1. Introduction The global incidence and prevalence of type 2 diabetes has quadrupled between 1980 and 2004.1 2 3 type 2 diabetes .4 type 2 diabetes are due to ASCVD, including 40% from coronary heart disease (CHD), 15% from heart failure (HF), and 10% from stroke.5 6
A plethora of evidence supports the association between hyperglycemia and elevated cardiovascular (CV) risk. In the United Kingdom Prospective Diabetes Study (UKPDS), for each 1% reduction in mean glycated hemoglobin (HbA1c) there are reductions in diabetes-related death and in myocardial infarction (MI) by 21% and 14%, respectively.7 8 9 10 11 12 13 14–16 17 18
In 2007, a provocative meta-analysis raised a tremendous concern19 19 Table 1 shows recent CV outcome trials, ranked by the baseline CV risk levels, i.e., the percentages of pre-existing ASCVD. The proportions of patients with pre-existing ASCVD ranging from 58% in the Outcome Reduction With an Initial Glargine Intervention (ORIGIN) trial20 Type 2 Diabetes Mellitus Patients–Removing Excess Glucose (EMPA-REG OUTCOME) trial21 22 23 Table 1 ). These results of these outcome trials are important for clinicians in their clinical practice, and also provide an opportunity for academic society to formulate treatment guidelines or consensus to provide specific recommendations for glucose control in various CV diseases.
Table 1: Background characteristics and event rates of the control groups of recent CV outcome trials ranked by CV risk levelsa .
The Taiwan Society of Cardiology (TSOC) and the Diabetes Association of Republic of China (DAROC), aiming to formulate a treatment consensus in type 2 diabetic patients with CVD, have appointed a jointed consensus group for the 2018 Consensus of TSOC/DAROC on the Management of Patients with Type 2 Diabetes and Cardiovascular Diseases. The consensus is comprised of 5 major parts: 1) Treatment of diabetes in patients with hypertension (HT), 2) Treatment of diabetes in patients with CHD, 3) Treatment of diabetes in patients with chronic kidney disease (CKD), 4) Treatment of diabetes in patients with a history of stroke, and 5) Treatment of diabetes in patients with HF.
The members of the consensus group comprehensively reviewed all the evidence, mainly RCTs, not limited to those shown in Table 1 , and also included meta-analyses, cohort studies, and studies using claim data. The rationale for prioritizing anti-diabetic agents for different CVD was based on the findings from RCTs first. The strongest evidence came from an RCT specifically testing one drug vs. another (or placebo) in patients with a specific disease condition such as CHD, stroke, or CKD. However, the number of such disease-specific trials is very limited. Most of the recent RCTs enrolled patients across the spectrum of ASCVDs including CHD, ischemic stroke, and peripheral artery disease rather than having a limited enrollment to a specific patient population. The second tier of evidence came from any subgroup analysis of the 3-point MACE in patients with or without a specific CVD. We examined if the efficacy remained significant or was even better in patients with pre-existing CVD. The third tier evidence is based on the assessments of the individual endpoint, i.e., MI or stroke, among the 3-point MACE and evaluated if any given drug reduced any specific endpoint. If the previous 3 level of evidence was not available or did not provide any significant information, meta-analysis was then taken into account, followed by cohort studies and claim data studies. All the available evidences were fully discussed and final decision was made by consensus. If there was disagreement in the discussion, the final decision was determined by votes.
This consensus was developed by a panel consist of experts from the Taiwan Society of Cardiology and the Diabetes Association of Republic of China (Taiwan). They had searched the most updated recommendations, along with their clinical experiences and rationale, focusing on treatment target of HbA1c and therapeutic choices. Less stringent goal for HbA1c may be needed for patients with a history of severe hypoglycemia, or poor cooperation. If a patient has more than one disease entity, and the optimal HbA1c and the choice of drug is different for these disease entities, safety should be the first priority, i.e., those drugs which are contraindicated for one disease entity, though indicated in another disease entity, should not be chosen. The consensus is not mandatory. The final decision may need to be individualized and based on clinicians' discretion.
2. Treatment of diabetes in patients with hypertension 2.1. Rationale HT is the most common co-morbidity in patients with diabetes. The estimated prevalence is 40–50% in general diabetic populations.24 10–12,17,21–23,25–30
2.2. Target of HbA1c The benefits of glucose lowering depend on duration of therapy, the degree of the HbA1c reduction, and the choice of drugs. The Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Study showed that targeting an HbA1c level of 7.0%, compared to 9.0%, resulted in a 57% reduction in the 3-point MACE in type 1 diabetic patients through a mean follow-up of 17 years.31 31 type 2 diabetes , almost all RCTs demonstrated numerically lower CV events with achieved HbA1c down to the level of 7.0%,17,21,27,28,30,31 22,23,25,26,29 14 21,27,28,30 23,25,26
Whether targeting an HbA1c level of 6.5% or lower would provide more vascular benefits has been examined in 3 target-driven RCTs.10–12 18 10,12
Further evidence to support targeting an HbA1c level of 7.0% rather than 6.5% or lower for diabetic hypertensive patients is from the combined analysis of the ACCORD-BP and ACCORD study.32 33
In this consensus, we recommended an HbA1c less than 7.0% for diabetic patients with HT.
2.3. Choice of drugs To establish the hierarchy of glucose-lowering agents for diabetic patients with HT, the relative efficacy in CV protection should be the first priority, followed by the relative efficacy in BP lowering effect.
Regarding the relative efficacy in CV protection, a recent meta-analysis including 301 RCTs of all available glucose-lowering agents (alone or in combination) for at least 24 weeks in patients with type 2 diabetes (1,417,367 patient-months) showed that there were no significant differences in the CV mortality or all-cause mortality among different classes of drugs.34 14 21,27,28,30 Type 2 Diabetes (SUSTAIN-6), and the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) were not included.27–30
Before assessing the relative efficacy of different glucose-lowering agents in BP reductions, we have to realize the following limitations. First, the majority of the information is from patients without hypertension or under antihypertensive treatment. Because the BP-lowering effect of any agent is directly related to baseline BP levels, the reported BP-lowering effect of a given glucose-lowering agent may be underestimated, and one agent could not be compared to other agents unless a head-to-head comparison had been conducted. Second, few head-to-head comparison of BP lowering effect between different glucose-lowering agents had been done.
For metformin, a meta-analysis including 41 RCTs (3074 patients) for at least 6 weeks’ duration showed an average BP reduction (placebo-corrected) of 1.1/1.0 mmHg (overall p > 0.05).35 p > 0.05).36 37 38 38 p = 0.53), and diastolic BP (78.2 mm Hg vs. 78.5, p = 0.93).38 p < 0.05) compared with placebo.39 p < 0.00001).40 p < 0.05).41 42 21,30 43
Another evidence in supporting the choice of anti-diabetic drugs came from the sub-group analysis of these RCTs to explore whether the benefits or the harmful effects exist in the sub-group of patients with hypertension compared to those without hypertension. Unfortunately, only some of RCTs provided these data: the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR) trial, the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) trial, the EMPA-REG OUTCOME trial, the Insulin Resistance Intervention after Stroke (IRIS) trial, and the CANVAS program.21,25,26,30,44 p values were >0.05. These data suggested that the effect of these anti-diabetic agents was comparable between hypertensive patients and non-hypertensive patients.
