STOP-NIDDM

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Chiasson JL, et al. "Acarbose for prevention of type 2 diabetes mellitus". The Lancet. 2005. 359(9323):2072-2077.
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Clinical Question

In patients with impaired glucose tolerance, does acarbose reduce the risk of progressing to type 2 diabetes mellitus (T2DM), as compared to placebo?

Bottom Line

In patients with impaired glucose tolerance, acarbose reduces the risk of progressing to T2DM, as compared to placebo. The most common adverse effects were flatulence and diarrhea.

Major Points

Impaired glucose tolerance is associated with a significant risk of progressing to type 2 diabetes mellitus (T2DM).[1] Alpha-glucosidase inhibitors (eg, acarbose) are reversible inhibitors of alpha-glucosidase, an enzyme located on the brush border of the small intestine.[2] The net effect is a delay in absorption of carbohydrates thus lowering postprandial glucose levels.

The "Study to Prevent NIDDM (STOP-NIDDM) Trial" randomized 1,429 patients with impaired glucose tolerance to receive acarbose or placebo. The primary endpoint is the incidence of diabetes. Acarbose significantly reduced the risk of the primary endpoint (32% vs. 42% in placebo, relative risk 0·75, 95% CI 0·63-0·90, P=0·0015). However, up to a quarter of patients discontinued treatment early. In the acarbose group, 13% of treatment discontinuation occurred due to gastrointestinal effects, mainly flatulence and diarrhea.

In a separate publication, the authors reported the beneficial effect of acarbose on cardiovascular (CV) risk.[3] Acarbose significantly reduced the relative risk of CV events (coronary heart disease, CV mortality, heart failure, cerebrovascular event, and peripheral vascular disease) by 49% (hazard ratio [HR] 0.51, 95% CI 0.28-0.95, P=0.03). The risk of hypertension was also reduced (HR 0.66, 95% CI 0.49-0.89, P=0.006).

The trial was included in a Cochrane review (5 trials, 2,360 participants).[4] The authors reported that acarbose decreases the incidence of T2DM (number needed to treat=10), post-load blood glucose level (-0.6 mmol/L, 95% CI -1.0 to -0.3) and BMI (0.3 kg/m2, 95% CI -0.1 to -0.5). There was a significant risk of gastrointestinal adverse effects (OR 3.5, 95% CI 2.7-4.4). However, the authors suggested that it was unclear if the effect acarbose on DM is due to prevention, masking or delay in the onset of diabetes.

Guidelines

ADA Standards of Medical Care in Diabetes (2016, adapted)[5]

  • Metformin is the preferred initial pharmacological agent for type 2 diabetes if well-tolerated and no contraindications exist. (Level of evidence: A)
  • If noninsulin monotherapy at maximum tolerated dose does not achieve or maintain the A1C target over 3 months, add a second oral agent, a GLP-1 receptor agonist, or basal insulin. (Level of evidence: A)
    • The choice of oral agents include sulfonylurea, thiazolidinedione, DPP-4 inhibitors and SGLT2 inhibitors
  • A patient-centered approach should be used to guide the choice of pharmacological agents. Considerations include efficacy, cost, potential side effects, weight, comorbidities, hypoglycemia risk, and patient preferences. (Level of evidence: E)

Design

  • Double-blind, randomized, placebo-controlled trial
  • N=1,429
    • Acarbose (n=714)
    • Placebo (n=715)
  • Setting: 9 countries
  • Enrollment: 1995-1998
  • Mean follow-up: 3.3 years
  • Analysis: intention-to-treat
  • Primary outcome: T2DM

Population

Inclusion Criteria

Published elsewhere[6]

  • Impaired glucose tolerance, defined as[7]
    • 2-h plasma glucose concentration 7·8-11 mmol/L after a 75 g glucose load
    • fasting plasma glucose concentration of 5·6-7·7 mmol/L
  • BMI 25-40 kg/m2

Exclusion Criteria

  • DM
  • serum creatinine ≥130 µmol/L (1.5 mg/Ll)
  • fasting serum triglyceride ≥10 mmol/L >886 mg/dL)
  • liver enzymes >1.8 times the upper limit of normal (ULN)
  • TSH >1.5 times above the ULN or below the lower limit of normal (<0.3 mU/L)
  • systemic glucocorticoids, ß-blockers, thiazide diuretics, and nicotinic acid treatment within last 3 months
  • use of drugs likely to impair intestinal motility or absorption
  • recent cardiovascular event

