Type 2 Diabetes

General Principles

  • T2DM results from defective insulin secretion followed by loss of β-cell mass in response to increased demand as a result of insulin resistance.1
  • T2DM is usually diagnosed in adults, with both incidence and prevalence increasing with age; however, T2DM now accounts for up to one-third of new cases of diabetes diagnosed between the ages of 5 and 15 years.
  • T2DM is associated with obesity, family history of diabetes, history of GDM or prediabetes, hypertension, physical inactivity, and race/ethnicity. African Americans, Latinos, Asian Indians, Native Americans, Pacific Islanders, and some groups of Asians have a greater risk of developing T2DM than Caucasians.2,3
  • T2DM may be asymptomatic and, therefore, can remain undiagnosed for months to years.
  • The loss of pancreatic β cells is progressive. Insulin secretion is usually sufficient to prevent ketosis, but DKA or HHS can develop during severe stress. T2DM in patients who present with or later develop ketosis or DKA, but who do not require insulin between episodes, is termed ketosis-prone T2DM.2
  • The mechanisms underlying the β-cell loss in T2DM are unknown, but programmed cell death in response to genetic and environmental factors has been demonstrated in animal models.4

Treatment

Medications

  • The achievement of glycemic control requires individualized therapy and a comprehensive approach that incorporates lifestyle and pharmacologic interventions. Guidelines have been published by several professional organizations regarding the choice and sequence of antidiabetic therapy.5,6
  • Considerations for selecting noninsulin therapy (Table 23-5) in patients with T2DM include the following:
    • Oral therapy should be initiated early in conjunction with diet and exercise.
      Table 23-5: Noninsulin Medications for Diabetes

      Renal Dosing Necessary?Main Adverse Effects
      Oral therapies
      Biguanide: Inhibits hepatic glucose output and stimulates glucose uptake by peripheral tissues. Weight neutral. Hold for 48 h after radiographic contrast procedure. Avoid in patients with cardiogenic or septic shock, moderate or severe CHF, severe liver disease, hypoxemia, and tissue hypoperfusion.
      Metformin (available in liquid and long-acting formulations)Reduce dose to 500 mg 2× daily if eGFR <45 mL/min/1.73 m; stop if eGFR <30 mL/min/1.73 mGI symptoms (20%–30%); lactic acidosis (3/100,000 patient-years)
      Sulfonylureas (SFU): Increase insulin secretion by binding specific β-cell receptors. Give 30–60 min before food. Never give if fasting. Start with lowest dose and increase over days to weeks to optimal dose (usually half the maximum approved dose).
      Glyburide (glibenclamide)Avoid if CrCl <50 mL/minHypoglycemia, weight gain; avoid with renal insufficiency; caution in elderly
      GlipizideYes; if CrCl <50 mL/minSame; fewer problems in kidney disease
      GlimepirideStart lowest dose and titrate slowlySame; fewer problems in kidney disease
      Gliclazidea
      Same; fewer problems in kidney disease
      Meglitinides: Increase insulin secretion; much shorter onset and half-life than SFUs. Dose before each meal. Never give if fasting.
      NateglinideNoHypoglycemia, weight gain; not as severe as SFUs
      • Give 10 min before meal
      • Metabolized by cytochrome P450


      RepaglinideYes; if CrCl ≤40 mL/minSame
      • Give 30 min before meal


      Mitiglinidea
      Same
      α-Glucosidase inhibitors: Block polysaccharide and disaccharide breakdown and decrease postprandial hyperglycemia. Give with food. Start with low dose and increase weekly. Do not use in patients with intestinal disease.
      AcarboseAvoid if serum Cr >2.0 mg/dL (176.8 µmol/L)Gas, bloating, diarrhea, abdominal pain (25%–50%); transaminase elevations
      MiglitolAvoid if serum Cr >2.0 mg/dL (176.8 µmol/L)Gas, bloating, diarrhea, abdominal pain (25%–50%)
      VogliboseaNo; not renally excreted; not studied in CKDSame
      Thiazolidinediones: Increase insulin sensitivity in muscle, adipose tissue, and liver. Start with low dose and increase after several weeks. Avoid in patients with New York Heart Association class III/IV heart failure. Caution in patients with coronary artery disease, hypertension, long-standing diabetes, left ventricular hypertrophy, preexisting edema or edema on therapy, insulin use, advanced age, renal failure, and aortic or mitral valve disease (Diabetes Care. 2004;27:256).
      PioglitazoneNoEdema, heart failure, fractures in women, possible increased risk of bladder cancer, mild pancytopenia
      • Alters levels of medicines metabolized by CYP3A4

