B.
Affiliations
  • Harvard University (US)
  • University of North Carolina at Chapel Hill (US)
  • Charles R. Drew University of Medicine and Science (US)
  • University of Pisa (IT)
  • University of Oxford (GB)
  • Yale University (US)
  • Mount Sinai Hospital (CA)
ORCID
Venue
Diabetes Care
Publisher
American Diabetes Association
Published
2009-01-01
Volume
32
Issue
1
Pages
193-203
ISSN
  • 0149-5992 (ISSN-L)
  • 1935-5548
DOI
10.2337/dc08-9025
PMC
PMC2606813
OpenAlex
W2146901298
Semantic Scholar
1cf454a7ca554873302c894d16550f4a80a5f19a
Cited by
3,834
References
108
Citations by year
2026: 35 · 2025: 66 · 2024: 67 · 2023: 62 · 2022: 88 · 2021: 95 · 2020: 101 · 2019: 121 · 2018: 109 · 2017: 144 · 2016: 203 · 2015: 221 · 2014: 299 · 2013: 349 · 2012: 458
FWCI
316.41
Type
journal article
Language
en
Open access
Locations
  • Diabetes Care (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
Funders
  • Bristol-Myers Squibb
  • Eli Lilly and Company
  • Pfizer
  • AstraZeneca
  • GlaxoSmithKline
  • Sanofi
  • Insulet Corporation
  • Novo Nordisk
  • Servier
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords
type 2 diabetes, hyperglycemia, medical management, consensus algorithms, thiazolidinediones, drug safety
MeSH terms
Algorithms, Blood Glucose, Diabetes Mellitus, Diabetes Mellitus, Type 2, Humans, Hyperglycemia, Hypoglycemic Agents, Controlled Clinical Trials as Topic

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