2.4. Treatment algorithm in diabetic patients with hypertension Table 2 shows the treatment algorithm in diabetic patients with hypertension. The target of HbA1c is <7%. Taking into account the totality of evidence and economical consideration, the consensus group recommended metformin being the first-line glucose-lowering agent for diabetic patients with hypertension, followed by SGLT2 inhibitors as the second-line glucose-lowering agent. The third-line agents include GLP-1 RAs, TZDs, DPP-4 inhibitors, sulfonylurea, glinides, and alpha-glucosidase inhibitors.
Table 2: Treatment algorithm in diabetic patients with hypertension.
3. Treatment of diabetes in patients with coronary heart disease 3.1. Rationale Diabetes is a CHD equivalent.45 5 7 7 9–12 9–12 4 p = 0.004).10 p = 0.04) and CV mortality (HR 1.35, 95% CI 1.04–1.76, p = 0.02), driven in part by a non-significant increase in fatal and non-fatal HF (HR 1.18, 95% CI 0.93–1.49, p = 0.17).10 18,46
3.2. Target of HbA1c The risk of CVD and total mortality has a linear relationship with the level of HbA1c.47 7 9–12 9–12 10 11,12 46 46 type 2 diabetes with a median age of 62.5 years, the risk of a combined outcome events (AMI, stroke, or death) gradually increased with rising levels of HbA1c achieved at 6 months, compared with a target HbA1c of <6.5%: adjusted HR 1.18 (95% CI 1.07–1.30) for 6.5–6.99%, HR 1.23 (95% CI 1.09–1.40) for 7.0–7.49%, HR 1.34 (95% CI 1.14–1.57) for 7.5–7.99%, and HR 1.59 (95% CI 1.37–1.84) for ≥8%.48 48
Given that most of the new anti-diabetic agents have a low risk of hypoglycemia, the consensus recommended HbA1c less than 7.0% as the treatment target for the diabetic patients with CHD. However, an HbA1c less than 6.5% may be considered in selected patients who are younger, highly educated and highly motivated, and have a low hypoglycemic risk, fewer co-morbidities, and short diabetes duration.
3.3. Choice of drugs There is only a trial testing the efficacy of anti-diabetic agent in patients with CHD (the ACE trial).38
3.3.1. Metformin In the UKPDS trial, metformin therapy in overweight patients was associated with a significantly lower risk of MI and total mortality compared with conventional lifestyle therapy (HR 0.61, 95% CI 0.41–0.89; HR 0.64, 95% CI 0.45–0.81, respectively).49 p = 0.005; HR 0.73, 95% CI 0.59–0.89, p = 0.002; respectively).14 p = 0.031), but not in active-comparator trials (OR 1.03, 95% CI 0.72–1.77, p = 0.89).50 p = 0.076).50 p = 0.016).50 51 type 2 diabetes , metformin monotherapy together with lifestyle recommendations was associated with a 33% reduction in CHD compared with lifestyle (HR 0.670, 95% CI 0.521–0.862, p = 0.002).52 53 p = 0.04; the percentage of presence of CAC, 75% versus 84%, p = 0.02), whereas metformin was not effective in women.53 54
Lactic acidosis is an uncommon but potentially lethal complication of metformin.55 56,57 2 .58
The consensus group recommended metformin as the first line therapy for patients with diabetes and CHD.
3.3.2. Sulfonylureas There are controversies in the CV safety of sulfonylureas. In the University Group Diabetes Program (UGDP) in early 1970, tolbutamide was associated with an increase in CV and total mortality.59 p = 0.052).9 11 p = 0.0003 for first generation sulfonylureas; HR 1.24, 95% CI 1.14–1.35, p < 0.001 for second generation sulfonylureas).60 60 type 2 diabetes initiating metformin monotherapy had longer survival than matched, non-diabetic controls, while those treated with sulfonylurea had a markedly reduced survival compared with both matched controls and those receiving metformin monotherapy.61 61 62 63 p < 0.001), MACE (HR 0.69, 95% CI 0.58–0.81, p < 0.001), and ischemic stroke (HR 0.62, 95% CI 0.51–0.75, p < 0.001) but not MI (HR 0.87, 95% CI 0.65–1.16, p = 0.338) and hospitalization for HF (HR 0.81, 95% CI 0.63–1.05, p = 0.112).64
It seems that not all sulfonylureas shared similar CV risk. In patients with previous MI from a Danish cohort, the HR of all-cause mortality was increased by a number of sulfonylureas compared with metformin (glimepiride 1.30, 95% CI 1.11–1.44; glibenclamide 1.47, 95% CI 1.22–1.76; glipizide 1.53, 95% CI 1.23–1.89; tolbutamide 1.47, 95% CI 1.17–1.84), but not for gliclazide (HR 0.90, 95% CI 0.68–1.20).65 66 Type 2 Diabetes (CAROLINA) trial (NCT01243424), comparing linagliptin with glimepiride in patients with type 2 diabetes , might help to clarify and define the CV safety of sulfonylurea.67
There are several drawbacks in using sulfonylureas for diabetic care. Hypoglycemia episodes are more common than other newer agents. In the ADVANCE trial severe hypoglycemia occurred more frequently in the intensive-control group using gliclazide than in the standard control group: 150 patients (2.7%) undergoing intensive control had at least one severe hypoglycemic episode, as compared with 81 patients (1.5%) undergoing standard control (HR 1.86, 95% CI 1.42 to 2.40; p < 0.001).11 p < 0.001 for all comparisons).68 49 ATP .69
The consensus group gave sulfonylureas a low priority in the treatment of diabetic patients with CHD.
3.3.3. Glinides There were no RCTs or observational studies to test the effect of repaglinide on the risk of MI. In the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial, 9306 participants with impaired glucose tolerance (IGT) and CVD (11.2% had a history of MI, 8.8% angina or positive stress test, 3.7% percutaneous coronary intervention, 4.0% multi-vessel coronary artery bypass graft) or its risk factors were assigned to nateglinide or placebo.70 p = 0.43) or the incidence of fatal and non-fatal MI (HR 0.95, 95% CI 0.75–1.20).70
3.3.4. Alpha-glucosidase inhibitor The Study to Prevent Non-insulin-dependent diabetes mellitus (STOP-NIDDM) trial evaluated the effect of acarbose on the risk of CVD in 1368 patients with IGT.71 p = 0.03) and MI (HR 0.09, 95% CI 0.01–0.72, p = 0.02) with the use of acarbose. One should be aware that there were only 13 patients with MI events in the whole trial (1 in the acarbose group, 12 in the placebo group), making a solid conclusion inappropriate.71 type 2 diabetes patients in Taiwan, there were 16.5% patients with pre-existing CHD.72 72 38 38 p = 0.0007).38
3.3.5. Thiazolidinedione In the PROactive trial, 5238 patients with type 2 diabetes and macrovascular disease were prospectively randomized to pioglitazone (15 mg–45 mg) and placebo for 34.5 months.17 p = 0.095).17 p = 0.027). Among the composite primary endpoints, non-fatal MI was numerically decreased by pioglitazone (HR 0.83, 95% CI 0.65–1.06).17 73 p = 0.045) and ACS (HR 0.63, 95% CI 0.41–0.97, p = 0.035).73
The finding of the beneficial effects of pioglitazone on MACE observed in the PROactive trial has been supported by a meta-analysis of controlled trials of over 16,000 subjects.74 p = 0.005). There was an increase in HF (HR 1.41, 95% CI 1.14–1.76; p = 0.002), but HF mortality was not increased.74 74 75 76
There is a concern with rosiglitazone in CV safety. In a meta-analysis of 42 trials, rosiglitazone was associated with an increased risk of MI and a trend of increased CV death (HR 1.43, 95% CI 1.03–1.98, p = 0.03; HR 1.64, 95% CI 0.98–2.74, p = 0.06, respectively).19 77 77 78 type 2 diabetes to rosiglitazone plus either metformin or sulfonylurea or an active control (metformin plus sulfonylurea). No elevated risk for MI or death in the rosiglitazone group was noted at 3.75 years follow-up.78 79
The consensus group gave a high priority to pioglitazone in the treatment of diabetes patients with CHD.