      DPP-4 inhibitors: Inhibit enzyme that breaks down endogenous GLP (incretin secreted from intestinal L cells). Increased GLP reduces blood glucose by inhibiting glucagon release and stimulating insulin secretion. Avoid in patients with a history of pancreatitis.
      AlogliptinYes; if eGFR <60 mL/minAnaphylaxis, angioedema, skin reactions, liver injury, URI
      LinagliptinNoAnaphylaxis, angioedema, exfoliative skin reactions, URI
      SaxagliptinYes; if eGFR ≤50 mL/min/1.73 mUrticaria, facial edema, URI
      SitagliptinYes; if eGFR <50 mL/min/1.73 mAKI, ESRD, anaphylaxis, angioedema, exfoliative skin reactions, URI
      Vildagliptina (not indicated in severe hepatic impairment, LFT >3× upper limit of normal)Yes; if eGFR <50 mL/min/1.73 m; not indicated in severe renal impairmentBlistering skin lesions in animals, increased LFTs
      SGLT-2 inhibitors: Inhibit sodium glucose cotransporter 2 in the proximal renal tubule, decreasing glucose reabsorption by the kidney.
      CanagliflozinYes; if eGFR 45–<60 mL/min/1.73 m use the lower dose, stop if eGFR <45 mL/min/1.73 mFemale genital mycotic infections, urinary tract infections, polyuria; hypotension, volume depletion, renal failure; increased LDL-C
      DapagliflozinNot indicated for eGFR <60 mL/min/1.73 mSame; possible increased risk for bladder cancer
      EmpagliflozinNot indicated for eGFR <45 mL/min/1.73 mSame
      Bile acid sequestrants
      Colesevelam hydrochloride (contraindicated in bowel obstruction or GI motility disorders; pregnancy class B; can be used in renal and hepatic disease; take on an empty stomach)NoConstipation, reduced absorption of some medications; raises triglycerides
      Dopamine agonists
      Bromocriptine mesylate (do not use with other dopamine agonists or antagonists)NoNausea, asthenia, dizziness, headache, constipation, diarrhea
      SC injectable therapies
      GLP-1 analogs: Structurally similar to endogenous GLP-1 but resist breakdown by DPP-4. They have a longer half-life and reach higher levels in blood and tissues. They are given by injection and can improve satiety and result in weight loss. Avoid in patients with history of pancreatitis. Avoid in patients with history of medullary thyroid cancer or MEN2 given increased C-cell tumors in rodents (all except immediate-release exenatide).
      Albiglutide (dosed weekly)No; monitor for GI side effects in patients with renal impairmentURI, diarrhea, nausea, injection site reaction
      Dulaglutide (dosed weekly)No; monitor for GI side effects in patients with renal impairmentDiarrhea, nausea, vomiting, abdominal pain, decreased appetite
      Exenatide (dosed twice daily)Do not use in severe renal impairment or ESRD; caution with moderate renal impairment or history of renal transplantNausea, vomiting, GI distress, reported cases of pancreatitis
      Exenatide extended release (dosed weekly)Do not use in severe renal impairment or ESRD; caution with moderate renal impairment or history of renal transplantNausea, vomiting, injection site reaction, headache, diarrhea, dyspepsia
      Liraglutide (dosed once daily)Caution when initiating or escalating dose in patients with renal impairmentHeadache, nausea, diarrhea, urticaria
      Amylin analogs: Blunt postprandial blood glucose response
      Pramlintide acetate (given as a separate injection with meals; insulin dose reduction is required when starting)Not defined with CrCl <20 mL/minNausea, vomiting, diarrhea, headache, hypoglycemia

      Please refer to country-specific prescribing information before using any of the antidiabetes therapies.

      aNot available in the United States.