Baseline Characteristics

From the acarbose group

  • Demographics: age 54.3 years, 48% male, 97% Caucasian
  • BMI: 31±4.3 kg/m2 ; waist circumference: 102.1±11.7 cm
  • Fasting plasma glucose: 6.23±0.5 mmol/L; 2-hour OGTT 9.26±1.06 mmol/L
  • BP: systolic 131.4±16.3 mm Hg, diastolic 82.8±9.4 mm Hg
  • LDL-C :3.66 mmol/L; HDL-C: 1·19 mmol/L; triglyceride: 2.07 mmol/L; total cholesterol 5.76 mmol/L
  • Other medical history: active smoker 12%

Interventions

  • Participants were randomized to acarbose or placebo in addition to their existing medications
  • Acarbose was initiated at 50mg mane and increased as tolerated to the maximum of 100 mg three times a day
  • Participants were reviewed every 6 months by the trial investigators
  • At the end of treatment, outcome measures were repeated after following all patients who had not developed diabetes on placebo in a single-blind fashion for 3 months

Outcomes

Comparisons are acarbose vs placebo

Primary outcomes

Diabetes mellitus
32.4% vs. 41.5% (RR 0·75, 95% CI 0·63-0.9, P=0·0015)

Other outcomes

Reversion to normal glucose tolerance
35% vs. 31% (P<0.0001)
Change in weight
-0.5 kg vs. +0.3 kg (difference 0·77 kg, 95% CI 0·01-1·54, P=0·0184)

Subgroup Analysis

  • There were no significant interactions in pre-specified subgroup analyses (age, sex, BMI).

Adverse events

Gastrointestinal events: 83% vs 60% (P<0.0001)

  • leading to discontinuation: 13% vs 3%
  • flatulence: 68% vs 27%
  • diarrhea: 32% vs 17%
  • abdominal pain: 17% vs 12%
  • dyspepsia: 7% vs 9%
  • constipation: 4% vs 5%

Cardiovascular events: 31% vs. 40% (P-value not given)

Respiratory events: 32% vs. 39% (P-value not given)

Musculoskeletal events: 34% vs. 39% (P-value not given)

Metabolic and nutritional events: 31% vs. 32% (P-value not given)

Nervous system events: 27% vs. 31% (P-value not given)

Urogenital events: 25% vs. 28% (P-value not given)

Skin events: 21% vs. 24% (P-value not given)

Haematological and lymphatic events: 4% vs. 6% (P-value not given)

Endocrine events: 4% vs. 4% (P-value not given)

Criticisms

  • It was unclear if the beneficial effects of acarbose seen in the trial were due to prevention, masking effect or delaying of the onset of DM.[8]
  • The changes in blood glucose level and HbA1c were not reported in the study.[9]

Funding

  • Bayer AG

Further Reading

  1. Saad Ml; Knowler WC, Pettitt DJ, Nelson RG, Mott DM, Bennett PH: The natural history of impaired glucose tolerance in the Pima Indians. N Engl J Med. 1998;319;1500-1506
  2. Campbell LK, White JR, Campbell RK. Acarbose: its role in the treatment of diabetes mellitus. Ann Pharmacother. 1996;30:1255-62
  3. Chiasson J, Josse RG, Gomis R, et al. Acarbose Treatment and the Risk of Cardiovascular Disease and Hypertension in Patients With Impaired Glucose Tolerance: The STOP-NIDDM Trial. JAMA.2003;290(4):486-494
  4. Van de Laar FA, Lucassen PLBJ, Akkermans RP, Van de Lisdonk EH, De Grauw WJC. Alpha-glucosidase inhibitors for people with impaired glucose tolerance or impaired fasting blood glucose. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD005061. DOI: 10.1002/14651858.CD005061.pub2.
  5. American Diabetes Association. 7. Approaches to Glycemic Treatment. Diabetes Care. 2016. 1;38(Supplement 1):S52-59.
  6. Chiasson J-L, Gomis R, Hanefeld M, Josse RG, Karasik A, Laakso M. for the STOP-NIDDM trial. An international study on the efficacy of an alpha-glucosidase inhibitor to prevent type 2 diabetes in a population with impaired glucose tolerance: rationale, design, and preliminary screening data. Diabetes Care 1998;21:1720-25
  7. WHO Study Group. Diabetes mellitus. WHO Tech Rep Ser 1985;
    727: 7-113.
  8. Scheen AJ. Acarbose for type 2 diabetes prevention. Lancet. 2002 Nov 9;360(9344):1516
  9. Mühlhauser I. Acarbose for type 2 diabetes prevention. Lancet. 2002;360(9344):1517