3.3.6. Insulin Only a few prospective interventional trials have specifically tested the CV effects of insulin treatment in type 2 diabetes . In the UKPDS trial, patients received insulin/sulfonylurea therapy had similar risk of MI compared with patients on conventional diet therapy for a follow-up of 10 years (HR 0.84, 95% CI 0.71–1.00, p = 0.052).9 14 type 2 diabetes were randomized to receive insulin glargine or standard care for a median follow-up of 6.2 years.20 20 type 2 diabetes were randomized to receive either insulin degludec (3818 patients) once daily or insulin glargine U100 (3819 patients) once daily in the Trial Comparing Cardiovascular Safety of Insulin Degludec versus Glargin in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) trial.80 p < 0.001 for superiority), the primary outcome did not show significant difference (HR, 0.91, 95% CI 0.78 to 1.06; p < 0.001 for noninferiority, p > 0.05 for superiority).80 p for interaction = 0.5742). Therefore, the consensus group did not give insulin a high priority in the initial therapy in diabetic patients with CHD.
3.3.7. DPP-4 inhibitors In the SAVOR trial, 16,492 patients with type 2 diabetes who had a history of, or were at risk for, CV events were randomized to receive saxagliptin or placebo and followed for a median of 2.1 years.25 p = 0.99 for superiority: p < 0.001 for noninferiority). The subgroup analysis of patients with or without a history of MI was not reported. Among the 3-point MACE, the risk of MI was not different with the use of saxagliptin compared with placebo (HR 0.95, 95% CI 0.80–1.12).25 23 p = 0.32). The subgroup analysis of patients with or without a history of AMI was not reported. Among the 3-point MACE, non-fatal MI was not different with the use of alogliptin compared with placebo (HR 1.08, 95% CI 0.88–1.33).23 type 2 diabetes and established CV disease were enrolled.26 26
3.3.8. GLP-1 receptor agonists In the ELIXA trial, 6068 patients with ACS within 180 days were randomized to daily lixisenatide or placebo.22 22
The LEADER trial examined the effects of a daily injection of liraglutide vs. placebo in 9340 high risk patients over a median follow-up of 3.8 years.27 p = 0.01).27 p = 0.0460), but not non-fatal MI (HR 0.88, 95% CI 0.75–1.03). The sub-group analysis showed a significant reduction of 3-point MACE in patients with established CVD compared with those without established CVD (HR 0.83, 95% CI 0.74–0.93 vs. HR 1.20, 95% CI 0.86–1.67, p for interaction 0.04), though specific data regarding patients with previous MI was not mentioned.27
In the SUSTAIN-6 trial, 3297 patients with high CV risk were enrolled. Among them, 60.5% had a history of CHD, including 32.5% had a history of MI.28 p = 0.02), including a non-significant reduction in the risk of non-fatal MI (HR 0.74, 95% CI 0.51–1.08).28 28
In the most recent EXSCEL trial, weekly injection of extended-release exenatide was compared with placebo in 14,752 high risk patients.29 29 29 27,29
3.3.9. SGLT-2 inhibitors In the landmark CV outcome trial of empagliflozin (the EMPA-REG OUTCOME trial), 7020 patients with previous CV events who received empagliflozin had reduced rates of CV mortality (HR 0.62, 95% CI 0.49–0.77, p < 0.001) and all-cause mortality (HR 0.68, 95% CI 0.57–0.82, p < 0.001) when compared with placebo, with no difference seen for 10 or 25 mg doses.21 p = 0.04).21 81 81 81
The CANVAS program randomized 10,142 participants with diabetes and high CV risk into canagliflozin or placebo groups.30 30 p = 0.02).30 p value for interaction was 0.18. The specific data from patients with a history of CHD was not reported. Among the 3-point MACE, the fatal or non-fatal MI was numerically lower by the use of canagliflozin (HR 0.89, 95% CI 0.73–1.09).30
The CV outcome trial of dapagliflozin, i.e., the Dapagliflozin Effect on Cardiovascular Events (DECLARE) trial, is still on-going. In a meta-analysis of 9339 patients, patients receiving dapagliflozin had a reduced risk of MI compared with the control group (HR 0.567, 95% CI 0.339–0.947).82 83 p < 0.0001), the 3-point MACE (HR 0.78, 95% CI 0.69–0.87, p < 0.0001), and hospital events for HF (HR 0.70, 95% CI 0.61–0.81; p < 0.0001).83 p values for interaction were not provided. Among the 3-point MACE, non-fatal MI was numerically lower in the group of SGLT-2 inhibitors (HR 0.87, 95% CI 0.73–1.03).83
The consensus group gave a high priority to SGLT-2 inhibitors in patients with diabetes and a history of CHD.
3.4. Treatment algorithm in diabetic patients with coronary heart disease Table 3 shows the algorithm for the treatment of diabetes in patients with CHD. The target of HbA1c is <7%. Metformin should be the first-line therapy in diabetic patients with CHD, mainly based on the findings from the UKPDS trial,14,49 50,51 52 53 17 74 75 76 provided strong evidence to support the role of pioglitazone. The ranking of SGLT-2 inhibitors is a little bit higher than GLP-1 RAs mainly because of a more convenient oral administration of the former. The EMPA-REG OUTCOME trial,21 30 83 27 28 23,25,26 9,11 64 38,70
Table 3: Treatment algorithm in diabetic patients with CHD.