      AKI, acute kidney injury; CKD, chronic kidney disease; CHF, congestive heart failure; Cr, creatinine; CrCl, creatinine clearance; DPP-4, dipeptidyl peptidase-4; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; GI, gastrointestinal; GLP, glucagon-like peptide; LDL-C, low-density lipoprotein cholesterol; LFT, liver function test; MEN2, multiple endocrine neoplasia type 2; URI, upper respiratory infection.

    • Metformin is the recommended first-line therapy if tolerated.
    • The glucose-lowering effects of metformin, insulin secretagogues, DPP-4 inhibitors glucagon-like peptide-1 (GLP-1) receptor analogs, and SGLT-2 inhibitors are observed within days to weeks, whereas the maximum effect of thiazolidinediones may not be observed for several weeks to months.
    • Combination therapy with two or more oral or injectable agents may be needed at the time of diagnosis to achieve A1C and glucose targets in patients presenting with significant hyperglycemia and will likely be needed as β-cell function deteriorates over time. The AACE recommends dual therapy for initial A1C ≥7.5% (>58 mmol/mol) and triple therapy or insulin for initial A1C >9% (>75 mmol/mol). A preference for medications with lower risk of hypoglycemia (metformin, GLP-1 receptor agonists, DPP-4 inhibitors, SGLT-2 inhibitors) reduces the risk of hypoglycemia.5 The American Diabetes Association (ADA) recommends proceeding to two-drug, three-drug, and injectable combinations if the A1C goal is not achieved in 3-month increments. Dual therapy is recommended at the time of diagnosis if the A1C is >9% (>75 mmol/mol).6 About 60% of patients on monotherapy may have worsening of metabolic control during the first 5 years of therapy, and concurrent use of two or more medications with different mechanisms of action may be necessary.5,6
    • Insulin therapy should be considered for patients presenting in DKA or with very high glucose levels (A1C >10% [>86 mmol/mol]). Insulin therapy can sometimes be stopped after glucose toxicity is corrected but may need to be continued in patients with persistent insulin deficiency.5,6
    • Because pancreatic β-cell function is required for the glucose-lowering effects of all noninsulin therapies, many patients will require insulin replacement therapy at some point. Insulin therapy can be initiated with basal insulin in addition to other therapies.
    • The toxicity profile of some oral and injectable antidiabetic agents may preclude their use in patients with preexisting illnesses.
    • Doses of noninsulin antidiabetes therapies may need to be reduced for declining kidney function. (Table 23-5)
    • Cardiovascular outcome trials (CVOTs) with antidiabetes medications have shown that none increase the risk of CVD. Studies with DPP-4 inhibitors have shown CVD safety but no benefit.7
    • The SGLT-2 inhibitor, empagliflozin, showed reduction in the composite major adverse cardiovascular endpoint (MACE) comprising death, MI, and stroke, with significant reduction in all-cause and cardiovascular mortality.8 Similar benefit was noted with canagliflozin; however, an increase in amputations was noted.9 Both empagliflozin and canagliflozin have been shown to slow down the progression of kidney disease in persons with diabetes.9,10
    • Two of the GLP-1 receptor agonists (liraglutide and semaglutide) reduced the three-point MACE, while two others had neutral effects (lixisenatide, exenatide) when compared with placebo.11,12,13,14 Liraglutide has also shown reduction in renal disease progression.15
  • Insulin therapy in T2DM is indicated in the following:
    • Patients in whom oral or injectable agents have failed to achieve or sustain glycemic control
    • Metabolic decompensation: DKA, HHS
    • Newly diagnosed patients with severe hyperglycemia
    • Patients with chronic kidney disease that precludes use of noninsulin therapies
    • Pregnancy and other situations in which oral agents are contraindicated
  • The success of insulin therapy depends on both the adequacy of the insulin TDD (0.6 to >1.0 units/kg of body weight per day) and the appropriateness of the insulin regimen for a given patient to achieve target glucose and A1C values.
    • A once-daily injection of intermediate- or long-acting insulin at bedtime or before breakfast (basal insulin) added to oral or injectable agents may achieve the target A1C goal.
    • Premeal insulin may be required if basal insulin plus other agents are not adequate. Short- or rapid-acting insulin administered before meals can be added to basal insulin. Alternatively, a premixed insulin can be given twice daily before breakfast and dinner. In general, the secretagogues are discontinued when premeal insulin is added, but sensitizing and other agents are continued on the basis of the individual patient needs.
    • The TDD of insulin required to achieve glycemic targets varies widely in patients with T2DM and is based on BMI, the continuation of oral agents, and the presence of comorbid conditions. Large doses of insulin (>100 units/d) may be required for optimal glycemic control. Weight gain with insulin use is a concern.
    • Insulin-induced hypoglycemia, the most dangerous side effect, may increase CV event rates and death. Avoidance of hypoglycemia while achieving an A1C as low as can be safely achieved requires close collaboration between physician, patient, and diabetes educators. The frequency of hypoglycemia increases as patients approach normal A1C levels or when deterioration of kidney function occurs.
  • Concentration: The standard insulin concentration is 100 units/mL (U-100), with vials containing 1000 units in 10 mL. A highly concentrated form of regular insulin containing 500 units/mL (Humulin U-500) is available for the rare patient with severe insulin resistance (usually T2DM). The vial size for U-500 insulin is 20 mL. Pens containing 3 mL are also available for U100 and U500 insulins. Concentrated forms of insulin glargine, a formulation that is 300 units/mL (U-300), and insulin degludec, formulated with 200 units/mL (U-200), are available in pens.
  • Mixed insulin therapy: Short- and rapid-acting insulins (regular, lispro, aspart, and glulisine) can be mixed with NPH insulin in the same syringe for convenience. The rapid-acting insulin should be drawn first, cross-contamination should be avoided, and the mixed insulin should be injected immediately. Commercial premixed insulin preparations do not allow dose adjustment of individual components but are convenient for patients who are unable or unwilling to do the mixing themselves. Premixed insulins are an option for patients with T2DM who have a regular eating and activity schedule and, in general, should not be used in T1DM.

