Rationale for diabetes reclassification
Variability of disease presentation and progression
Novel subtypes of diabetes reflecting differences in disease development and progression
Diabetes subgroup | Metabolic characteristics | Diabetes-related complications |
---|---|---|
SAID | Early-onset diabetes Low BMI High HbA1c Insulin deficiency Presence of GADA | Ketoacidosis at diagnosis [6] High risk of retinopathy [29] High incidence of CKD but dependent on baseline eGFR [28] |
SIDD | Early-onset diabetes Low BMI High HbA1c Insulin deficiency GADA negative | Ketoacidosis at diagnosis [6] High risk of retinopathy [6] Highest prevalence of DSPN [26] Highest prevalence of CAN [26] High prevalence of erectile dysfunction [33] |
SIRD | Late-onset diabetes High BMI Most insulin-resistant GADA negative | Highest liver fat content, fatty liver index, NAFLD fibrosis score and prevalence of NAFLD [6, 26, 29] High risk of coronary event and stroke (dependent on age and sex) [6] High prevalence of erectile dysfunction [33] |
MOD | Early-onset diabetes High BMI Intermediate insulin resistance GADA negative | |
MARD | Late-onset diabetes Low BMI GADA negative | High risk of coronary events and stroke (dependent on age and sex) [6] |
Cohort characteristic | Clustering variables | Subgroups | Specific findings | Ref. |
---|---|---|---|---|
VNDS, Italy (739 with T2D) | Age, BMI, HOMA-2 estimates of beta cell function and insulin resistance | SIDD MARD OIRD EOD | Replication of SIDD and MARD OIRD comprising MOD and SIRD MARD associated with CVD Highest HbA1c after 14-month follow-up in SIDD | [34] |
Three cohort studies from Europe: Hoorn DCS; GoDARTS; ANDIS (15,940 people with T2D, within 2 years of diagnosis) | Age, BMI, HbA1c, random or fasting C-peptide, HDL-cholesterol | Five distinct T2D subgroups | Three subgroups could be mapped back to the original ANDIS clusters (SIDD, SIRD, MOD) Two subgroups (MD and MDH related to MARD) Progression to insulin fastest for SIDD and slowest for MDH | [35] |
MASALA and MESA multi-ethnic cohorts from USA (1293 people with diabetes; mean diabetes duration 5.7 years) | Age at diagnosis, BMI HbA1c, HOMA estimates of beta cell function and insulin resistance | Five T2D subgroups: older age, severe hyperglycaemia, severe obesity, younger age at onset; requiring insulin medication use | Older age most common subgroup for all race/ethnicities apart from South Asians Severe hyperglycaemia subgroup most frequent in South Asians Risk for renal complications and subclinical CVD differed by subgroup and by race/ethnicity | [36] |
Look AHEAD (5145 overweight/obese people with T2D and 10 years of lifestyle intervention or control group) | Age at diagnosis, BMI, WC, HbA1c | Four subgroups: by older age at diabetes onset; poor glucose control; severe obesity; younger age at diabetes onset | Interaction between lifestyle intervention and diabetes subgroups for three composite cardiovascular outcomes Increased cardiovascular risk for people in subgroup with poor glucose control randomised to lifestyle intervention | [37] |
NHANES (USA) and four Mexican cohorts (1758 people with T2D in NHANES; 9887 people with T2D in the open-population Mexican cohorts) | Models based on different combinations of years since diagnosis, BMI, HbA1c, HOMA-2 estimates of beta cell function and insulin resistance, fasting plasma glucose, METS-IR, METS-VF, age at diabetes onset | Four subgroups: obesity-related; insulin-deficient; insulin-resistant; age-related | Risk of retinopathy highest for insulin-deficient subgroup and lowest for obesity-related subgroup Subgroup transitions observed after 3 months, 1 year and 2 years | [38] |
Thirteen cohort studies from nine countries in Latin America and the Caribbean (8361 people with T2D) | Age, sex, BMI, WC, systolic/diastolic BP, T2D family history | Four clusters: Cluster 0, highest BP; Cluster 1, highest BMI and WC, highest proportion of positive family history of diabetes; Cluster 2, most beneficial risk profile; Cluster 3, highest age | Heterogeneous distribution of clusters across countries | [39] |
Electronic medical records of a tertiary diabetes centre, India (19,804 people with T2D; diabetes duration <5 years) | Age at diagnosis, BMI, WC, HbA1c, triacylglycerols, HDL-cholesterol, C-peptide (fasting and stimulated) | Four clusters: Cluster 1, SIDD; Cluster 2, IROD; Cluster 3, CIRDD; Cluster 4, MARD | SIDD and MARD similar to diabetes subgroups in other populations IROD and CIRDD unique to Asian Indian population IROD showed highest BMI and highest C-peptide levels CIRRD showed lowest age of onset, highest serum triacylglycerols, highest risk for kidney disease | [40] |
Retrospective clinic-based study sample, PR China (5414 people with T2D; mean diabetes duration 8.6 years) | Age at diagnosis, BMI, HbA1c, HOMA-2 estimates of beta cell function and insulin resistance, GADA; additional model with triacylglycerols and uric acid | Replication of SAID, SIRD and MARD when using the original six clustering variables Replication of SAID, SIDD, SIRD, MOD and MARD and identification of novel subgroups (UARD, IRD) when all clustering variables were used | Higher risk for retinopathy, peripheral neuropathy, hypertension and CKD for SIRD (vs IRD) Higher risk for retinopathy and diabetic foot for SIDD (vs IRD) | [41] |
Three global cardiovascular outcomes trials: DEVOTE, LEADER, SUSTAIN-6 (20,274 people with T2D; follow-up of 2.0–3.8 years) | Age at diagnosis, BMI, HbA1c | Identification of four subgroups: clusters A–D | Differences between clusters for major adverse cardiovascular events, cardiovascular death, nephropathy and severe hypoglycaemia when comparing subgroups in at least one cohort | [42] |
Subgroups of individuals with different risk of progression to type 2 diabetes and complications
Translation into clinical practice: therapeutic implications
Diabetes subgroup | Therapy in cohort studies | Response to therapy in ADOPT | Comment |
---|---|---|---|
SAID | Shortest time to sustained insulin use [6] | Not analysed in the context of novel diabetes subgroups | Findings are in line with the established treatment for type 1 diabetes and LADA |
SIDD | Frequent use of insulin at baseline and short time to sustained insulin use, although less pronounced than for SAID [6] Shortest time to treatment with oral medication other than metformin and longest time to reach HbA1c treatment goal [6] | Initial treatment response best with sulfonylureas but highest HbA1c increase thereafter with sulfonylureas | Data are in line with the low beta cell reserves in this subgroup |
SIRD | Most frequently treated with metformin or without glucose-lowering therapy [6] Evidence for higher insulin use later after diabetes diagnosis [29] | HbA1c benefit with thiazolidinedione therapy | Findings are plausible given the pronounced insulin resistance and high prevalence of NAFLD in SIRD |
MOD | Most frequently treated with metformin or without glucose-lowering therapy [6] Lowest baseline use of insulin [29] | Initial treatment response best with sulfonylureas but highest HbA1c increase thereafter with sulfonylureas | Data indicate a mild form and mild progression of diabetes |
MARD | Most frequently treated with metformin or without glucose-lowering therapy [6] Low cumulative incidence of treatment with oral medication other than metformin or of sustained insulin use [6] | HbA1c benefit with sulfonylurea therapy, limited to about 2 years, vs metformin and thiazolidinedione treatment | Data indicate a mild form and mild progression of diabetes |