4. Treatment of diabetes in patients with stage 3 chronic kidney disease 4.1. Rationale Diabetes-related CKD is a very common complication for patients with type 2 diabetes . It leads to end-stage renal disease (ESRD, defined as the need for dialysis or kidney transplantation, or death due to kidney disease), accounting for approximately 50% of cases in the developed world.84 2 ) is 14.1%, while 26.2% have either.85 86 87 2 ) was 7.1% (stage 3 = 6.8%, stage 4 = 0.2%, and stage 5 = 0.1%), and the DM prevalence was 14.5%, 25.6%, and 23.6%, respectively.88
An array of factors involving the development of CHD contribute to the development of CKD in diabetes, including hyperglycemia, hypertension, dyslipidemia, smoking, ethnicity, sex, age, and a long diabetes duration. Good glycemic control is the mainstay for preventing microvascular complications, including CKD, in patients with diabetes.84 89 2 , or development of overt diabetic nephropathy) was reduced by 20% (HR 0.80, 95% CI 0.72 to 0.88, p < 0·0001) by intensive glycemic control, primarily driven by reduced risks of development of micro- and macro-albuminuria.89 2 , doubling of serum creatinine, or ESRD).89 90 p < 0.01).91 92 2 (or CKD stage 1 and 2) and only about 10–25% had CKD stage 3, while patients with CKD stage 4 and 5 were excluded.89
4.2. Target of HbA1c Glycemic control in patients with CKD has special challenges, considering that the risk of severe hypoglycemia is doubled when the eGFR is less than 60 mL/min/1.73 m2 .93 94 91 post-hoc analysis of the ACCORD data.95 96 http://www.tsn.org.tw/UI/H/H00202.aspx http://w3.nhri.org.tw/nhri_org/rl/lib/NewWeb/nhri/ebook/39000400094863
4.3. Choice of drugs There are no specific trials testing the efficacy and safety in CV events of anti-diabetic agents in patients with CKD. However, the subgroup analysis comparing patient with or without CKD were generally provided. The renal events should be considered too though they are not the primary endpoints.
4.3.1. Conventional glucose-lowering agents There have been no large RCTs specifically examining the renal protective effects of insulin, sulfonylureas, glinides, alpha-glucosidase inhibitors or metformin. The ORIGIN trial20 38
4.3.2. Thiazolidinedione Among the 5238 patients in the PROactive trial, GFR data were available for 5154 (98.4%) patients. In the post-hoc analysis of the PROactive trial, 597 (11.6%) of the 5154 study patients had CKD (GFR <60 mL/min/1.73 m2 ).97 97 2 /yr) than with placebo.97
In a meta-analysis of 15 studies involving 2860 patients, the effect of TZDs on urinary albumin excretion was inconsistent.98 99
4.3.3. DPP-4 inhibitors In the SAVOR trial, 9696 (58.8%) subjects had normoalbuminuria (ACR <30 mg/g), 4426 (26.8%) had microalbuminuria (ACR 30–300 mg/g), and 1638 (9.9%) had macroalbuminuria (ACR >300 mg/g); whereas 2% had eGFR less than 30 mL/min/1.73 m2 , 13.5% eGFR between 30 and 50 mL/min/1.73 m2 , and 84.5% eGFR>50 mL/min/1.73 m2 .100 p = 0.021, p < 0.001, and p = 0.049 for individuals with baseline normoalbuminuria, microalbuminuria, and macroalbuminuria, respectively). The changes in ACR did not correlate with that in HbA1c. The change in eGFR was similar in the saxagliptin and placebo groups. Renal safety outcomes, including doubling of serum creatinine, initiation of chronic dialysis, renal transplantation, or serum creatinine >6.0 mg/dL, were similar as well.100 101
In the TECOS trial, 14,671 participants were categorized at baseline into eGFR stages 1, 2, 3a, and 3b (≥90, 60–89, 45–59, or 30–44 mL/min/1.73 m2 , respectively).102 102
There was no secondary publication of the renal effect of alogliptin in the EXAMINE trial. A small study of 36 CKD patients with type 2 diabetes treated with alogliptin for 6 months did not show any significant change in eGFR in patients with an eGFR less than 60 mL/min/1.73 m2 .103 type 2 diabetes and varying degrees of renal impairment, but dose adjustments for renal impairment are required.104 Type 2 Diabetes Mellitus (CARMELINA) trial (NCT01897532) are ongoing. In a pooled analysis of clinical trial data involving 3505 participants treated with the linagliptin and 1961 treated with placebo, linagliptin significantly reduced the hazard of kidney events by 16% compared with placebo (HR = 0.84; 95% CI: 0.72–0.97).105 105 105
The consensus group gave a neutral position to DPP-4 inhibitors in patients with stage 3 CKD.
4.3.4. GLP-1 receptor agonists In the ELIXA trial, 6068 patients with ACS were randomized to daily lixisenatide or placebo.22 2 were not provided. The pre-specified analysis of the percentage change in the ACR, but not eGFR, showed a modest difference in favor of lixisenatide over placebo from baseline to 108 weeks (24% vs. 34%, p = 0.004).22
The LEADER trial examined the effects of a daily injection of liraglutide vs. placebo in 9340 high risk patients over a median follow-up of 3.8 years.27 p = 0.01). A total of 22.3% of the trial participants had an eGFR <60 mL/min/1.73 m2 . Patients with eGFR levels <60 mL/min/1.73 m2 benefited more than those with eGFR levels ≥60 mL/min/1.73 m2 (HR 0.69, 95% CI 0.57–0.85 vs. HR 0.94, 95% CI 0.85–1.07, p for interaction 0.01).27 2 , end-stage renal diseases or death due to renal disease (HR 0.78, 95% CI 0.67–0.92, p = 0.003).106 p = 0.004) without any significant changes in eGFR. A non-significant reduction in doubling of serum creatinine (HR 0.89, 95% CI 0.67–1.19) and the need for the initiation of renal replacement therapy (HR 0.87, 95% CI 0.61–1.24) were also observed in liraglutide-treated patients.106
In the SUSTAIN-6 trial, 3297 patients with high CV risk were enrolled.28 p = 0.02).28 2 . There is no significant treatment interactions regarding eGFR status.28 2 , or the need for continuous renal replacement therapy) was significantly reduced (HR 0.64, 95% CI 0.46–0.88, p = 0.005)28 , mainly driven by a reduction in the progression to macroalbuminuria (HR 0.54, 95% CI 0.37–0.77, p = 0.001). There was no significant reduction in progression of eGFR (HR 1.28, 95% CI 0.64–2.58) and need of renal replacement therapy (HR 0.91, 95% CI 0.40–2.07).28
In the most recent EXSCEL trial, weekly injection of extended-release exenatide was compared with placebo in 14,752 high risk patients.29 p < 0.001 for noninferiority, p = 0.06 for superiority).29 2 vs. those with eGFR levels ≥60 mL/min/1.73 m2 (HR 1.01, 95% CI 0.86–1.19 vs. HR 0.86, 95% CI 0.77–0.97, p for interaction 0.12).29 29
In summary, all these RCTs show a positive trend of use of GLP-1 RAs in 3-point MACE and renal events. The consensus group gave a high priority to GLP-1 RAs in patients with diabetes and CKD.