References

  1. Weyer C, Bogardus C, Mott DM, et al. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest. 1999;104:787-794.  [PMID:10491414]
  2. American Diabetes Association. Classification and diagnosis of diabetes: standards of medical care in diabetes – 2018. Diabetes Care. 2018;41(suppl 1):S13-S27.
  3. American Diabetes Association. Prevention or delay of type 2 diabetes: standards of medical care in diabetes – 2018. Diabetes Care. 2018;41(suppl 1):S51-S54.
  4. Leahy JL, Bonner-Weir S, Weir GC. Beta-cell dysfunction induced by chronic hyperglycemia. Current ideas on mechanism of impaired glucose-induced insulin secretion. Diabetes Care. 1992;15:442-455.  [PMID:1559411]
  5. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm – 2018 executive summary. Endocr Pract. 2018;24(1):91-120.  [PMID:29368965]
  6. American Diabetes Association. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2018. Diabetes Care. 2018;41(suppl 1):S73-S85.
  7. Secrest MH, Udell JA, Filion KB. The cardiovascular safety trials of DPP-4 inhibitors, GLP-1 agonists, and SGLT2 inhibitors. Trends in Cardiovasc Med. 2017;27(3):194-202.
  8. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-2128.  [PMID:26378978]
  9. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644-657.  [PMID:28605608]
  10. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375:323-334.  [PMID:27299675]
  11. Pfeffer MA, Claggett B, Diaz R, Dickstein K, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373:2247-2257.  [PMID:26630143]
  12. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;275:311-322.
  13. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834-1844.  [PMID:27633186]
  14. Holman RR, Bethel MA, Mentz RJ, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017;377:1228-1239.  [PMID:28910237]
  15. Mann JFE, Orsted DD, Brown-Frandsen K, et al. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med. 2017;377:839-848.  [PMID:28854085]

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