4.3.5. SGLT-2 inhibitors In the EMPA-REG OUTCOME trial, 7020 patients with previous CV events who received empagliflozin (with no differences seen for 10 or 25 mg doses) had reduced rates of CV mortality and all-cause mortality when compared with placebo.21 2 vs. those ≥60 mL/min/1.73 m2 . Empagliflozin reduced renal outcomes in the EMPA-REG OUTCOME trial.107 2 , and approximately 25% had an eGFR <60 mL/min/1.73 m2 , 11% had macroalbuminuria, and 29% had microalbuminuria. The primary renal end point of the trial was the composite of new onset or worsening of nephropathy (progression to macroalbuminuria, doubling of serum creatinine level associated with an eGFR < 45 mL/min/1.73 m2 , initiation of renal replacement therapy and death from renal disease). This endpoint occurred in 18.8% in the placebo group and 12.7% in the empaglifozin group (HR 0.61, 95% CI 0.53–0.70, p < 0.001).107 2 (HR 0.56, 95% CI 0.39–0.79, p < 0.001), and a 55% risk reduction in initiation of renal replacement therapy (HR 0.45, 95% CI 0.21–0.97, p = 0.04).107 p < 0.001).107
The time course of the changes in eGFR in the empagliflozin group and the placebo group were different in the EMPA-REG OUTCOME trial.107 2 in the 10-mg group and 0.82 ± 0.04 mL/min/1.73 m2 in the 25-mg group, as compared with a small increase of 0.01 ± 0.04 mL/min/1.73 m2 in the placebo group (p < 0.001 for both comparisons with placebo).107 2 in the 10-mg and 25-mg empagliflozin groups, as compared with a decrease of 1.67 ± 0.13 mL/min/1.73 m2 in the placebo group (P < 0.001 for both comparisons with placebo).107
The CANVAS program randomized 10,142 participants with diabetes and high CV risk into canagliflozin or placebo groups.30 p = 0.02).30 2 had a significant reduction in the 3-point MACE (HR 0.70, 95% CI 0.55–0.90), but the inter-group difference compared with patients with an eGFR ≥ 60 mL/min/1.73 m2 was non-significant (P for interaction 0.20).30 30
The CV outcome trial of dapagliflozin (DECLARE-TIMI 58, NCT01730534) is ongoing. In a pooled analysis of 12 double-blind RCTs (N = 4545),108 type 2 diabetes with normal or mildly impaired renal function (eGFR 60 to <90 mL/min/1.73 m2 ) were treated with dapagliflozin (2.5, 5, or 10 mg/day) or placebo. The use of dapagliflozin was not associated with an increased risk of acute renal toxicity or deterioration of renal function.108
The mechanisms responsible for the reno-protective effect of the class of SGLT-2 inhibitor class are different from renin-angiotensin-aldosterone system (RAAS) inhibitors. RAAS inhibitors reduce intraglomerular pressure via efferent arteriolar vasodilatation, leading to reductions in intraglomerular hypertension and renal hyperfiltration.109 110 111–113 114 115 110 110
The consensus group gave a high priority to SGLT-2 inhibitors in patients with diabetes and mild-to-moderate CKD (eGFR ≥ 30 mL/min/1.73 m2 ).
4.4. Dose consideration in chronic kidney disease CKD can impact the pharmacokinetics or pharmacodynamics of anti-diabetic agents. A dose reduction may be needed in CKD patients.116–118 Fig. 1 shows the dose adjustment of anti-diabetic agents in CKD. Traditionally, insulin was suggested for the treatment of diabetes in patients with more advanced CKD. However, insulin dose should be reduced in patients with CKD regardless of the type of insulin (rapid, intermediate, or long-acting).116
Fig. 1.:
Dose adjustment of anti-diabetic agents in chronic kidney disease. The green color means that dose adjustment is not required. The yellow color means that dose reduction and frequent monitoring should be considered. The red color means that these drugs are contraindicated. * = expected to be withdrawn from market at July 2018. bid = twice daily; DPP-4 i = dipeptidyl peptidase 4 inhibitor; eGFR = estimated glomerular filtration rate; GLP-1 RA = glucagon-like peptide-1 receptor agonist; qw = once weekly; SGLT-2 i = sodium glucose co-transporter 2 inhibitor. Adapted from Di Lullo et al.,
118 Davies et al.
117 and Garla et al.
116 with permission.
Metformin was excreted by the kidney and the dose should be reduced to avoid possible lactic acidosis. 2018 ADA guidelines suggest that metformin may be safely used in patients with eGFR as low as 30 mL/min/1.73 m2 ,119 2 .119 2 .120
There are five available DPP-4 inhibitors. Sitagliptin, saxagliptin, alogliptin, and vildagliptin require dose adjustment in patients with CKD.116–118 117 2 (empagliflozin) or ≥60 mL/min/1.73 m2 (dapagliflozin and canagliflozin), although SGLT-2 inhibitors have been used in CKD stage 3 patients in RCTs. There have been post-marketing reports of acute kidney injury in patients receiving SGLT-2 inhibitors, some requiring hospitalization and dialysis. It is suggested that before initiating SGLT-2 inhibitors factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, and concomitant medications (diuretics, ACE inhibitors, ARBs, NSAIDs) should be examined, and renal function needs to be evaluated prior to initiation and be monitored thereafter.117
4.5. Treatment algorithm in diabetic patients with stage 3 chronic kidney disease Table 4 shows the algorithm for the treatment of diabetes in patients with stage 3 CKD. Metformin should be the first-line therapy in diabetic patients with CKD stage 3 because it has long-standing evidence for efficacy and safety, and is inexpensive, though a dosage reduction is necessary. For dual therapy, we recommend metformin plus SGLT-2 inhibitors. The use of SGLT-2 inhibitors is compelling based on their effects in reducing 3-point MACE and renal endpoints in the EMPA-REG OUTCOME trial107 30 27,106 28 97
Table 4: Treatment algorithm in diabetic patients with stage 3 CKD.
5. Treatment of diabetes in patients with a history of stroke 5.1. Rationale Diabetes is associated with a higher risk of ischemic stroke.5 121 122 123 124 125 124,126
Whether glycemic control reduces stroke risk remains an open question. There has been no large-scaled RCT specifically testing anti-diabetic agents in diabetic patients with previous stroke, except one trial done in patients with insulin resistance.44 9 14 10–12 type 2 diabetes , the stroke risk was not reduced in tight glycemic control versus standard glycemic control during a mean treatment period of 5 years (HR 0.96, 95% CI 0.83–1.1).127 type 2 diabetes from 20 RCTs.128 128 13 p = 0.007).44 p = 0.04) in high risk diabetic patients.28
5.2. Target of HbA1c Although diabetes is associated with an increased risk of stroke and a worse post-stroke outcome,124
5.3. Choice of drugs 5.3.1. Metformin In the UKPDS trial, metformin therapy was associated with a non-significant reduction in the risk of stroke compared with conventional lifestyle therapy (HR 0.59, 95% CI 0.29–1.18) in overweight patients.49 type 2 diabetes , metformin monotherapy together with lifestyle recommendations was associated with a 25% reduction in the risk of stroke compared with lifestyle (HR 0.750, 95% CI 0.573–0.982, p = 0.036).52 129 130
5.3.2. Sulfonylureas In the UKPDS trial, sulfonylurea did not decrease the risk of stroke.9 11 63 64 p < 0.001).64 type 2 diabetes , might help to clarify the CV effect of them.67
5.3.3. Glinides There was no RCT or observational study testing the efficacy of repaglinide on the risk of stroke. In the NAVIGATOR trial, 9306 participants with IGT and CVD (only 3% had a history of stroke) or its risk factors were randomized to nateglinide or placebo.70 p = 0.43) or the incidence of non-fatal strokes (HR 0.89, 95% CI 0.69–1.15).70
5.3.4. Alpha-glucosidase inhibitor The STOP-NIDDM trial evaluated the effect of acarbose on the risk of CVD in 1368 patients with IGT.71 p = 0.03).71 p = 0.51).71 type 2 diabetes in Taiwan, acarbose has no effect on ischemic stroke when compared with metformin (HR 1.05, 95% CI 1.00–1.10).72 38 131 38 p = 0.0007).38
5.3.5. Thiazolidinedione Among patients with a history of stroke who entered the PROactive trial, pioglitazone therapy was associated with a 47% relative risk (RR) reduction in recurrent stroke (HR 0.53, 95% CI 0.34–0.85, p = 0.0085) and a 28% RR reduction in 3-point MACE (HR, 0.72, 95% CI 0.53–1.00, p = 0.00467).132 type 2 diabetes and a history of stroke, a non-significant reduction in secondary stroke was shown (4.8% vs. 10.5%, p = 0.49).133 44 p = 0.007), and a trend towards lower stroke rates (HR 0.82, 95% CI 0.61–1.10).44 p = 0.01) in patients with insulin resistance, prediabetes, and diabetes mellitus. There was no effect on all-cause mortality and heart failure.134
5.3.6. Insulin Only a few prospective interventional trials specifically tested the CV effects of insulin in type 2 diabetes . In patients receiving insulin/sulfonylurea therapy in the UKPDS, no significant difference was reported in risk of stroke compared with patients on conventional diet therapy after a follow-up of about 10 years (HR 0.91, 95% CI 0.73–1.13).14 type 2 diabetes were randomized to insulin glargine or standard care for a median follow-up of 6.2 years.20 20
5.3.7. DPP-4 inhibitors There was no trial testing the effect of DPP-4 inhibitors in patients with a history of stroke specifically. In the SAVOR trial, 12.7% of patients had a history of stroke.25 25 23 23 23 26 26 26 p = 0.0213), including non-fatal stroke (3 vs. 11 patients; relative risk 0.27, 95% CI 0.08–0.97, p = 0.03).135 136
5.3.8. GLP-1 receptor agonists In the ELIXA trial, only 6.2% patients had a history of stroke.22 22 27 p = 0.01), and a trend of reduction in the risk of stroke (HR 0.86, 95% CI 0.71–1.06, p = 0.16).27 p for interaction 0.04), though specific data regarding patients with previous stroke was not mentioned.27 28 p < 0.0001), including a significant reduction in the risk of non-fatal stroke (HR 0.61, 95% CI 0.38–0.99, p = 0.04).28 p value for interaction was 0.49).28 29 29
5.3.9. SGLT-2 inhibitors In the EMPA-REG OUTCOME trial, 23.7% of patients had a history of stroke.21 p = 0.04), but the subgroup analysis showed that there was no difference in patients with a history of stroke.21 21 p = 0.26).21 137 p = 0.60).137
In the CANVAS program, 19.3% patients had a history of stroke.30 p = 0.02).30 p = 0.18). The specific data from patients with a history of stroke was not reported. Among the 3-point MACE, the risk of fatal or non-fatal stroke was numerically lower, but did not reach statistical significance (HR 0.87, 95% CI 0.69–1.09).30
The CV outcome trial of dapagliflozin, i.e., the DECLARE trial, has not been finished. In a meta-analysis of 9339 patients, patients receiving dapagliflozin had a similar risk of stroke compared with the control group (HR 0.999, 95% CI 0.536–1.864).82 83 p < 0.0001 for all).83 83
The consensus group gave a moderate priority to SGLT-2 inhibitors in diabetic patients with a history of stroke.
5.4. Treatment algorithm in diabetic patients with a history of stroke Table 5 shows the algorithm for the treatment of diabetes in patients with a history of stroke. The target HbA1c is <7%. Metformin should be the first-line therapy in diabetic patients with a history of stroke, mainly based on the findings from the UKPDS trial and several observational studies in Taiwan and Asia. For dual therapy, we recommend metformin plus TZDs, followed by metformin plus GLP-1 RAs, and then metformin + SGLT-2 inhibitors. The PROactive trial, the IRIS trial, and an important meta-analysis provided strong evidence to support the role of TZDs. The SUSTAIN-6 trial and the LEADER trial gave a rationale for the use of GLP-1 RAs. The CANVAS program gave some support to use SGLT-2 inhibitors. If the fourth drug is to be added, DPP-4 inhibitors are recommended due to their neutral effects and safety. Sulfonylurea did not have any positive trial to support and a Taiwanese cohort showed a worse outcome. In addition, the risk of hypoglycemia is well-known. Glinides and acarbose have low priority due to lack of any supporting evidence.
Table 5: Treatment algorithm in diabetic patients with a history of stroke.
6. Treatment of diabetes in patients with heart failure 6.1. Rationale 6.1.1. Diabetes is a risk factor for developing heart failure In the Framingham study, diabetic males and females had a 2.4–fold and a 5-fold risk of HF, respectively.138 139 140 140 141 142
In a recent cohort study consisted of 1,921,260 individuals from UK, HF is the second most common manifestation of CVD in patients with type 2 diabetes , ranked after peripheral arterial occlusive disease.143 144 145 Table 1 ).
6.1.2. Heart failure patients have a higher risk of developing diabetes HF is an established risk factor for development diabetes.146,147 148 149–153 149 150 151 152 153
6.1.3. Higher CV risk in patients with diabetes and concomitant heart failure HF has been called “the frequent, forgotten, and often fatal” complication of diabetes.154 155,156 156 156 157 145,157
Among patients with HFrEF, those with diabetes had a higher risk of HF hospitalization and CV mortality (adjusted HR 1.64, p < 0.001) compared with those without a history of diabetes in the sub-study of the Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor with Angiotensin-Converting-Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM) trial.158 p < 0.0001).159 160 p < 0.001).161
6.2. Target of HbA1c In a meta-analysis of 4 RCTs comparing intensive vs. standard glucose lowering strategy, intensive strategy had no impact on HF admission.46 p < 0.01), which remained significant after multivariate analysis (HR 2.3, 95% CI 1.0–5.2).162 163 164 165
6.3. Choice of drugs There is no completed RCT testing the efficacy of anti-diabetic agents in reducing CV events in patients specifically with diabetes and HF, though a few are ongoing (DAPA-HF , Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure, NCT03036124; EMPEROR-Reduced , EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction, NCT03057977; EMPEROR-Preserved , EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction, NCT03057951). Some anti-diabetic agents increased HF admission in RCTs, though HF admission was generally not primary endpoint. The drugs which increased HF admission should be avoided in patients with pre-existing HF.166
6.3.1. Metformin In the UKPDS trial, patients with pre-existing HF were excluded.49 49 p < 0.00001) and a 7% reduction in HF admission (p = 0.01).167 p = 0.003) and a 13% reduction in HF admission (p = 0.009).168
6.3.2. Sulfonylureas In the UKPDS trial, the combination of sulfonylurea and insulin did not increase the risk of HF when compared with conventional dietary-based therapy (HR 0.91, 95% CI 0.54–1.52).9 11 60,169 170
6.3.3. Glinides In the Left Ventricular Dysfunction in Diabetes (DYDA) study, 960 patients with type 2 diabetes but without overt heart disease were followed up for 2 years to examine the LV dysfunction and CV outcomes.171 p = 0.01).171 172 70 70
6.3.4. Alpha-glucosidase inhibitor In the STOP-NIDDM trial, the effect of acarbose on CVD, including HF, was tested in 1368 patients with IGT.71 71 38
6.3.5. Thiazolidinedione TZDs activate a sodium channel in collecting tubules and enhance sodium retention and fluid overload,173 174 p = 0.007).17 175 176 44 74,177–179
6.3.6. Insulin Insulin has an anti-natriuretic property and may increase sodium and fluid retention in diabetic patients.180 9 181 20
In patients with diabetes and HF, there are several pieces of evidence to suggest a harmful effect of insulin. In a large contemporary HF population in the Candesartan in Heart Failure-Assessment of Mortality and Morbidity (CHARM) program, including patients with HFpEF and HFrEF, insulin-treated diabetes was found to be the most strong independent predictor for CV death plus HF hospitalization, and the HR (2.03, 95% CI 1.80–2.29) was higher than those who had not been treated with insulin (HR 1.58 95% CI 1.43–1.74).182 182 183
6.3.7. DPP-4 inhibitors The effects of DPP-4 inhibitors in diabetic patients with high CV risk have been studied in major CV outcome trials. In the SAVOR trial, 12.8% patients had pre-existing HF. The use of saxagliptin increased HF admission (HR 1.27, 95% CI 1.07–1.51, p = 0.007).25 p = 0.15; absolute risk 1.5%, NNH 67).155 p = 0.02; absolute risk 0.6%, number needed to harm [NNH] 167).155 p = 0.001 at 180 days; HR 1.46, 95% CI 1.15–1.88, p = 0.002 at 360 days; HR 1.27, 95% CI 1.07–1.51, p = 0.007 at 720 days).155 155 23 184 184 https://www.fda.gov/Drugs/DrugSafety/ucm486096.htm
There were several registries suggested an association of sitagliptin with HF.185,186 26 187 187
There was no CV outcome trial for vildagliptin. In the Vildagliptin in Ventricular Dysfunction Diabetes (VIVVID) study, patients with type 2 diabetes and HF (NYHA I-III and LVEF <0.40) were randomized to 52 weeks treatment with vildagliptin or placebo.188 188 p = 0.062; +17.06 mL, 95% CI 4.62–29.51, p = 0.007; respectively). The CV death and total death were numerically higher in those receiving vildagliptin compared with placebo (5.5% vs. 3.2%; 8.6% vs. 3.2%, respectively, all p > 0.05). Therefore, we suggest not to use vildagliptin in patients with diabetes and HF.
For linagliptin, the CAROLINA trial (NCT01243424) and the CARMELINA trial (NCT01897532) are ongoing. In a patient-level pooled analysis of 5847 patients, linagliptin did not increase the risk of HF admission compared with other drugs (HR 1.04, 95% CI 0.43–2.47).189
Overall, the consensus group gave a neutral position to DPP-4 inhibitors in patients with diabetes and HF, but did not recommend saxagliptin, alogliptin, and vildagliptin in patients with HF.
6.3.8. GLP-1 receptor agonists The effects of various GLP-1 RAs on CV events, including HF, have been tested in several RCTs. Lixisenatide was studied in the ELIXA trial in patients with ACS.22 22 27 p = 0.01), but the risk of HF admission was not significantly changed (HR 0.87, 95% CI 0.73–1.05).27 28 p = 0.02). The risk of HF admission was not significantly different (HR 1.11, 95% CI 0.77–1.61).28 29 p < 0.001 for noninferiority, p = 0.06 for superiority). There was no significant difference in the risk of HF admission (HR 0.94, 95% CI 0.78–1.13).29
An important RCT with GLP-1 RA in patients with HF is the Functional Impact of GLP-1 for Heart Failure Treatment (FIGHT) trial.190 type 2 diabetes .190 p = 0.31). There were no significant between-group differences in the number of deaths (19 [12%] in the liraglutide group vs. 16 [11%] in the placebo group; HR, 1.10, 95% CI 0.57–2.14, p = 0.78) or re-hospitalizations for HF (63 [41%] vs. 50 [34%], respectively; HR, 1.30, 95% CI 0.89–1.88, P = 0.17). Pre-specified subgroup analyses in patients with diabetes did not reveal any significant between-group difference.190
6.3.9. SGLT-2 inhibitors There are several RCTs testing the effects of SGLT-2 inhibitors on CV outcomes, and two of them have been published.21,30 21 p = 0.04 for superiority). There were no significant differences in the rates of MI or stroke, but in the empagliflozin group there were significantly lower rates of CV death (HR 0.62, 95% CI 0.49–0.77, p < 0.001), hospitalization for HF (HR 0.65, 95% CI 0.50–0.85, p = 0.002), and all-cause mortality (HR 0.68, 95% CI 0.57–0.82, p < 0.001).21 156
The CANVAS program randomized 10,142 participants with diabetes and high CV risk, including 65.6% with pre-existing CVD and 14.4% with pre-existing HF, into canagliflozin or placebo groups.30 p < 0.001 for noninferiority; p = 0.02 for superiority). The HF admission was significantly reduced (HR 0.67, 95% CI 0.52–0.87). There was, however, an increased risk of amputation (6.3 vs. 3.4 participants per 1000 patient-years; HR, 1.97; 95% CI 1.41 to 2.75); amputations were primarily at the level of the toe or metatarsal.30
Other meta-analyses and real-world evidence (RWE) were also in favor of a class effect of SGLT-2 inhibitors in reducing HF admission in patients with diabetes. In a systematic review and meta-analysis of 6 regulatory submissions (37,525 participants) and 57 published trials (33,385 participants), the data for seven different SGLT-2 inhibitors were analyzed.191 p = 0.006), CV death (RR 0.63, 95% CI 0.51–0.77; p < 0.0001), HF (RR 0.65, 95% CI 0.50–0.85; p = 0.002), and all-cause mortality (RR 0.71, 95% CI 0.61–0.83; p < 0.0001). There was no clear evidence that the individual drugs had different effects on CV outcomes or death.191 192 p < 0.001); death (HR 0.49; 95% CI 0.41–0.57; p < 0.001); and HF admission or death (HR 0.54; 95% CI 0.48–0.60; p < 0.001) with no significant heterogeneity by country.192 83 p < 0·0001 for all).83
No one could have expected SGLT-2 inhibitors would decrease HF admission and mortality.193 110 194 2 , P = 0.01] and improved diastolic function.195 196
It has been hypothesized that patients with diabetes are overloaded with sodium, mainly because of increased sodium retention in the kidney as a consequence of hyperglycemia and hyperinsulinemia.197 197 110 198 23 NaMRI, can reflect the whole body sodium content.198 199 200
BP-lowering effects of SGL-2 inhibitors have also been identified as a possible contributor to the beneficial effects in the outcome trials.110,201 42 202 p = 0.0002), while the systolic BP on 24-h ambulatory BP monitoring (ABPM) was decreased by 4.45 mmHg (p < 0.01).202 p < 0.001) and central pulse pressure by 2.77 mmHg (p = 0.12), compared with placebo.203
Other mechanisms may also play some roles in the beneficial effects of SGLT-2 inhibitors on CV outcomes. Body weight was generally decreased by about 2 kg by SGLT-2 inhibitors in CV outcome trials.21,30 204 204 205,206 110
SGLT-2 inhibitor is a unique class of anti-diabetic agents that decrease HF admission in both HF and non-HF diabetic patients. It has been consistently shown in RCTs and by RWE. Therefore, the consensus group recommended SGLT-2 inhibitors as the first line therapy in patients with diabetes and HF.
6.4. Treatment algorithm in diabetic patients with heart failure Table 6 shows the algorithm for the treatment of diabetes in patients with HF. The target of HBA1c is <8%. SGLT-2 inhibitors or metformin are the first line therapy. The use of SGLT-2 inhibitors is compelling, based on their effects in reducing 3-point MACE and HF admission in the EMPA-REG OUTCOME trial,21 30 192 167,168 27 28 29 190 26 25 23 188 189
Table 6: Treatment algorithm in diabetic patients with heart failure.
7. Adverse events of anti-diabetic agents Important adverse events (AEs) of common anti-diabetic agents were shown in Fig. 2 . Hypoglycemia and some emerging AEs of newer anti-diabetic agents were noted here.
Fig. 2.:
Important adverse events of common anti-diabetic agents. The green color means a decreased risk. The empty box means a neutral effect. The red color means an increased risk. AGI = alpha-glucosidase inhibitor; AKI = acute kidney injury; alo = alogliptin; cana = canagliflozin; DKA = diabetic ketoacidosis; DPP-4 i = dipeptidyl peptidase 4 inhibitor; GI = gastrointestinal side effects; GLP-1 RA = glucagon-like peptide-1 receptor agonist; GTI = genital tract infection; HF = heart failure; saxa = saxagliptin; SGLT-2 i = sodium glucose co-transporter 2 inhibitor; SU = sulfonylurea; TZD = thiazolidinedione; vilda = vildagliptin.
7.1. Hypoglycemia Minimizing risk of both severe and non-severe hypoglycemia is a priority in the management of diabetes.207 208 type 2 diabetes in Taiwan from 2000 to 2010 (adjusted incidence rate ratio 4.88, 95% CI 3.94–6.05, p < 0.001).209 p < 0.0001), all-cause hospitalization (HR 2.51, 95% CI 2.00–3.16, p < 0.0001), and total mortality (HR 2.48, 95% CI 1.41–4.38, p < 0.0001).13 210 p < 0.001) for mild hypoglycemia and 2.33 (95% CI 2.07–2.61, p < 0.001, p for trend 0.02) for severe hypoglycemia.210
Among anti-diabetic agents, sulfonylureas,64 211 212 213 64,214–216 217 218
7.2. Genital tract infection The risk of genital tract infection (GTI) is increased by SGLT-2 inhibitors. In the EMPA-REG OUTCOME trial, the annual incidence of GTI was significantly higher with empagliflozin than with placebo group in both men and women (5.0% vs. 1.5%, P < 0.001 for men; 10.0% vs. 2.6%, P < 0.001 for women).21 p < 0.001 for men; 6.88% vs. 1.75%, p < 0.001 for women).30
7.3. Acute kidney injury In 2016, the US FDA issued a warning of acute kidney injury (AKI) for canagliflozin and dapagliflozin (https://www.fda.gov/Drugs/DrugSafety/ucm505860.htm p < 0.001).219 220 p = 0.004; adjusted HR 0.6, 95% CI 0.4–1.1, p = 0.09, respectively).221 p < 0.05).21 p = 0.33).30
7.4. Diabetic ketoacidosis From the data of FAERS from March 2013 to May 2015, 73 cases of diabetic ketoacidosis (DKA) in patients with type 1 and type 2 diabetes treated with SGLT-2 inhibitors were identified. Therefore, in May 2015, the US FDA added warnings of diabetic ketoacidosis to the labels of SGLT-2 inhibitors (https://www.fda.gov/Drugs/DrugSafety/ucm475463.htm 222 223 223
In the EMPA-REG OUTCOME trial, the incidence of DKA was very low; only 4 out of 4687 patients (0.1%) in the pooled empagliflozin group, compared with 1 of 2333 patients (<0.1%) in the placebo group, had DKA.21 p = 0.14).30 224,225
Because DKA is a potentially lethal complication, the consensus group recommend that potential triggering factors should be identified during the exposure period to SGLT-2 inhibitors, which include inter-current illness, reduced food and fluid intake, reduced insulin doses, and history of alcohol intake.226,227 228 228 229
7.5. Amputation In the CANVAS program, there was a higher risk of amputation of toes, feet, or legs with canagliflozin than with placebo (6.3 vs. 3.4 participants with amputation per 1000 patient-years, HR 1.97, 95% CI 1.41–2.75, p < 0.001).30 230 230 230 231 p < 0.0001). In contrast, the PRR for dapagliflozin was 0.25 (95% CI 0.03–1.76, p = 0.163) and for empagliflozin was 2.37 (95% CI 0.99–5.70, p = 0.054).231 https://www.fda.gov/Drugs/DrugSafety/ucm557507.htm 21,30
Amputation of the toe and middle of foot were the most common; however, amputations involving the leg, below and above the knee, also occurred.30,231 30,231
7.6. Fracture Thiazolidinediones have been shown to exert detrimental effects on the skeleton,232 233 p = 0.003).44
Canagliflozin decreased bone mineral density,234 235 https://www.fda.gov/Drugs/DrugSafety/ucm461449.htm 30 30 21 21
8. Summary and conclusions The prevalence of type 2 diabetes has been escalating in recent decades. The CV complications created a huge economic burden to our society. Treatment of diabetes should now be expanded from a glucose-centric concept to an event-driven strategy. Fortunately, we have many new anti-diabetic agents, proven to be effective in CV and renal protection. Just in these few years, many RCTs have demonstrated significant reductions in MI, stroke, CV death, all-cause death, HF, and ESRD, in patients with pre-existing CVD. At this very moment, TSOC and the DAROC (Taiwan) have worked together to formulate a treatment consensus for type 2 diabetic patients with 5 different categories of CVD, including HT, CHD, CKD, stroke, and HF. This consensus provides physicians most updated information and recommendations regarding targets of HbA1c and choice of drugs. The consensus is not mandatory, and the physician's decision remains most important in diabetes management.
Acknowledgments This work was supported, in part, by grants from the Ministry of Health and Welfare (MOHW107-TDU-B-211–123001), and from the Ministry of Science and Technology (MOST 106–2314-B-075–046), and intramural grants from the Taipei Veterans General Hospital (V107C-015).
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Appendix
Conflicts of Interest Chern-En Chiang has received honorarium from AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, MSD, Novartis, Pfizer, Sanofi.
Tzung-Dau Wang has received honorarium from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Cordis, Daiichi-Sankyo, GSK, Medtronic, MSD, Novartis, Pfizer, Sanofi, and Takeda.
Hung-I Yeh has received honorarium from AstraZeneca, Boehringer Ingelheim, and Tanabe.
Kuan-Cheng Chang has received honorarium from AstraZeneca, Boehringer Ingelheim, Takeda, and Tanabe.
Kang-Ling Wang has received honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Orient EuroPharma, and Tanabe.
Ting-Hsing Chao received honorarium from AstraZeneca, MSD, and Novartis.
Wayne Huey-Herng Sheu acted as Advisor and/or Speaker for AstraZeneca, Bayer Health Care, Boehringer Ingelheim Pharmaceuticals., Daiichi-Sankyo, Eli Lilly and Company, MSD, Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals, Novo Nordisk, Pfizer, Sanofi, Takeda Pharmaceutical Company.
Others reported no conflict of interest.
